TAP Vol 5 Issue 13

Triple-Negative Breast Cancer 5, 20 | Sexual Health Issues After Cancer 107 | Vasectomies and Prostate Cancer Risk

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VOLUME 5, ISSUE 13

AUGUST 15, 2014

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

FDA Update

Recent FDA Drug Approvals Foster Growing Treatment Armamentarium for Chronic Lymphocytic Leukemia and Rare B-Cell Lymphomas

R

ecent approvals announced by the U.S. Food and Drug Administration (FDA) have led to increased treatment options for managing several difficult-to-treat hematologic B-cell cancers. The newly approved drugs and/or their indications include the oral PI3K delta inhibitor idelalisib (Zydelig) for the treatment of patients with relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-Hodgkin lymphoma, and relapsed small lymphocytic lymphoma, and the oral Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment patients with chronic lymphocytic leukemia who carry deletions of the short arm of chromosome 17.

Difficult-to-Treat Patient Populations “[Idelalisib] is a much needed new treatment option for appropriate patients with [chronic lymphocytic leukemia] and these indolent lymphomas who have experienced relapses and have limited, if any, treatment op-

tions,” said Bruce Cheson, MD, Professor of Medicine, Head of Hematology and Director of Hematology Research at Lombardi Comprehensive Cancer Center at Georgetown University, and a Principal Investigator on the pivotal phase III trial Bruce Cheson, MD of idelalisib in chronic lym1 phocytic leukemia.

“In clinical studies among patients with relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma, [idelalisib] produced strong responses, including a significant improvement in progression-free survival in chronic lymphocytic leukemia. I believe it helps fill a significant unmet need for these patients,” he said.1,2 continued on page 12

Issues in Oncology

Who Will Care for Patients With Cancer?

The confluence of looming oncology workforce shortages just as demand for cancer care explodes has experts searching for solutions.

By Hagop Kantarjian, MD

M

any concerns were raised and dire speculations predicted during the further implementation of the Affordable Care Act this year. So far, the trickling news is good: An estimated total of 20 million people gained coverage under the new law as of May 1,1 about 6 million enrolled in the law’s Medicaid expansion, 7.8 million young adults (aged 19–25) gained insurance under their parents’ coverage, the rate of uninsured fell from 18% to close to 13%,2 more people (39%) felt they benefited from the Affordable Care Act than were negatively affected (29%), and 46% of people switched to plans continued on page 172

Dr. Kantarjian is Chairman of the Leukemia Department at The University of Texas MD Anderson Cancer Center and a Baker Institute Scholar for Health Policies at Rice University, Houston.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE

By Jo Cavallo

T

Does the United States Have the Best Health-Care System in the World?

he workforce numbers show a disturbing trend. According to a recent study by ASCO, by 2025, overall demand for oncology services is projected to grow by 40%, but physician supply is predicted to increase by only 25%, generating a shortage of 2,258 oncolo-

gists providing full-time equivalent clinical care.1 And that number could increase to 2,393 once the Patient Protection and Affordable Care Act is fully implemented in 2018. Exacerbating the problem are even greater shortages projected for primary care physicians, nurse practitioners, and physician assistants—medical profesThere are really only two kinds of sionals who will be needed solutions that can be pursued. to supplement care for the increasing numbers of paOne is hiring and using advanced tients with cancer as they practice providers in our offices transition to long-term survivorship care. and clinics.… And the other is to According to a study encourage more doctors to enter the published in the Annals of Family Medicine,2 a conflufield of oncology. ence of circumstances led —Richard L. Schilsky, MD, FACP, FASCO

Oncology Meetings Coverage 2014 ASCO Annual Meeting ����� 3, 5, 10, 16 Pan Pacific Lymphoma Conference ��������� 19 5th World Congress on Head and Neck Cancer �����������������������������22 MASCC/ISOO Symposium ���� 23, 27, 29 Stephen B. Riggs, MD, on Germ Cell Tumors ������������������������������������� 40 Kathy D. Miller, MD, on Breast Cancer ����������������������������������������������50 Direct From ASCO �������������������������� 56–59 Inside the Black Box: Ceritinib in NSCLC ���������������������������������� 60 Anthony L. Zietman, MD, and John A. Fracchia, MD, on Active Surveillance ���������������������������� 83, 84

continued on page 146

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The ASCO Post | AUGUST 15, 2014

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ASCO Annual Meeting Genitourinary Oncology

Anti–PD-1 Agent Shows Activity in Renal Cell Carcinoma

By Caroline Helwick

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enal cell carcinoma can be added to the growing list of tumors that respond to programmed death (PD)-1 immune checkpoint inhibitors, according to the results of the CheckMate trials, presented at the 2014 ASCO Annual Meeting.

The phase II CheckMate-010 trial evaluated three doses of nivolumab as a single agent in patients with previously treated renal cell carcinoma, while the phase Ib CheckMate-016 trial evaluated the drug at different doses and schedules in combination with other agents.

“The data from the trials are encouraging, as we seek to identify new treatments for patients, particularly those who show disease progression following treatment with antiangiogenic therapy, as these patients have limited options,” said Robert J. Motzer, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, New York, who presented CheckMate-010.

Nivolumab as a Single Agent CheckMate-010 enrolled 168 patients with advanced disease who had

received one to three prior systemic therapies, including at least one agent targeting the vascular endothelial growth factor (VEGF) pathway.1 Responses were observed in 20%, and median overall survival exceeded 2 years, Dr. Motzer reported (Table 1).

Treatment-related severe adverse events occurred in 7.2% of patients across all doses. The investigators observed no grade 3/4 pneumonitis.

The data from the trials are encouraging, as we seek to identify new treatments for [renal cell carcinoma] patients, particularly those who show disease progression following treatment with antiangiogenic therapy, as these patients have limited options.

Nivolumab Plus Ipilimumab The phase Ib CheckMate-016 study evaluated the safety and tolerability of nivolumab at different doses and schedules in combination with other agents in both previously treated and treatment-naive patients. The data for nivolumab plus ipilimumab (Yervoy) in 44 patients was presented by Hans J. Hammers, MD, PhD, Assistant Professor of Oncology at the Sidney Kimmel Compehensive Cancer Center at Johns Hopkins Medicine, Baltimore.2 Patients were randomly assigned to one of two regimens, each given every 3 weeks for four cycles: nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (arm

—Robert J. Motzer, MD

N3+I1) or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (arm N1+I3).

Both arms received maintenance nivolumab at 3 mg/kg every 2 weeks until disease progression. Patients were previously treated or treatment-naive.

“Nivolumab plus ipilimumab showed acceptable safety and evidence of antitumor activity in metastatic [renal cell carcinoma],” Dr. Hammers reported. “The objective response rate suggests greater activity than reported previously with either agent as monotherapy in [renal cell carcinoma].”

Confirmed responses were observed in 43% of the N3+I1 arm and in 48% of the N1+I3 arm. Median duration of response was 31.1 weeks with N3+I1 and was not reached in the other arm after 40 weeks of follow-up. Ongoing responses were observed in approximately 80% of the responders.

Median progression-free survival was 36.6 weeks and 38.3 weeks in the N3+I1 and N1+I3 arms, respectively, and at 24 weeks, approximately 65% of both arms were progression-free, he said. continued on page 4

EXPERT POINT OF VIEW

I

n her discussion of the renal cell carcinoma studies at the ASCO Annual Meeting, Lauren C. Harshman, MD, Assistant Professor of Medical Oncology at Dana-Farber Cancer Institute, Boston, suggested, “Given the plateau in efficacy with current treatments, there is space and need for agents with new modes of activity. Especially because of the durability of response, tolerability, and promising overall survival data, I think anti–PD-1 agents should be developed in [renal cell carcinoma].”

But Dr. Harshman pointed out that as monotherapy, the results with nivolumab were less robust than were seen in a previous phase I trial. “The progression-free survival data were somewhat disappointing compared to the phase I results, but they do confirm the activity of nivolumab, at least in a subset of patients,” she said. “Especially at the higher doses, the overall survival [associated with] nivolumab was encouraging.”

With the cautions of comparing a phase II trial to more rigorously tested phase III studies, she noted that the median overall survival at over 2 years was

favorable compared to upwards of 16 months for the targeted therapies in their phase III second and third-line trials.

Greater Promise in Combinations Dr. Harshman said the greater promise may lie in combining anti– PD-1 agents with tyrosine kinase inhibitors, as was done in the study by Amin and colleagues. The combina-

mune environment.” The response rate with the combination therapy was 52%, compared with 20% to 22% in the nivolumab monotherapy trial, and some degree of tumor elimination was observed in almost all patients.

“What was exciting was the lack of treatment-refractory disease. We saw primary tumor escape in only 3%, vs 40% in the phase II [monotherapy] study,” she pointed out.

Especially because of the durability of responses, tolerability, and promising overall survival data, I think anti–PD-1 agents should be developed in [renal cell carcinoma].

—Lauren C. Harshman, MD

tion of nivolumab with an anti–vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor makes sense, she suggested, as VEGF inhibition “may induce a more hospitable im-

Nevertheless, she reminded listeners that in treatment-naive patients sunitinib alone can produce response rates of 25% to 47%, and achieve median progression-free survival times of

9.5 to 11 months. In the nivolumab/ tyrosine kinase inhibitor combination study, median progression-free survival was 12 months, which was encouraging, but it must be noted that 60% of patients were treatment-naive.

Other Considerations The efficacy, however, “comes at a cost,” she continued. Grade 3/4 adverse events were observed in 70% to 80% of patients, and in the sunitinib arm, which will go on to further study, 35% of patients discontinued treatment due to adverse events.

“Durability of response is a distinct feature of PD-1 blockade that we should build upon. We can see continued response or disease stabilization, even off therapy,” she said.

There remains a need to identify the optimal candidate for this strategy, the optimal timing of the VEGF inhibitor, and the best and simplest combinations, “and move these forward,” she said. n Disclosure: Dr. Harshman reported no potential conflicts of interest.

The ASCO Post | AUGUST 15, 2014

PAGE 4

ASCO Annual Meeting Anti–PD-1 Agent

Table 1: Nivolumab Monotherapy in Previously Treated Renal Cell Carcinoma

continued from page 3

“Grade 3/4 events were manageable within established treatment guidelines,” he said.

“The encouraging antitumor activity reported with this combination is the basis for a planned phase III combination trial in first-line metastatic renal cell carcinoma (CheckMate-214),” he said.

Endpoint

0.3 mg/kg (n = 60)

2 mg/kg (n = 54)

10 mg/kg (n = 54)

Overall response

12 (20%)

12 (22%)

11 (20%)

Median progression-free survival

2.7 months

4.0 months

4.2 months

Median overall survival

18.2 months

25.5 months

24.7 months

1-year overall survival

63%

72%

70%

Treatment-related serious adverse events

2 (3.4%)

6 (11%)

4 (7.4%)

Other Nivolumab Combinations

Data from Motzer RJ, et al.1

Asim Amin, MD, PhD, medical oncologist at the Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, presented the findings for nivolumab in combination with a VEGF tyrosine kinase inhibitor, either sunitinib (Sutent) or pazopanib (Votrient). “Nivolumab plus a [tyrosine kinase inhibitor] showed encouraging activity, with a manageable

inhibiting dendritic cell maturation and promoting myeloid-derived suppressor cells and regulatory T cells. VEGF tyrosine kinase inhibitors have been shown to reverse this immune suppression.

Nivolumab blocks PD-1 from switching off T cells.

“In combination, we could give the VEGF [tyrosine kinase inhibitor] to

Nivolumab in Renal Cell Carcinoma ■■ In the phase II CheckMate-010 trial, nivolumab monotherapy produced a 20% response rate and yielded a median overall survival of more than 2 years in patients with advanced renal cell carcinoma.

■■ In the phase Ib CheckMate-016 trial, nivolumab combined with ipilimumab produced responses in 43% to 48% of patients, and at 24 weeks 65% of patients were progression-free.

■■ In the other arms of the phase Ib trial, nivolumab plus sunitinib yielded a 52% response rate, with a median duration of response of 37 weeks.

toxicity profile. The objective responses rates were higher with the combinations than were previously seen with nivolumab or VEGF [tyrosine kinase inhibitor] monotherapy.”

The combination makes biologic sense, he commented. VEGF suppresses the tumor immune environment by

condition the immune microenvironment and then give nivolumab for immune modulation,” he explained.

The phase Ib dose-escalating/expansion study evaluated nivolumab given either with sunitinib (n = 33) or pazopanib (n = 20). In the dose-escalation phase, patients were allowed

prior treatment with one tyrosine kinase inhibitor. Based on the toxicities observed in the dose-escalation phase, the sunitinib arm proceeded to the expansion phase, which included treatment-naive patients.

The objective response rate was 52% with sunitinib and 45% with pazopanib; median duration of response was 37 weeks and 30 weeks, respectively, and ongoing responses were observed in 59% of responders to sunitinib/ nivolumab (which included treatmentnaive patients) and 33% of responders to pazopanib/nivolumab (the entire cohort had prior treatment). About onethird of each arm achieved stable disease.

“We saw robust responses across all three groups, without obvious differences related to prior treatment status,” Dr. Amin reported.

Median progression-free survival was 48.9 weeks with sunitinib and 31.4 weeks with pazopanib. Ongoing responses were observed in 58.8% and 33.3%, respectively.

Adverse events, however, were common, including grade 3/4 events in 82% receiving sunitinib and 70% receiving pazopanib, including 20% of patients

with grade 3/4 elevation in transaminases. “This is more than we have previously seen with [tyrosine kinase inhibitors],” he noted. “Renal and hepatic adverse event [rates] were higher than expected with either agent alone.”

With sunitinib, increases in blood creatinine, autoimmune nephritis, and acute renal failure were observed in one patient each. More than one-third of the sunitinib arm discontinued therapy due to adverse events.

“The combination of a PD-1 inhibitor and a VEGF inhibitor warrants further investigation, but should be approached with caution,” Dr. Amin concluded. n

Disclosure: Dr. Motzer is a consultant or advisor for AVEO, Bayer, Genentech, Merck, and Pfizer, has received research funding from Bristol-Myers Squibb, GlaxoSmithKline, Novartis, and Pfizer, and has given expert testimony for Pfizer. Dr. Hammers has received research funding from Bristol-Myers Squibb.

Dr. Amin is a consultant or advisor for and has received honoraria and research funding from Bristol-Myers Squibb. For full disclosures of all study authors, visit meetinglibrary.asco.org.

References 1. Motzer RJ, Rini BI, McDermott DF, et al: Nivolumab for metastatic renal cell carcinoma: Results of a randomized, doseranging phase II trial. ASCO Annual Meeting. Abstract 5009. Presented May 31, 2014.

2. Hammers HJ, Plimack ER, Infante JR, et al: Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma. ASCO Annual Meeting.

Abstract 4504. Presented June 2, 2014.

3. Amin A, Plimack ER, Infante JR, et al: Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients with metastatic renal cell carcinoma. ASCO Annual Meeting. Abstract 5010. Presented May 31, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Massimo Cristofanilli, MD, FACP, on circulating tumor cells in metastatic breast cancer see page 68

Anthony L. Zietman, MD, on low-risk prostate cancer see page 83

John A. Fracchia, MD, FACS, on active surveillance for low-risk prostate cancer see page 84

Michel Sadelain, MD, PhD, on the challenges and promises of immunotherapy for cancer see page 91

Don S. Dizon, MD, FACP, on discussing sexual health issues with female cancer survivors see page 107

Mohummad Minhaj Siddiqui, MD, on increased risk for lethal prostate cancer in men who have had vasectomies see page 156

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | AUGUST 15, 2014

PAGE 5

ASCO Annual Meeting Breast Cancer

Studies Assess Response to Platinum Therapy in Triple-Negative Breast Cancer

By Caroline Helwick

S

tudies in triple-negative breast cancer presented at the 2014 ASCO Annual Meeting sought to determine predictors of response to platinum agents. One identified a subset of responders to neoadjuvant chemotherapy, but prediction proved more elusive in metastatic disease.

ily history or a genetic alteration, but were highest when both factors were present,” said Dr. von Minckwitz, Chairman of the German Breast Group and Professor of Gynecology at the University of Frankfurt.

“Without these risk factors, the gain in pathologic complete response was

Compared to patients with no risk factors, pathologic complete response rates tended to be higher in patients with a family history or a genetic alteration, but were highest when both factors were present.

—Gunter von Minckwitz, MD, PhD

Neoadjuvant Carboplatin The addition of carboplatin to neoadjuvant chemotherapy mainly benefits triple-negative breast cancer patients with either a family history of breast or ovarian cancer or a germline BRCA or RAD51C/D mutation, according to an analysis of the GeparSixto study presented by Gunter von Minckwitz, MD, PhD.1 “Compared to patients with no risk factors, pathologic complete response rates tended to be higher in patients with a fam-

only marginal, 11%,” he said.

The GeparSixto analysis of germline status and family history “might help identify patients with higher benefit from using carboplatin as part of neoadjuvant chemotherapy, to justify the associated increase in toxicity,” he said.

As background, Dr. von Minckwitz noted that triple-negative breast cancer patients, especially those with BRCA mutations, are sensitive to DNA-damaging agents; that deleterious germline or somatic mutations, not only of BRCA1/2

Platinum Therapy in Triple-Negative Breast Cancer ■■ An analysis from the GeparSixto trial in triple-negative breast cancer identified subsets of patients who responded the best to the addition of carboplatin to paclitaxel/anthracycline.

■■ Pathologic complete response rates were highest (64%) among patients with both a BRCA/RAD mutation and a family history of breast or ovarian cancer.

■■ In the TBCRC009 trial of single-agent platinum in metastatic disease, several presumed biomarkers did not predict response, but homologous recombination deficiency assays may correlate with higher response.

but also RAD51C/D, predict high platinum sensitivity in ovarian cancer; and that the addition of carboplatin to anthracycline/taxane-based chemotherapy can increase pathologic complete response rates in triple-negative patients.

The randomized phase II GeparSixto study further explored these findings by evaluating the effect of carboplatin added to weekly paclitaxel and nonpegylated liposomal doxorubicin in 595 patients with triple-negative or HER2-positive breast cancer. The main results, recently published,2 showed pathologic complete response rates increased by 33% when carboplatin was added (P = .17; P = .2 was the level of statistical significance in GeparSixto), but the effect was completely derived from the subgroup of

triple-negative patients, whose odds of pathologic complete response increased by 94% and who achieved a complete response rate of 53.2% (P = .005).

Germline Status and Family History Dr. von Minckwitz presented an analysis of response to carboplatin in 294 patients, using a conservative definition of pathologic complete response (ypT0, ypN0). As a secondary endpoint, the group also evaluated response according to germline BRCA/RAD mutations and family history of breast or ovarian cancer.

About 14% of patients had BRCA1/2 mutations, 1% had RAD50/51C alterations, and 34% had a relevant family history. continued on page 8

EXPERT POINT OF VIEW

“T

he potential of individualizing systemic treatment based on BRCA1/2 status has not yet been realized. BRCA1/2 germline status currently does not factor into systemic therapy decisions,” said Melinda L. Telli, MD, of Standard University School of Medicine, Palo Alto, California, who discussed the triple-negative breast cancer studies presented

by Dr. von Minckwitz and Dr. Isakoff.

She noted that poly(ADP-ribose) polymerase (PARP) inhibitors have single-agent activity in advanced BRCA1/2 mutation–associated breast cancer, but no drugs are yet approved. Responses to standard chemotherapy drugs in mutation carriers are not well characterized, and most therapeutic trials do not determine BRCA status, even in patients with triple-negative disease. The role of BRCA mutation testing has been confined to informing recommendations for screening and risk reduction.

“For mutation carriers diagnosed

with breast cancer, our treatment approach today is no different from that of a patient with sporadic breast cancer,” Dr. Telli said, but she acknowledged that this practice is poised for change.

With the results of the latest research, she said, “Some 20 years after the cloning of BRCA1, we are moving close to integrating germline BRCA status and markers of genomic instability to individualize therapy.”

In the GeparSixto study, “the finding of a carboplatin benefit among patients with a family history but lacking a germline mutation is fascinating,” she remarked. “It is potentially related to asyet undiscovered BRCA1/2 mutations, or, on the other hand, to germline mutations in other homologous recombinant DNA repair pathway genes.”

Further Biomarker Evidence Commenting on Dr. Isakoff’s study, she said the finding of higher homologous recombination deficiency scores

Ultimately, measures of global genomic instability like homologous recombination deficiency may have the greatest potential to identify patients who stand to benefit most from a DNA repair defect-targeted approach.

—Melinda L. Telli, MD

in responders is “further evidence of the potential of this biomarker for platinum sensitivity in non-BRCA triple-negative breast cancer.”

In addition, “we have new and important evidence that germline BRCA status does influence systemic treatment response in triple-negative breast cancer, and this has implications for all therapeutic studies in this disease,” Dr. Telli said.

“Looking beyond BRCA, other germline biomarkers associated with

therapeutic sensitivity likely exist, and additional studies are needed in this space,” she added.

“Ultimately, measures of global genomic instability like homologous recombination deficiency may have the greatest potential to identify patients who stand to benefit most from a DNA repair defect-­ targeted approach,” she concluded. n Disclosure: Dr. Telli reported no potential conflicts of interest.

Now Approved New Indication

(ofatumumab)

Injection, for intravenous infusion Indications ARZERRA® (ofatumumab) is indicated: • In combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate • For the treatment of patients with CLL refractory to fludarabine and alemtuzumab

Important Safety Information for ARZERRA WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)].

• Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)].

Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions.

Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment.

Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available.

Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication.

Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms

of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment.

Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, ie, increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy.

In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment.

Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation.

First-line Treatment for CLL ARZERRA is now approved in combination with chlorambucil for previously untreated patients with CLL for whom fludarabinebased therapy is considered inappropriate.1 ARZERRA J-Code: J9302

i

To learn more, please visit www.ARZERRAhcp.com.

CLL=chronic lymphocytic leukemia.

Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis.

Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.

Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.

Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied.

Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

Most Common Adverse Reactions In the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%).

In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia.

Infections were the most common adverse reactions leading to drug discontinuation.

Laboratory Abnormalities In the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with ≥5% incidence in patients receiving ARZERRA plus chlorambucil and also ≥2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%).

Reference: 1. ARZERRA (ofatumumab) [package insert].

Research Triangle Park, NC: GlaxoSmithKline; 2014.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for ARZERRA on the following pages.

www.GSKSource.com ©2014 GSK group of companies.

All rights reserved. Printed in USA. AZA438R0 May 2014

The ASCO Post  |   AUGUST 15, 2014

PAGE 8

ASCO Annual Meeting Triple-Negative Breast Cancer continued from page 5

The pathologic complete response rate was 40% for patients without mutations or family history, 49% for those with a family history, 55% for those with genetic alterations, and 64% for patients with both family history and genetic alteration, he reported.

“By the more commonly used definition for pathologic complete response, which includes cases of ductal carcinoma in situ, the group with two factors present had a pathologic complete response rate that increased to 81.8%,� he added.

The absolute gain in pathologic complete response with the addition of carboplatin was highest in those with

family history (+27%) and germline alterations (+23%). Without risk factors, the gain was minimal (11%). The analysis is ongoing, and additional BRCA mutations will be found, he said.

Biomarkers in Metastatic Setting Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital and Harvard

Medical School, Boston, reported that established biomarkers were unable to predict response to platinum therapy in patients with metastatic triple-negative breast cancer in the TBCRC009 study.3 TBCRC009 was a single-arm multicenter phase II study evaluating platinum monotherapy (carboplatin or cisplatin) in the first- or second-line treatment of

BRIEF SUMMARY

discontinue ARZERRA andBRIEF any concomitant institute SUMMARY chemotherapy, discontinue and ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRAappropriate in patients whose HBVResumption of ARZERRA in patients whose HBV treatment. ÂŽ ARZERRAÂŽ (ofatumumab) Injection, for intravenous infusion reactivation resolves should be discussed with physicians expertise in be discussed with physicians with expertise in ARZERRA (ofatumumab) Injection, for intravenous infusion reactivationwith resolves should managing hepatitis B. InsufďŹ cient data exist regarding the hepatitis safety of B. resuming managing InsufďŹ cient data exist regarding the safety of resuming The following is a brief summary only; see full prescribing information, The following is a brief summary only; see full prescribing information, ARZERRA in patients who develop HBV reactivation.

(EPATITIS " 6IRUS ARZERRA in patients who develop HBV reactivation. (EPATITIS " 6IRUS including Boxed Warning, for complete product information. including Boxed Warning, for complete product information.

Infection Fatal infection due to hepatitis B in patients whoFatal haveinfection not beendue to hepatitis B in patients who have not been Infection WARNING: HEPATITIS B VIRUS REACTIVATIONWARNING: AND PROGRESSIVE infectedAND hasPROGRESSIVE been observed with ARZERRA. Monitor patients HEPATITIS B VIRUSpreviously REACTIVATION previously infected has been observed with ARZERRA. Monitor patients MULTIFOCAL LEUKOENCEPHALOPATHY for clinical and laboratory signs of hepatitis. 5.4for Progressive MULTIFOCAL LEUKOENCEPHALOPATHY clinical andMultifocal laboratory signs of hepatitis. 5.4 Progressive Multifocal s (EPATITIS " 6IRUS ("6 REACTIVATION CAN OCCUR IN PATIENTS ,EUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy (PML) s (EPATITIS " 6IRUS ("6 REACTIVATION CAN OCCUR IN PATIENTS ,EUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy (PML) ÂŽ receiving CD20-directed cytolytic antibodies, receiving including CD20-directed ARZERRAÂŽ, cytolytic resultingantibodies, in death has occurredARZERRA with ARZERRA. Consider in any including , resulting PML in death haspatient occurred with ARZERRA. Consider PML in any patient IN SOME CASES RESULTING IN FULMINANT HEPATITIS HEPATIC FAILURE

with new onset of or changes in pre-existing neurological signs or symptoms.

IN SOME CASES RESULTING IN FULMINANT HEPATITIS HEPATIC FAILURE

with new onset of or changes in pre-existing neurological signs or symptoms. and death [see Warnings and Precautions (5.2)].

If PML is suspected, discontinue ARZERRA and initiate evaluation fordiscontinue PML and death [see Warnings and Precautions (5.2)].

If PML is suspected, ARZERRA and initiate evaluation for PML s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY 0-, RESULTING including neurology consultation. 5.5 Tumor Lysis Syndrome Tumorconsultation. lysis s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY 0-, RESULTING including neurology 5.5 Tumor Lysis Syndrome Tumor lysis IN DEATH CAN OCCUR IN PATIENTS RECEIVING #$ DIRECTED syndrome (TLS), including the need for hospitalization, has(TLS), occurred in the need for hospitalization, has occurred in IN DEATH CAN OCCUR IN PATIENTS RECEIVING #$ DIRECTED syndrome including cytolytic antibodies, including ARZERRA [seecytolytic Warnings patients treated [see with ARZERRA. tumor burden high antibodies, including ARZERRA WarningsPatients with highpatients treatedand/or with ARZERRA. Patients with high tumor burden and/or high and Precautions (5.4)]. greater risk for developing and Precautions (5.4)]. circulating lymphocyte counts (>25 x 109/L) are at circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of prior to infusion of ARZERRA. For treatment of beginning 12 to 24 hours 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE TLS, administer aggressive intravenous andadminister anti-hyperuricemic aggressive intravenous hydration and anti-hyperuricemic 0REVIOUSLY 5NTREATED #HRONIC ,YMPHOCYTIC ,EUKEMIA ARZERRA 0REVIOUSLY 5NTREATED #HRONIC ,YMPHOCYTIC ,EUKEMIA ARZERRA hydrationTLS, agents, correct electrolyte abnormalities, and monitor renal function. agents, correct electrolyte abnormalities, and monitor renal function. (ofatumumab) is indicated, in combination with (ofatumumab) chlorambucil, for the is indicated, in combination with chlorambucil, for the Severelymphocytic cytopenias,leukemia including neutropenia, thrombocytopenia, #YTOPENIAS Severe cytopenias, including neutropenia, thrombocytopenia, treatment of previously untreated patients with treatment chronic lymphocytic leukemia of previously untreated #YTOPENIAS patients with chronic and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and (CLL) for whom udarabine-based therapy is considered inappropriate [see (CLL) for whom udarabine-based therapy is considered inappropriate [see fatal neutropenic sepsis occurred in patientsfatal whoneutropenic received ARZERRA in occurred in patients who received ARZERRA in sepsis have Clinical Studies (14.1) of full prescribing information].

Refractory Clinical1.2 Studies (14.1) CLL of full prescribing information].

1.2 have Refractory CLL combination with with chlorambucil.

Gradeto3 or 4 late-onset neutropenia (onset at Grade 3 or 4 late-onset neutropenia (onset at combination with chlorambucil.

ARZERRA is indicated for the treatment of patients with CLL refractoryfor to the treatment ARZERRA is indicated of patients CLL refractory 42 days after(14.2) last treatment dose) and/or prolonged neutropenia least 42 days after last(not treatment dose) and/or prolonged neutropenia (not udarabine and alemtuzumab [see Clinical Studies (14.2) ofand full alemtuzumab prescribing [seeleast udarabine Clinical Studies of full prescribing resolved between 24 and 42 days after last treatment dose) were 24 reported resolved between and 42 days after last treatment dose) were reported information]. information]. in patients who received ARZERRA [see AdverseinReactions (6.1)].

MonitorARZERRA [see Adverse Reactions (6.1)]. Monitor patients who received complete blood counts at regular intervals during and after conclusion 4 CONTRAINDICATIONS complete blood counts of at regular intervals during and after conclusion of 4 CONTRAINDICATIONS therapy, and increase the frequency of monitoring in patients who develop therapy, and increase the frequency of monitoring in patients who develop None.

None.

Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of 4immunization Grade 3 or cytopenias. 5.7 Immunizations The safety of immunization 5 WARNINGS AND PRECAUTIONS of ARZERRA 5 WARNINGS AND PRECAUTIONSwith live viral vaccines during or following administration with live viral vaccineshas during or following administration of ARZERRA has 5.1 Infusion Reactions ARZERRA can cause serious, including fatal, ARZERRAnot studied.

Doincluding not administer to studied. patients Do whonothave 5.1 Infusion Reactions canbeen cause serious, fatal, live viral vaccines not been administer live viral vaccines to patients who have infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, as bronchospasm, recently receiveddyspnea, ARZERRA. The ability to generate an immune response to The ability to generate an immune response to infusion reactions manifesting laryngeal edema, recently received ARZERRA. pulmonary edema, ushing, hypertension, hypotension, syncope, any vaccine following syncope, administration of ARZERRA not been studied. pulmonary edema,cardiac ushing, hypertension, hypotension, cardiac anyhas vaccine following administration of ARZERRA has not been studied. events (e.g., myocardial ischemia/infarction, acute coronary syndrome, ischemia/infarction, acute coronary syndrome, events (e.g., myocardial arrhythmia, bradycardia), back pain, abdominal arrhythmia, pain, pyrexia, rash, urticaria, 6 ADVERSE bradycardia), back pain, abdominalREACTIONS pain, pyrexia, rash, urticaria, 6 ADVERSE REACTIONS angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic The following serious adverse reactions are discussed in greater detailadverse in angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic The following serious reactions are discussed in greater detail in reactions. Infusion reactions occur more frequently with the ďŹ rst 2 reactions infusions.occurother of the reactions.

Infusion moresections frequently withlabeling: the ďŹ rst 2 infusions. other sections of the labeling: These reactions may result in temporary interruption withdrawal s )NFUSION 2EACTIONS [see Warnings (5.1)] Theseorreactions mayofresult in temporary interruption or withdrawal of and Precautions s )NFUSION 2EACTIONS [see Warnings and Precautions (5.1)] treatment [see Adverse Reactions (6.1)]. Premedicate with[see acetaminophen, (EPATITIS " 6IRUS 2EACTIVATION [see Warnings and Precautions (5.2)] treatment Adverse Reactions s (6.1)].

Premedicate with acetaminophen, s (EPATITIS " 6IRUS 2EACTIVATION [see Warnings and Precautions (5.2)] an antihistamine, and a corticosteroid [see Dosage and Administration s (EPATITIS " 6IRUS )NFECTION [see Warnings Precautions (5.3)] an antihistamine, and a(2.1, corticosteroid [see Dosage and Administration (2.1, ands (EPATITIS " 6IRUS )NFECTION [see Warnings and Precautions (5.3)] 2.4) of full prescribing information]. Infusion reactions occur despite s Infusion 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY [see Warnings and 2.4) of may full prescribing information]. reactions may occur despite s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY [see Warnings and premedication. Interrupt infusion with ARZERRApremedication. for infusion reactions of infusion withPrecautions (5.4)] Interrupt ARZERRA for infusion reactions of Precautions (5.4)] any severity. Institute medical management for severe infusion reactions s 4UMOR ,YSIS 3YNDROME [see Warnings and Precautions (5.5)] any severity.

Institute medical management for severe infusion reactions s 4UMOR ,YSIS 3YNDROME [see Warnings and Precautions (5.5)] including angina or other signs and symptoms ofincluding myocardial ischemia #YTOPENIAS [see Warnings and Precautions (5.6)] angina or other signs ands symptoms of myocardial ischemia s #YTOPENIAS [see Warnings and Precautions (5.6)] [see Dosage and Administration (2.3) of full prescribing information].

If an Previously Untreated CLL: The mostIfcommon adverse reactions (≼10%) [see Dosage and Administration (2.3) of full prescribing information]. an Previously Untreated CLL: The most common adverse reactions (≼10%) anaphylactic reaction occurs, immediately and permanently were infusion reactions anddiscontinue neutropenia (Table 1).

Refractory The and neutropenia (Table 1). Refractory CLL: The anaphylactic discontinue reaction occurs, immediately and permanently were infusion CLL: reactions ARZERRA and initiate appropriate medical treatment.

(EPATITIS " common adverse reactions (≼10%) were neutropenia, pneumonia, ARZERRA and initiate appropriate most medical treatment.

(EPATITIS " most common adverse reactions (≼10%) were neutropenia, pneumonia, Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases pyrexia, diarrhea, anemia, fatigue, dyspnea, rash,cough, nausea, bronchitis, Virus Reactivation Hepatitis B virus (HBV)cough, reactivation, in some cases pyrexia, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, resulting in fulminant hepatitis, hepatic failure, and death,inhas occurred in and upper respiratory tract 3). The serious resulting fulminant hepatitis, hepatic failure, and death, hasinfections occurred (Table in and most uppercommon respiratory tract infections (Table 3). The most common serious patients treated with ARZERRA. Cases have been reported in patients who adverse were infections pneumonia and sepsis), patients treated with ARZERRA. Cases havereactions been reported in patients(including who adverse reactions were infections (including pneumonia and sepsis), are hepatitis B surface antigen (HBsAg) positiveare andhepatitis also in patients who neutropenia, Infectionswho were the most common and adverse B surface antigen (HBsAg) positiveand andpyrexia. also in patients neutropenia, pyrexia. Infections were the most common adverse are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. reactions drug discontinuation. are HBsAg negative but are hepatitis B coreleading antibodyto(anti-HBc) positive. #LINICAL 4RIALS %XPERIENCE reactions leading to drug discontinuation. #LINICAL 4RIALS %XPERIENCE Reactivation also has occurred in patients who appear to have resolved Because who clinical trialstoare conducted varying conditions, Reactivation also has occurred in patients appear have resolvedunder widely Because clinical trials are conducted under widely varying conditions, hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B adverseanti-HBc reaction positive, rates observed in the clinical trials of a reaction drug cannot hepatitis B infection (i.e., HBsAg negative, and hepatitis B adverse ratesbeobserved in the clinical trials of a drug cannot be surface antibody [anti-HBs] positive). HBV reactivation is deďŹ ned an abruptpositive). directly compared with rates in clinical trialsdirectly of another drug and surface antibodyas[anti-HBs] HBV reactivation is deďŹ ned asthe an abrupt compared withmay rates in the clinical trials of another drug and may increase in HBV replication manifesting as a rapid increase in serum HBV manifesting not reect rates observed in practice.

Untreated CLL: observed The increase in HBV replication as a the rapid increase in serum HBV Previously not reect the rates in practice. Previously Untreated CLL: The DNA level or detection of HBsAg in a person whoDNA waslevel previously HBsAgof HBsAg insafety of ARZERRA evaluated in an open-label, parallel-arm, or detection a person who waswas previously HBsAg safety of ARZERRArandomized was evaluated in an open-label, parallel-arm, randomized negative and anti-HBc positive. Reactivation of HBV replication is oftenpositive. Reactivation trial (Studyof1)HBV in 444 patients iswith previously untreated CLL.1)Patients were with previously untreated CLL. Patients were negative and anti-HBc replication often trial (Study in 444 patients followed by hepatitis, i.e., increase in transaminase levelsbyand, in severe to receive infusion everyeither ARZERRA as an intravenous infusion every followed hepatitis, i.e., increaserandomized in transaminase levelseither and, ARZERRA in severe as an intravenous randomized to receive cases, increase in bilirubin levels, liver failure, and death.

Screeninall patients in combination with chlorambucil or chlorambucil as with a chlorambucil (n = 217) or chlorambucil as a cases, increase bilirubin levels, 28 liverdays failure, and death. Screen all patients(n = 217) 28 days in combination for HBV infection by measuring HBsAg and anti-HBc before initiating singleand agent (n = 227).

In initiating both arms, patients received chlorambucil for HBV infection by measuring HBsAg anti-HBc before single agent (n = 227). In both arms, patients received chlorambucil 2 schedule treatment with ARZERRA. For patients who showtreatment evidencewith of hepatitis B For patients 10 mg/m ARZERRA. who 2show hepatitis orallyevidence on Days of 1 to 7 everyB28 days. The infusion 10 mg/m orally on Days 1 to 7 every 28 days. The infusion schedule infection (HBsAg positive [regardless of antibodyinfection status] or HBsAgpositive negative (HBsAg [regardless of antibodywas status] or HBsAg negativeon Cyclefor1 ARZERRA for ARZERRA 300 mg administered Day 1, 1,000 wasmg 300 mg administered on Cycle 1 Day 1, 1,000 mg but anti-HBc positive), consult physicians with expertise in managing but anti-HBc positive), consult physicians with expertise managing administered on Cycle in 1 Day 8, and 1,000 mg administered 1 of1 Day 8, and 1,000 mg administered on Day 1 of administeredon onDay Cycle hepatitis B regarding monitoring and consideration for HBV antiviral therapy. hepatitis B regarding monitoring and consideration forcycles.

HBV antiviral therapy. subsequent 28-day The median numbersubsequent of cycles of 28-day ARZERRA cycles. The median number of cycles of ARZERRA Monitor patients with evidence of current or prior HBV infection clinical Monitor patientsfor with evidence of completed current or prior HBV for clinical was 6.

Theinfection data described in Table 1completed include relevant was 6.adverse The data described in Table 1 include relevant adverse and laboratory signs of hepatitis or HBV reactivation during andsigns for several and laboratory of hepatitis orreactions HBV reactivation anddays for several occurringduring up to 60 after the last dose of study medication; reactions occurring up to 60 days after the last dose of study medication; months following treatment with ARZERRA. HBVmonths reactivation has been following treatment with ARZERRA. HBV reactivation has been laboratoryTable Table 2 includes relevant hematologic abnormalities.

2 includes relevant hematologic laboratory abnormalities. reported for at least 12 months following completion of therapy.

In patients reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receivingwho ARZERRA, developimmediately reactivation of HBV while receiving ARZERRA, immediately (cont’d)

(cont’d)

ASCOPost.com | AUGUST 15, 2014

PAGE 9

ASCO Annual Meeting 86 metastatic triple-negative breast cancer patients. The study found that platinum monotherapy was active in sporadic and BRCA1/2-associated disease.

Response rates varied notably by germline BRCA1/2 status, with responses observed in 54.5% of BRCA carriers compared to 19.7% of wildtype patients (P = .022). However,

BRCA1/2 status did not predict for longer progression-free or overall survival.

“A meaningful subset of patients achieved durable responses and remain progression-free for over 4 years, but durable responses were not associated with a BRCA1/2 mutation,” he said.

Neither response nor durable response was predicted by p63/p73 expression,

p53/PIK3CA mutation, or molecular subtype. “Caution, therefore, is necessary when evaluating biomarkers developed in the pretreatment setting for use in metastatic disease,” he commented. n Disclosure: Drs. von Minckwitz and Isakoff reported no potential conflicts of interest.

For full disclosures of all study authors, visit meetinglibrary.asco.org.

References 1. von Minckwitz G, Hahnen E, ­Fasching PA, et al: ASCO Annual Meeting. Abstract 1005. Presented June 3, 2014.

2. von Minckwitz G, Schneeweiss A, L ­ oibl S, et al: Lancet Oncol 15:747-756, 2014.

3. Isakoff SJ, He L, Mayer EL, et al: ASCO Annual Meeting. Abstract 1020.

Presented June 3, 2014.

Table 1. Adverse Reactions With ≥5% Incidence in 1.

Patients Receiving receivedinall 12 infusions.

The median and age was years (range: 41 Table Adverse Reactions With and ≥5%55% Incidence Patients Receiving 55%63 received all 12 infusions.

The median age was 63 years (range: 41 ARZERRA Plus Chlorambucil and Also ≥2% More Than Plus Patients 86 years), 72% Than were Patients male, and 97% were white.

ARZERRA Chlorambucil andtoAlso ≥2% More to 86 years), 72% were male, and 97% were white.

Receiving Chlorambucil Receiving Chlorambucil Table 3. Incidence of All Adverse Reactions Occurring in ≥5% ofofPatients Table 3. Incidence All Adverse Reactions Occurring in ≥5% of Patients ARZERRA Plus ARZERRA Plus and in the Fludarabine- and Alemtuzumab-refractory and in theSubset Fludarabine- and Alemtuzumab-refractory Subset Chlorambucil Chlorambucil Chlorambucil Chlorambucil Fludarabine- and (N = 217) (N = 227) Fludarabine- and (N = 217) (N = 227) AlemtuzumabAlemtuzumabAll All All All refractory 4OTAL 0OPULATION refractory 4OTAL 0OPULATION Grades Grade ≥3 Grades Grade ≥3 (N = 59) (N =≥3 154) Grades Grade ≥3 Grades Grade (N = 59) (N = 154) Adverse Adverse Reactions % % Reactions % % % % % Grade All All % Grade Grade All Grade All ≥3 Grades ≥3 Adverse Grades0 ≥3 Grades ≥3 Grades Infusion reactionsa 67 10 Infusion 0reactionsa 0 67 Adverse10 0 % % % Reaction % Reaction % % % % Neutropenia 27 26 Neutropenia 18 14 27 26 18 14 Pneumoniaa 23 14 Pneumonia 25 a 15 23 14 25 15 Asthenia 8 <1 Asthenia5 0 8 <1 5 0 Pyrexia 20 3 25 5 Pyrexia 20 3 25 5 Headache 7 <1 Headache 3 0 7 <1 3 0 Cough 19 0 0 Cough19 19 0 19 0 Leukopenia 6 3 Leukopenia 2 <1 6 3 2 <1 Diarrhea 18 0 19 0 Diarrhea 18 0 19 0 b 6 0 Herpes simplex 4 <1 Herpes simplexb 6 0 4 <1 Anemia 16 5 17 8 Anemia 16 5 17 8 Lower respiratory tract 5 1 Lower respiratory 3 <1 tract 5 1 3 <1 Fatigue 15 0 15 0 Fatigue 15 0 15 0 infection infection Dyspnea 14 2 19 5 Dyspnea 14 2 19 5 Arthralgia 5 <1 Arthralgia3 0 5 <1 3 0 b 14 0 <1 5 Rash 0 3 a <1 a infusion or within Includes events which occurred on the day of an Includes events which occurred onBronchitis the day of an infusion or within11 24 hours of the end of an infusion and resulted 24 in an interruption or of an infusion and hours of the end resulted in an interruption 11 or Nausea 0 discontinuation of treatment. Infusion reactions discontinuation may include, butofare not treatment.

Infusion reactions may include, but are not respiratory tractpain, pruritus, 11 0 limited to, chills, dyspnea, flushing, hypotension,limited nausea, to,pain, chills,pruritus, dyspnea, flushing,Upper hypotension, nausea, infection pyrexia, rash, and urticaria. pyrexia, rash, and urticaria. b b Includes oral herpes, herpes, herpes virus infection, genital Includes oralherpes, herpes,and herpes, herpes virus peripheral infection, genital herpes,9 and Edema <1 herpes simplex. herpes simplex.

Back pain 8 1 Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring Chills 8 0 With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil 8 0 and Also ≥2% More Than Patients Receivingand Chlorambucil Also ≥2% More Than PatientsNasopharyngitis Receiving Chlorambucil

Upper abdominal pain

5

0 Upper abdominal 3 pain0

ARZERRA Plus Chlorambucil (N = 217)

8 8 Chlorambucil (N = 227)7

8

2

14

<1

17

2

19 Bronchitis

2

11

<1

19

2

12 Nausea

0

11

0

12

0

0 Upper 3respiratory tract infection

11

0

3

0

Edema8peripheral 2

9

<1

8

2

12 Back pain

2

8

1

12

2

Chills 10

0

8

0

10

0

0

8

0

8

0

10

8

8

10

10

8 Nasopharyngitis c Sepsis10

0

5 Urticaria

0

8

0

5

0

0

10 Insomnia

0

7

0

10

0

Grade All≥3 Grades Headache Grade ≥3 All Grades Grade ≥3 0 6 7 0 Headache 6 0 7 0 % % % % % Herpes zoster 6 1 7 2 Herpes zoster 6 1 7 2 Leukopenia 67 23 28 4 67 Leukopenia 23 28 4 Hyperhidrosis 5 0 5 0 Hyperhidrosis 5 0 5 0 Neutropenia 66 29 56 24 66 Neutropenia 29 56 24 Hypertension 5 0 8 0 Hypertension 5 0 8 0 Lymphopenia 52 29 20 7 52 Lymphopenia 29 20 7 Hypotension 5 0 3 0 Hypotension 5 0 3 0 Infusion Reactions: Overall, 67% of patients whoInfusion received ARZERRAOverall, in Reactions: 67% of patients who received ARZERRA in Muscle spasms 5 0 3 0 Muscle spasms 5 0 3 0 combination with chlorambucil experienced onecombination or more symptoms of with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal).(10% Infusion 5 2 3 2 infusion reactions were Grade Sinusitis 3 or greater; none were fatal). Infusion Sinusitis 5 2 3 2 reactions that were either Grade 3 or greater, serious, or led treatment reactions thattowere either Grade 3 or greater, serious, or led to treatment Tachycardia 5 <1 7 2 Tachycardia 5 <1 7 2 interruption or discontinuation occurred most frequently during Cycle 1 (56% occurred most frequently during Cycle 1 (56% interruption or discontinuation a a on Day 1 [6% were Grade 3 or greater] and 23%ononDay Day1 8[6% [3%were wereGrade Grade3 3or greater] and 23% on Day 8lung [3%infection, were Grade Includes pneumonia, lobar3 pneumonia, andpneumonia, lung infection, lobar pneumonia, and Includes or greater]) and decreased with subsequent infusions.

Infusion or greater]) andreactions decreasedledwith subsequent infusions. Infusion reactions led bronchopneumonia. bronchopneumonia. b to discontinuation of treatment in 3% of patients. adverse of events to Serious discontinuation treatment in 3% of patients. adverseand events Includes rash,Serious rash macular, rash vesicular.b Includes rash, rash macular, and rash vesicular. c of patients. Neutropenia: Overall, 3% c and septic shock. of infusion reactions occurred in 2% of patients.ofNeutropenia: Overall,occurred 3% infusion reactions in 2% Includes sepsis, neutropenic sepsis, bacteremia, Includes sepsis, neutropenic sepsis, bacteremia, and septic shock. of patients had neutropenia as a serious adverseofevent, reported up to patients had neutropenia as a serious adverse event, reported up to Infusion Reactions: Infusion reactions occurred in 44% patients onInfusion the reactions occurred in 44% of patients on the InfusionofReactions: 60 days after the last dose. One patient died with sepsis 60neutropenic days after the last and dose. One patient died with neutropenic sepsis and day of the first infusion (300 mg), 29% on the day of the second infusion day of the first infusion (300 mg), 29% on the day of the second infusion agranulocytosis. Prolonged neutropenia occurred in 6% of patients receivingneutropenia occurred in 6% of patients receiving agranulocytosis.

Prolonged (2,000 mg), and less frequently during subsequent infusions.

Infections: A (2,000 mg), and less frequently during subsequent infusions. Infections: A ARZERRA in combination with chlorambucil compared within 4% of patientswith chlorambucil ARZERRA combination compared with 4% of patients total of 108 patients (70%) experienced bacterial,total viral,ofor108 fungal infections.

Aexperienced bacterial, viral, or fungal infections. A patients (70%) receiving chlorambucil. Late-onset neutropenia receiving occurred chlorambucil. in 6% of patients Late-onset neutropenia occurred in 6% of patients total of 45 patients (29%) experienced Grade 3 ortotal greater of which of 45infections, patients (29%) experienced Grade 3 or greater infections, of which receiving ARZERRA in combination with chlorambucil compared within 1% receiving ARZERRA combination with chlorambucil compared with 1% 19 (12%) were fatal. The proportion of fatal infections in thewere fludarabine19 (12%) fatal. Theand proportion of fatal infections in the fludarabine- and of patients receiving chlorambucil alone. Refractory CLL: The safety of of patients receiving chlorambucil alone. Refractory CLL: The safety of alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with monotherapy with ARZERRA was evaluated in 181 patients with or was evaluated monotherapy withrelapsed ARZERRA in 181 patients with relapsed or normal neutrophil counts at baseline, 45 (42%) developed Grade 3 counts or greater normal neutrophil at baseline, 45 (42%) developed Grade 3 or greater refractory CLL in 2 open-label, non-randomized,refractory single-arm studies.

In these non-randomized, CLL in 2 open-label, single-arm studies. In these neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Nineteen Some patients (18%) developed Grade 4 neutropenia. Some patients studies, ARZERRA was administered at 2,000 mg beginning with the second studies, ARZERRA was administered at 2,000 mg beginning with the second experienced new onset Grade 4 neutropenia >2 weeks in duration. experienced new onset Grade 4 neutropenia >2 weeks in duration. dose for 11 doses (Study 2 [n = 154]) or 3 dosesdose (Study 3 [ndoses = 27]).

The data for 11 (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]). The data 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic described in Table 3 and other sections below are derived in from 1543 patients described Table and other sections below are derived from 154 patients proteins such as ofatumumab. Serum samples from moresuch thanas 300 patients Serum samples from more than 300 patients proteins ofatumumab. in Study 2. All patients received 2,000 mg weekly from the second dose in Study 2. All patients received 2,000 mg weekly from the second dose with CLL were tested during and after treatment with for antibodies ARZERRA. CLL were to tested during and after treatment for antibodies to ARZERRA. onward. Ninety percent of patients received at least 8 infusions of ARZERRA onward.

Ninety percent of patients received at least 8 infusions of ARZERRA All Grades %

Grade ≥3 %

Chlorambucil (N = 227)

Sepsisc ARZERRA Plus Urticaria Chlorambucil (N = 217) Insomnia

Rashb17

All Grades %

(cont’d)

(cont’d)

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; AUGUST 15, 2014

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ASCO Annual Meeting Thoracic Oncology

Mixed Results for Targeting MET in Nonâ&#x20AC;&#x201C;Small Cell Lung Cancer

By Alice Goodman

T

wo different abstracts explored the potential for MET as a therapeutic target in patients with metastatic nonâ&#x20AC;&#x201C;small cell lung cancer (NSCLC), with different results. A phase III study

found that onartuzumab, an antibody that targets the MET receptor, combined with erlotinib (Tarceva) was not as effective as erlotinib alone for the treatment of metastatic NSCLC. How-

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and speciďŹ city, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading. 0OSTMARKETING %XPERIENCE The following adverse reactions have been identiďŹ ed during post-approval use of ARZERRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda.

7 DRUG INTERACTIONS Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or wellcontrolled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity.

Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential beneďŹ t to the mother justiďŹ es the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older.

Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufďŹ cient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 2ENAL )MPAIRMENT No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information].

(EPATIC )MPAIRMENT No formal studies of ARZERRA in patients with hepatic impairment have been conducted.

10 OVERDOSAGE No data are available regarding overdosage with ARZERRA. 13 NONCLINICAL TOXICOLOGY #ARCINOGENESIS -UTAGENESIS )MPAIRMENT OF &ERTILITY No carcinogenicity or mutagenicity studies of ofatumumab have been conducted.

In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

ever, analysis of a phase I study suggests that crizotinib (Xalkori) may be a worthy strategy to pursue in smokers with MET-amplified metastatic NSCLC. The MET pathway is a target of

2EPRODUCTIVE AND $EVELOPMENTAL 4OXICOLOGY Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the ďŹ nal dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared with control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological signiďŹ cance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: s 3IGNS AND SYMPTOMS OF INFUSION REACTIONS INCLUDING FEVER CHILLS RASH

or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)] s 3YMPTOMS OF HEPATITIS INCLUDING WORSENING FATIGUE OR YELLOW DISCOLORATION of skin or eyes [see Warnings and Precautions (5.2, 5.3)] s .EW NEUROLOGICAL SYMPTOMS SUCH AS CONFUSION DIZZINESS OR LOSS OF balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.4)] s "LEEDING EASY BRUISING PETECHIAE PALLOR WORSENING WEAKNESS OR FATIGUE [see Warnings and Precautions (5.6)] s 3IGNS OF INFECTIONS INCLUDING FEVER AND COUGH [see Warnings and Precautions (5.6), Adverse Reactions (6.1)] s 0REGNANCY OR NURSING [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: s -ONITORING AND POSSIBLE NEED FOR TREATMENT IF THEY HAVE A HISTORY of hepatitis B infection (based on the blood test) [see Warnings and Precautions (5.2)] s 0ERIODIC MONITORING FOR BLOOD COUNTS [see Warnings and Precautions (5.6)] s !VOIDING VACCINATION WITH LIVE VIRAL VACCINES [see Warnings and Precautions (5.7)] ARZERRA is a registered trademark of the GSK group of companies.

Manufactured by: GLAXO GROUP LIMITED Brentford, Middlesex, TW8 9GS, United Kingdom U.S. License 1809

David R. Spigel, MD

interest in NSCLC for the following reasons: Dysregulation of the MET pathway is associated with a worse prognosis in NSCLC and other solid tumors. In NSCLC, a high MET copy number is associated with shorter survival and higher risk of death after resection, explained lead author of the global phase III METLung trial, David R. Spigel, MD, an oncologist at Sarah Cannon Cancer Center, Nashville.1 Additionally, MET and epidermal growth factor receptor (EGFR) are often coexpressed and coactivated in NSCLC. MET amplification occurs in lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors. Dr. Spigel continued.

METLung Trial On the heels of a positive phase II trial suggesting that onartuzumab would be more effective in patients selected for MET expression, the METLung trial was undertaken to study the effect of onartuzumab combined with erlotinib (an EGFR tyrosine kinase inhibitor) vs erlotinib alone in previously treated stage IIIB or IV NSCLC. The study was supported by Genentech and Roche.

METLung was stopped early because the futility boundary was crossed, and onartuzumab added to erlotinib was shown to be not superior to erlotinib alone in patients selected for high MET expression. â&#x20AC;&#x153;The results of this global phase III trial involving 27 countries turned out

Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 Š2014, the GSK group of companies. All rights reserved.

Revised: 04/2014 ARZ:8BRS Š2014 GSK group of companies.

All rights reserved. Printed in USA. AZA438R0 May 2014

Targeting MET in Lung Cancer â&#x2013; â&#x2013; Targeting the MET receptor did not pan out in a global phase III study, but using a MET-targeted agent in patients with intermediate and high levels of MET expression may benefit a small subset of patients with NSCLC. â&#x2013; â&#x2013; MET expressers are likely to have a smoking history.

ASCOPost.com | AUGUST 15, 2014

PAGE 11

ASCO Annual Meeting to be negative. They did not confirm the phase II findings in the MET-positive population, and the lack of benefit for the addition of onartuzumab was consistent across subgroups,” Dr. Spigel said. “Onartuzumab did not provide a benefit to the EGFR-positive patients either,” he added.

METLung included patients with centrally confirmed high MET expression with good performance status.

EGFR mutation status was analyzed at the same time as MET. Between 2012 and 2013, 499 patients were randomly assigned 1:1 to erlotinib plus onartuzumab or erlotinib plus placebo and treated until disease progression. Median follow-up was 7.7 months.

Patients enrolled in the phase III trial had demographics “identical” to those in the pivotal phase II trial, he said. Most patients had nonsquamous histology.

About two-thirds were in second-line therapy and one-third had received at least two prior therapies. In each arm, 11% had EGFR-mutated tumors. Most of the patients had high MET expression in at least 50% of cells, he added.

Median overall survival was 6.8 months for erlotinib plus onartuzumab

Our results suggest that METamplified disease may represent a novel targetable subtype of NSCLC, notably present among those with smoking activity.

—D. Ross Camidge, MD

vs 9.1 months for erlotinib. An intentto-treat analysis of progression-free survival showed almost identical curves for the two regimens: 2.6 months for erlotinib alone vs 2.7 months for the combination. No subgroup stood out as having preferential benefit from the combination for either overall or progression-free survival.

The combination was well tolerated, with rash and diarrhea being the most frequently reported adverse events in both arms. Adverse events reported more frequently with the combination included peripheral edema and hypoalbuminemia.

Crizotinib Study “The MET gene is amplified in up to 7% of all NSCLC, where it may be

functioning as a primary oncogenic driver. Amplification is a continuous variable though, and the relevant cutpoint for defining ‘presence’ may be different from that defining its predictive role for identifying benefit from MET inhibition,” noted D. Ross Camidge, MD, Director of the Thoracic Oncology Clinical Program at the University of Colorado School of Medicine, Denver, who presented the first results of crizotinib treatment in MET-amplified NSCLC from the original phase I study of crizotinib.2 MET amplification has also been described as a secondary event in EGFR mutant patients resistant to EGFR tyrosine kinase inhibitors, but this is a different medical scenario from its role as a primary driver, he added.

EXPERT POINT OF VIEW

F

ederico Cappuzzo, MD, Director of the Medical Oncology Department at Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy, pointed out that the abstracts presented by Spigel et al and Camidge et al at the ASCO Annual Meeting explored the same target but with different results.

The first evaluated the role of the antiMET agent onartuzumab combined with erlotinib (Tarceva) in METpositive non–small cell lung cancer

were all current or former smokers.

“This is an important message. If we are looking for patients with MET amplification, we should probably look at smoking history and not only at histology,” he stated.

MET Testing Issues Previous studies have shown that not all MET-positive patients on immunohistochemistry (IHC) are always MET-amplified on fluorescence

New studies with anti-MET agents should be conducted only in properly selected patients.

—Federico Cappuzzo, MD

(NSCLC), and the second evaluated the effects of crizotinib (Xalkori) in MET-amplified NSCLC. Dr. Cappuzzo described previous data showing that patients with squamous NSCLC with intermediate or high levels of MET expression

in situ hybridization (FISH) and suggest that anti-MET agents would be effective in only 3% to 4% of patients.

“Perhaps that is why the study presented by Dr. Spigel was negative.

We saw detrimental effects, especially where we expected the drug to

work—that is, in epidermal growth factor receptor (EGFR)-mutated NSCLC,” he said.

Dr. Cappuzzo said it is possible that the negative findings were related to the difficulties in testing for MET. The study included patients evaluated only with IHC, but a consistent proportion of patients who test positive for MET expression on IHC do not have MET-amplified disease, he said.

“An IHC +3 score needs to be confirmed by FISH,” he stated.

“MET remains an important target, but only in 3% to 4% of cases of NSCLC with gene amplification.

We need to define the best methods and cutoff for MET amplification. We know this is detectable in smokers irrespective of histology,” he said.

“IHC or MET gene copy number are not optimal for detecting patients potentially sensitive to anti-MET strategies,” Dr. Cappuzzo continued.

“Finally, new studies with anti-MET agents should be conducted only in properly selected patients,” he emphasized. n Disclosure: Dr. Cappuzzo reported no potential conflicts of interset.

Patients with NSCLC entered in the trial were stratified according to three levels of MET amplification (as determined by MET/CEP7 ratio) on fluorescence in situ hybridization (FISH) testing (low, intermediate, and high) in this phase I study. Notably, these patients were not selected by EGFR status, nor was an EGFR inhibitor involved in the trial.

At the time of the ASCO Annual Meeting, 14 patients were accrued to the NSCLC cohort (2 categorized as low-MET, 6 intermediate-MET, and 6 high-MET), mostly patients with adenocarcinoma. Overall duration of treatment was longer in those with higher levels of MET expression. Interestingly, 86% of those with MET amplification (any level) had a history of smoking in this study.

Treatment-related adverse events were similar in the three groups according to MET amplification. Results suggested improved efficacy as the MET amplification ratio increased: in the intermediate-MET group, four patients had stable disease and one had a partial response, and in the high-MET group, three had a partial response and one had a complete response. Objective partial response rates were 0%, 17%, and 67% in the low-, intermediate-, and high-MET groups, respectively. “These responses [in the intermediate- and high-MET groups] were persistent,” Dr. Camidge said.

“Our results suggest that MET-amplified disease may represent a novel targetable subtype of NSCLC, notably present among those with smoking activity,” he concluded. “These findings warrant further study of crizotinib in MET-amplified advanced NSCLC.” The optimal methods, optimal biomarker, and meaningful thresholds of MET expression remain to be defined, he added. n Disclosure: Dr. Spigel is a consultant or advisor for Genentech. Dr. Camidge is a consultant or advisor for and has received research funding from Pfizer.

References 1. Spigel DR, Edelman MJ, O’Byrne K, et al: Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial. ASCO Annual Meeting. Abstract 8000.

Presented June 2, 2014.

2. Camidge DR, Ou SI, Shapiro G, et al: Efficacy and safety of crizotinib in patients with advanced C-MET amplified non-small cell lung cancer (NSCLC).

ASCO Annual Meeting. Abstract 8001.

Presented June 2, 2014.

The ASCO Post | AUGUST 15, 2014

PAGE 12

FDA Update Recent Drug Approvals continued from page 1

Idelalisib in Chronic Lymphocytic Leukemia Idelalisib is being granted traditional approval to treat patients with relapsed chronic lymphocytic leukemia. Used in combination with rituximab ­(Rituxan), idelalisib is to be used in patients for whom rituximab alone would be considered appropriate therapy due to other existing comorbidities. Idelalisib is the fifth new drug with Breakthrough Therapy designation to be approved by the FDA and the third drug with this designation approved to treat chronic lymphocytic leukemia.

Idelalisib’s safety and effectiveness to treat relapsed chronic lymphocytic leukemia were established in a clinical trial of 220 participants who were randomly assigned to receive idelalisib and rituximab or placebo and rituximab. The trial was stopped for efficacy following the first prespecified interim analy-

lymphocytic lymphoma under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new

drugs while the company conducts confirmatory clinical trials.

Idelalisib Boxed Warning Idelalisib carries a Boxed Warning alerting patients and health-care proS:6.75” fessionals of fatal and serious toxicities including liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation

that can occur in idelalisib-treated patients. The drug is also being approved with a Risk Evaluation and Mitigation Strategy (REMS) comprising a communication plan to ensure health-care providers who are likely to prescribe idelalisib are fully informed about these risks.

Common side effects include diarrhea, pyrexia, fatigue, nausea, cough,

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

sis point, which showed participants treated with idelalisib and rituximab had a median progression-free survival of 10.7 months compared to about 5.5 months for participants treated with placebo and rituximab. Results from a second interim analysis continued to show a statistically significant improvement for idelalisib and rituximab over placebo and rituximab.

Idelalisib in Non-Hodgkin B-Cell Lymphomas The FDA is also granting idelalisib accelerated approval to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma. Idelalisib is intended for use in patients who have received at least two prior systemic therapies.

Idelalisib’s safety and effectiveness to treat relapsed follicular lymphoma and relapsed small lymphocytic lymphoma were established in a clinical trial with 123 participants who had indolent nonHodgkin lymphomas. All participants were treated with idelalisib and were evaluated for objective response rate.

Results showed 54% of participants with relapsed follicular lymphoma and 58% of participants with small lymphocytic lymphoma experienced complete or partial disappearance of their cancer.

The FDA is approving idelalisib to treat follicular lymphoma and small

Attack from multiple angles COMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro • These tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.

Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%).

Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA

05/14 [COM-0086]

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FDA Update

pneumonia, abdominal pain, chills, and rash. Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia, and elevated levels of liver enzymes.

Ibrutinib in Chronic Lymphocytic Leukemia The FDA also expanded the ap-

proved use of ibrutinib (Imbruvica) to treat patients with chronic lymphocytic leukemia who carry deletions of the short arm of chromosome 17, which are associated with poor responses to standard treatment for the disease. Ibrutinib received a S:6.75” Breakthrough Therapy designation for this use.

The FDA is also approving new la-

beling to reflect that ibrutinib’s clinical benefit in treating chronic lymphocytic leukemia has been verified. In February 2014, ibrutinib received accelerated approval for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy based on its effect on overall response rate. New clinical trial results examining

progression-free survival and overall survival have confirmed the drug’s clinical benefit.

RESONATE Trial The recent approvals for ibrutinib are based on data from the phase III RESONATE trial of 391 patients with continued on page 14

Statistically significant efficacy in patients with progressive, metastatic MTC • COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry PROD

• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001) • Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)

ED

• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the planned interim analysis

PFS

1.0

COMETRIQ® (n=219) Placebo (n=111)

0.9 0.8 0.6

CW

HR=0.28 95% CI: 0.19, 0.40 P<0.0001

0.7 0.5 0.4

median

median

4.0 4.0

0.3

11.2 11.2 months months

months months

0.2

CD

Probability of patients who are progression free

AE/AS

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Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.

Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330).

Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).

Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).

In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.

Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

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FDA Update RESONATE Trial continued from page 13

previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma, 127 of whom had chronic lymphocytic leukemia with 17p deletion.3 Participants were randomly assigned to receive ibrutinib or ofatumumab (Arzerra) until disease progression or side

effects became intolerable.

The trial was stopped early for efficacy after a preplanned interim analysis showed ibrutinib-treated participants experienced a 78% reduction in risk of disease progression or death. Results also showed a 57% reduction in risk of death in participants treated with ibrutinib. Of the 127 participants who had

chronic lymphocytic leukemia with 17p deletion, those treated with ibrutinib experienced a 75% reduction in risk of disease progression or death.

The most common side effects associated with ibrutinib included thrombocytopenia, neutropenia, diarrhea, S:6.75” anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash,

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning.

Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules.

Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions.

Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment.

In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.

In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg.

4. CONTRAINDICATIONS None.

5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively.

All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients.

Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.

5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

nausea, and pyrexia.

The FDA reviewed ibrutinib’s application for this new use under the agency’s Priority Review program, which provides for an expedited review of drugs that are intended to treat a serious disease or condition and, if approved, would offer significant improvement compared to marketed products. Ibru-

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days.

The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0.

Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5 Palmar-plantar erythrodysesthesia syndrome.

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FDA Update

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Recent Drug Approvals for Leukemias and Lymphomas ■■ The oral PI3K delta inhibitor idelalisib (Zydelig) has received FDA approval for the treatment of patients with relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma.

■■ Ibrutinib (Imbruvica), an oral Bruton’s tyrosine kinase inhibitor, received FDA approval for the treatment patients with chronic lymphocytic leukemia who carry deletions of the short arm of chromosome 17. In February 2014, ibrutinib received accelerated approval for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy based on its effect on overall response rate.

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References 1. Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997-1007, 2014.

2. Gopal AK, Kahl BS, deVos S, et al: PI3Kdelta inhibition by idelalisib in patients with indolent lymphoma. N Engl J Med 370:1008-1018, 2014.

3. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 2014 S:9.75”

Stage 2: Systolic ≥160 mmHg or Diastolic ≥100 mmHg

Placebo N=1073 (%) 15

Disclosure: Dr. Cheson was Principal Investigator for the pivotal trial of idelalisib and has received honoraria from Gilead Sciences.

Dr. Pazdur reported no potential conflicts of interest.

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Table 3.

Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose).

8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.

8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility.

Cabozantinib impaired male and female fertility in animal studies.

8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal).

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established.

8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.

10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy.

• COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

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Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.

2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

3 Subjects with at least two blood pressure measurements after the first dose.

other two drugs, idelalisib was also granted Orphan Drug designation because it is intended to treat a rare disease.

Dr. Pazdur noted that the recent approvals of drugs previously given Breakthrough Therapy designation “[reflects] the promise of the Breakthrough Therapy designation program and the FDA’s commitment to working cooperatively with companies to expedite the development, review, and approval of these important new drugs.” n

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Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade 3-4 All Grades Grade 3-4 Grades CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

Richard Pazdur, MD

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“In less than a year, we have seen considerable progress in the avail-

treat patients populations.”

The FDA approved obinutuzumab (Gazyva) in November 2013, ibrutinib (Imbruvica) in February 2014, and a new use for ofatumumab (Arzerra) in April 2014 to treat chronic lymphocytic leukemia. Both obinutuzumab and ofatumu­ mab also received Breakthrough Therapy designation for this indication. Like the

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Breakthrough Therapy Designation

ability of treatments for chronic lymphocytic leukemia,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We continue to see advances S:6.75”in the availability of therapies to treat chronic lymphocytic leukemia, especially for difficult-to-

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ASCO Annual Meeting New Research Presented in Wilms Tumor, Pediatric Sarcoma, Head and Neck Cancer, and Non–Small Cell Lung Cancer

By Alice Goodman and Caroline Helwick

I

n the past few months, numerous presentations from this year’s ASCO Annual Meeting have been covered in depth in the pages of The ASCO Post and online at ASCOPost.com. The brief summaries below capture additional important highlights that have not been covered thus far. We hope you will find them of interest.

Better Outcomes for Wilms Tumor In a select group of patients with newly diagnosed stage IV Wilms tumor, the addition of cyclophosphamide and etoposide to standard treatment with chemotherapy and radiation improved event-free survival and overall survival, according to the results of the AREN0533 study, conducted by the Children’s Oncology Group.1 AREN0533 evaluated whether therapy can be tailored based on the completeness of the lung metastasis response after 6 weeks of DD4A chemotherapy (vincristine, dactinomycin, and doxorubicin). The study enrolled 391 patients with newly diagnosed stage IV favorable histology Wilms tumor. Of these, 279 had isolated lung metastases, and within this group, 163 (58%) had a “slow incomplete response” to DD4A; the remaining patients had resolution

David B. Dix, MD

of lung metastases and continued on DD4A alone. In the slow incomplete response group, etoposide with cyclophosphamide and whole-lung irradiation were added to DD4A (called Regimen M). The patients with a slow incomplete response were treated every 3 weeks with Regimen M for an additional 27 weeks.

Based on historic controls, the number of expected events while on treatment was 38.6 for patients with a slow incomplete response. However, only 15 events were recorded in the study.

David B. Dix, MD, of the British Columbia Children’s Hospital in Vancou-

ver, reported that the 3-year event-free survival rate in the slow incomplete response group was 88%, while 3-year overall survival in these patients was 92%.

Although the data are not mature, Dr. Dix commented, “The AREN0533 Study Committee is encouraged by these results, and recommends that physicians consider these data when planning treatment for their patients.”

Final data are expected in 2016, after a median follow-up of 6 years.

Algorithm for Rare Pediatric Sarcomas A risk-stratification algorithm appears to accurately segregate pediatric patients with non-rhabdomyosarcoma

Sheri L. Spunt, MD, MBA

soft-tissue sarcoma into distinct prognostic subgroups for treatment assignment.2 Use of this algorithm can spare low-risk patients from more toxic therapy, and high-risk patients can be treated with more intensive approaches, according to the first study since the 1990s to be conducted in these rare childhood soft-tissue sarcomas.

The algorithm identifies specific low-risk subsets of patients who can be treated safely with surgery alone, and it shows that patients with intermediate- and high-risk disease can be safely treated with neoadjuvant combined chemotherapy and lower doses of radiotherapy followed by delayed resection without having a negative effect on outcomes.

The risk-stratification scheme applied in the study will be used to determine which children should receive investigational therapies and which ones should not, according to lead author Sheri L. Spunt, MD, MBA, of Lucile Packard Children’s Hospital, Stanford University School of Medicine, Palo Alto, California. The category of nonrhabdomyosarcoma soft-tissue sarcoma accounts for about 50% of all childhood

soft-tissue sarcomas and is a “wastebasket” term for an assortment of more than 30 cancer types that haven’t gotten much research attention, she explained.

ARST0332 enrolled 551 eligible patients with non-rhabdomyosarcoma soft-tissue sarcoma, and is the largest prospective study in the United States conducted in these tumors. Median age was 13.7 years (range, 0.1–29.8 years).

Tumor types included all histologic subtypes as well as localized and metastatic disease.

Characteristics including tumor grade, size, extent of resection, margin status, and extent of disease were used to assign newly diagnosed patients into risk groups. Low-risk patients had either surgery alone (ie, those with grossly excised low-grade and ≤ 5 cm widely excised high-grade tumors) or had adjuvant radiotherapy added (ie, those with ≤ 5 cm marginally resected high-grade tumors); patients with i­ntermediate-risk (ie, > 5 cm grossly resected tumor or unresected at study entry, without metastases) or high-risk disease (ie, metastatic) were managed with surgery alone or upfront/delayed surgery (based on resection potential) plus adjuvant or neoadjuvant chemoradiotherapy.

At a median of 2.6 years of follow-up, a clear distribution of clinical outcomes was observed. The 4-year survival rates were 97% (surgery alone), 100% (surgery plus radiotherapy), 80% (adjuvant chemoradiotherapy), and 63% (neoadjuvant chemoradiotherapy). There were no deaths; unexpected grade 4 toxicity occurred in 10 patients (2%).

Induction Therapy in Head and Neck Cancer Induction therapy follwed by concomitant treatment improved survival and other outcomes compared with concomitant therapy alone in patients with locally advanced squamous cell carcinoma of the head and neck, according to a multicenter phase II/III study presented

by Maria Grazia Ghi, MD, of Ospedale Civile, Venice, Italy.3 The phase II part of the study was previously published and supported the use of three cycles of induction therapy with TPF (docetaxel, cisplatin, and fluorouracil) without compromising delivery of chemoradiotherapy. In the phase III study, concomitant therapy with cetuximab (Erbitux) plus radiation therapy

was added to the induction and noninduction arms (2×2 factorial design). This is the first study to compare these two regimens, she stated.

The phase III trial included 421 patients with stage III or IV unresectable squamous cell carcinoma of the head and neck randomly assigned from the beginning to induction with TPF followed by chemoradiotherapy or cetuximab/ radiotherapy vs concomitant treatment alone. The treatment arms (induction vs no induction) were well balanced for demographics and disease characteristics.

Median progression-free survival was 29.7 months in the induction arm vs 18.5 in the noninduction arm (P = .0155). Median overall survival was 53.7 months vs 30 months, respectively (P = .025). Overall response rate was not different in the induction and noninduction arms after concomitant therapy, but the complete response rate was significantly higher in the induction arm: 43.5% vs 28% (P = .0023).

Induction therapy did not affect compliance with concomitant therapy, she said. The study was not powered to compare the two concomitant regimens, and a larger study would be required to do that.

Toxicity was not significantly different in the two arms, with the exception of more grade 4 neutropenia in the TPF arm (4% vs 1%, respectively, P = .037).

Ceritinib in ALK-Positive Lung Cancer In the ASCEND-1 trial, ceritinib (Zykadia) produced positive results in ALK-positive patients with non–small cell lung cancer (NSCLC), including those previously treated with an ALK inhibitor (crizotinib [Xalkori]) as well as those who were crizotinib-naive.4 With ceritinib, tumor shrinkage was also observed in brain metastases present at baseline.

The overall response rate was 58%, and median progression-free survival was 8.2 months; results were similar in patients who previously received an ALK inhibitor and those who were ALK inhibitor–naive at baseline.

Dong-Wan Kim, MD, of Seoul National University Hospital, South Korea, who presented these results, emphasized that this drug works in both pre–ALK inhibitor–treated and ALK inhibitor– continued on page 18

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The ASCO Post | AUGUST 15, 2014

PAGE 18

Perspective Genetics/Genomics

Precision Medicine: Precisely Where Are We Really?

By John F. Smyth, MD

H

aving attended ASCO Annual Meetings for almost 40 years, I believe that this year’s 50th anniversary celebration was one of the best ever. In many of the presentations and discussions, I experienced a sense of reality about the true state of cancer management that in previous years has sometimes been overshadowed by excitement for novelty, exaggeration of findings, and a sense of forced optimism created by a demanding public and threatened finances.

Complex Problem Of course, there should always be excitement—and you cannot pursue oncology unless you are essentially an optimist.

But I was greatly encouraged by the open and frank appraisals of some of the huge challenges that we still face in improving the outcome of cancer treatment.

Nowhere was this more apparent than in the realm of “personalized medicine,” now known as “precision medicine”—in my opinion, a much more appropriate term. The speed of advancement in our knowledge of the genetic detail of individual tumors and of their patient host is truly astonishing. That progress is undeniably exciting, but we must realize that the more we know, the greater the complexity of the problem.

And the more we “individualize” the problem, the harder it becomes to define personalized prescriptions for management. Where once we thought that cancers such as breast, colon, lung, Dr. Smyth is Emeritus Professor of Medical Oncology at the University of Edinburgh, Scotland, United Kingdom.

ALK-Positive Lung Cancer continued from page 16

naive patients, and he was especially impressed with the drug’s activity in metastatic brain cancer. “This [ie, brain metastasis] is currently one of the biggest challenges in treating ALK-positive NSCLC,” he said.

“Ceritinib achieved a high rate of durable responses and prolonged progression-free survival in both ALK inhibitor–treated and ALK inhibitor– naive patients. In ALK inhibitor–naive patients, median duration of response and median progression-free survival have not yet been reached,” he noted.

ASCEND-1 was a global phase I trial

and melanoma could be subdivided by pathologists into a small number of subsets, we now appreciate an everincreasing diversity within these pathologic groupings. Why does this matter?

Several Concerns There are several concerns, and foremost among them is this: the public may think that we can already apply this new knowledge to offer much more specific or precise treatments.

istration (FDA) and European Medicines Agency (EMA) are conscious of this requirement and will need robust reassurance if they are to approve new products based on much smaller patient groupings in pivotal trials—a direct consequence of splitting cancers from, say, two types of breast cancer into 12, or event malignant melanoma into two different categories, depending on wild-type or mutant BRAF, for example.

Both the medical profession and the public at large need to be educated about the concept of iterative drug development with the goal of developing more precise medicines in a shorter time frame—but with an altered benefit/risk concept, which will be modified over time.

—John F. Smyth, MD

That of course is the goal, but we have not yet reached it.

Two of the greatest challenges concern the validity of the genetic testing on which subsets are defined, and the dilution factor of having smaller numbers in a specific category within clinical trials. If we are going to depend on genetic profiling in order to develop and assign more precise medicines, then we have to improve the quality assurance of the myriad genetic platforms currently in use, and this has to be regulated.

The U.S. Food and Drug Admin-

conducted at 20 centers in 11 countries that included 255 patients with ALKpositive tumors. Of these, 163 had received an ALK inhibitor, while 83 where ALK inhibitor–naive at baseline.

Mean age was 53, 62% were never smokers, and 92.7% had adenocarcinoma histology. Median time from initial diagnosis was 18 months. At the time of cutoff, 52% of patients were still on treatment. Median duration of response was 9.7 months.

Most common toxicities were gastrointestinal and included nausea, vomiting, diarrhea, and constipation (mostly grades 1 and 2). Approximately 34% of patients reported decreased appetite.

Ceritinib is the only U.S. Food and

Real Progress Real progress is being made between the drug development community and regulators to address these issues, and the EMA’s recent announcement about Adaptive Licensing confirm their wish to have a realistic dialogue with industry and academia. They make it clear that this will be an iterative process to speed up the whole drug development process, hopefully to achieve the goal of offering more precise treatment to individuals.

If, however, they are able to release new drugs on the market earlier than

Drug Administration–approved therapy for patients with ALK-positive metastatic NSCLC who have had disease progression on or are intolerant to crizotinib. Two phase II trials of ceritinib have been completed, and two phase III trials are ongoing. n

Disclosure: Drs. Dix, Spunt, and Ghi reported no potential conflicts of interest. Dr. Kim is a consultant or advisor for Novartis.

References 1. Dix DB, Gratias EJ, Seibel N, et al: Treatment of stage IV favorable histology Wilms tumor with incomplete lung metastases response after chemotherapy. ASCO Annual Meeting.

Abstract 10001. Presented May 31, 2014.

2. Spunt SL, Million L, Anderson JR, et al: Risk-based treatment for nonrhabdomyosar-

at present, then the medical profession must respond to control off-label uses, and the public must be educated to understand the issues around benefit/risk if clinical trials are smaller and therefore the database less robust.

At ASCO 2014, I did not hear any particularly encouraging comments about the costs of cancer care. In theory, if we use genomics to speed up drug development and improve efficiency by selecting the most appropriate patients for any given medicine, then the costs of that medicine should be reduced. Companies argue that the additional testing required—for example, companion diagnostics—outweigh any such cost reduction. I am not holding my breath, but as I say, to be an oncologist you must remain essentially an optimist.

Take-Home Message In summary, one of the important take-home messages I took from the Annual Meeting was that precision medicine is moving at a really exciting, if challenging, pace. We have to address specific issues about the quality assurance of genomic platforms, and we have to work with licensing authorities to give confidence around smaller pivotal trials. Both the medical profession and the public at large need to be educated about the concept of iterative drug development with the goal of developing more precise medicines in a shorter time frame—but with an altered benefit/risk concept, which will be modified over time. n Disclosure: Dr. Smyth reported no potential conflicts of interest.

coma soft tissue sarcomas (NRSTS) in patients under 30 years of age. ASCO Annual Meeting.

Abstract 10008. Presented May 31, 2014.

3. Ghi MG, Paccagnella A, Ferrari D, et al: Concomitant chemoradiation (CRT) or cetuximab/RT (EET/RT) followed by induction docetaxel/cisplatin/5-fluorouracil (TPF) followed by CT or CET/RT in patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN). ASCO Annual Meeting. Abstract 6004. Presented June 2, 2014.

4. Kim D, Mehra R, Tan DS, et al: Ceratinib in anaplastic lymphoma kinase (ALK)rearranged (ALK+) non-small cell lung cancer (NSCLC). ASCO Annual Meeting. Abstract 8003. Presented June 2, 2014.

ASCOPost.com | AUGUST 15, 2014

PAGE 19

Pan Pacific Lymphoma Conference Hematology

Rational Strategies Are Advancing Combination Lymphoma Therapies

By Susan London

R

ational strategies informed by knowledge of a drug’s molecular mechanisms are helping to bring new combinations of lymphoma therapies to the clinic, according to Anas Younes, MD, Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York.

The Challenge of Too Many Drugs The number of oncology drugs in development has risen exponentially in recent years, Dr. Younes told attendees of the Pan Pacific Lymphoma Conference, held recently in Kohala Coast, Hawaii. “It’s good news that we have more drugs right now, but that also presents a new challenge. How do you choose and how do you prioritize? It is really challenging for drug development,” he maintained.

“Every once in a while we hit the jackpot and the drug looks very good in a phase I trial,” but response rates in these trials are typically on the order of 20% in unselected patients with diverse lymphoma histologies, Dr. Younes said. “This is again a challenge: what do you do with this phase I data? There is clearly a signal, but then what’s the next step? Of course, we tend to prioritize based on unmet need, how much money the company has, and interest in a phase II trial with multiple arms” for different histologies.

Rational Combinations Rationally designed, mechanismbased combination is one strategy for improving the success rate of novel agents, according to Dr. Younes. The U.S. Food and Drug Administration (FDA) has issued some guidance for trial designers intended to improve the likelihood of eventual approval of novel-novel combinations.1 First, they recommend a compelling biological rationale for using the combination: the two agents must block different targets in the same molecular signaling pathway, must block multiple pathways, or must block resistance/ feedback loops. Second, they recommend preclinical or preliminary clinical studies suggesting that the combination provides greater than additive activity or a more durable response than the single agents alone.

An example is the combination of everolimus (Affinitor), an inhibi-

tor of mammalian target of rapamycin (mTOR), and panobinostat, a histone deacetylase (HDAC) inhibitor, which has shown synergy against Hodgkin lymphoma.2 In this case, the combination inhibits negative feedback loops involving the PI3 kinase pathway.

“You can then sort of extend this to a class effect with any PI3 kinase pathway inhibitor, not just an mTOR inhibitor. Other PI3 kinase inhibitors will do the same thing when you combine it with an HDAC inhibitor,” Dr. Younes noted. This combination was taken forward in a phase I trial among patients with diverse types of lymphoma, where it showed a promising 43% response rate, although thrombocytopenia was ­problematic.3

Clues From Clinical Studies “Patient response can give clues on what could be potentially targeted for a combination strategy,” Dr. Younes noted. For example, in patients having residual disease after treatment with a novel agent, the remaining tumor likely harbors a potentially targetable resistance to that agent that can be identified through biopsy. “That will require multiple biopsies of patients who have a good response but fail to

Molecular Assays and New Trial Designs Molecular laboratory testing is also helping identify promising novel drug combinations, but even though largely automated, this approach is still laborious, given the numerous drugs, many possible combinations, and different types of lymphomas, Dr. Younes noted. “This is a tremendous effort of bioinformatics and biostatistical analysis, because these cells lines have differences in genetics, cell of origin, and so forth. So you really don’t expect to see these combina-

That’s why it’s very important to biopsy tumors on treatment, especially if they are not responding well, to see if there is any evidence of activation of a secondary pathway on therapy that can justify a combination strategy.

—Anas Younes, MD

achieve a complete response…. This again is challenging but really needs to be done more frequently in the setting of clinical trials, either at the time of conversion or at the time of mixed response,” he said.

“Baseline biomarkers could not predict that this should be an appropriate combination,” Dr. Younes stressed.

“Only when you biopsy a patient on therapy, you can pick up this secondary pathway activation that could guide future combination therapies. That’s why it’s very important to biopsy tumors on treatment, especially if they are not responding well, to see if there is any evidence of activation of a secondary pathway on therapy that can justify a combination strategy.”

tions to work across the board. You just have to find out where they work preferentially and test this in patients in the clinical setting.”

Those combinations showing greatest synergy are moved into clinical testing. “A new clinical trial design is contributing to this changing landscape,” Dr. Younes noted. The design allows simultaneous screening of multiple novel combinations in a single phase I trial, as has been done in testing an antibody that targets TRAIL receptor 2 both with bortezomib (Velcade) and with vorinostat (Zolinza) in relapsed lymphoma.4 “You start one doublet and while you are waiting for safety, enroll two or three patients in the second doublet,” he explained. “I think this

needs to be done more frequently in the future to make the system more ­efficient.” n Disclosure: Dr. Younes has received research support of clinical trials from Curis, Novartis, GlaxoSmithKline, Janssen, and Pharmacyclics, and has received honoraria from Celgene, Seattle Genetics, Sanofi, Incyte, and Millennium.

References 1. U.S. Food and Drug Administration: Guidance for Industry Codevelopment of Two or More New Investigational Drugs for Use in Combination. June 2013. http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM236669. pdf.

2. Lemoine M, Derenzini E, Buglio D, et al: The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines. Blood 119(17):4017-4025, 2012.

3. Oki Y, Buglio D, Fanale M, et al: Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin Cancer Res 19(24):68826890, 2013.

4. Younes A: Targeted Therapy of Lymphoma. 2007.

More on Lymphoma Watch future issues of The ASCO Post for more reports from the 2014 Pan Pacific Lymhoma Conference, held recently in Kohala Coast, Hawaii. For information about this and future lymphoma conferences, visit https://www.unmc.edu/cce/ panpacificlymphoma.htm

The ASCO Post | AUGUST 15, 2014

PAGE 20

New Orleans Summer Cancer Meeting Breast Cancer

Tackling the Heterogeneity of Triple-Negative Breast Cancer

By Caroline Helwick

T

riple-negative breast cancer is now recognized as a very complex subtype for which one treatment will not be applicable to all, according to Mohammad Jahanzeb, MD, Professor of Clinical Medicine at the University of Miami and Director of the UM Sylvester Deerfield Campus, who gave an update on this challenging tumor at the 9th Annual New Orleans Summer Cancer Meeting.

Triple-negative breast cancer geneexpression subtypes are associated with distinct molecular features. The vast majority are basal-like, but in a recent study that applied the PAM50 signature to the triple-negative intrinsic subtypes, there was no uniform distribution of the basal-like signature.1 This suggests that there are distinctly different groups within triple-negative breast cancer that may respond to different therapies.

“It supports the notion that [triplenegative breast cancer] is not a uniform group of patients,” he said.

In another recent study, Masuda et al2 showed that triple-negative breast cancer subtype was an independent predictor of pathologic complete response to neoadjuvant chemotherapy (P = .022), again suggesting that patients may respond differently to the same neoadjuvant regimen. Within the basal-like-1 subtype, a pathologic complete response was achieved by 52%, compared to just 10% within the luminal androgen receptor subtype.

Finding the Right Treatment “We now accept the heterogeneity of [triple-negative breast cancer], and it’s natural that we think of these groups differently in terms of treatment,” Dr. Jahanzeb said. “Maybe for BRCA-mutated patients we will treat with a platinum, [poly(ADP-ribose) polymerase] (PARP) inhibitor, or stem cell inhibitor, while using androgen blockade for the luminal androgen receptor group, and epidermal growth factor inhibitors or immune therapies for other histologic types,” he added.

“There is not a single approved treatment restricted to [triple-negative breast cancer], and no guidelines that direct us to a gold standard,” he noted.

Triple-negative breast cancer patients can be highly sensitive to cytotoxic chemotherapy with numerous agents, though some surprises do occur, he said. At the ASCO Annual Meeting 2 years ago, Rugo et al report-

ed disappointing results from Cancer and Leukemia Group B (CALGB) 40502, which compared nab-paclitaxel ­(Abraxane)/bevacizumab (Avastin), paclitaxel/bevacizumab, and ixabepilone (Ixempra)/bevacizumab.3 The nabpaclitaxel and paclitaxel arms produced comparable results, while ixabepilone proved inferior.

In an earlier study, the doublet of ixabepilone plus capecitabine was more effective than capecitabine alone in terms of progression-free survival and response rate, but this did not translate into an overall survival benefit.4 When triple-negative breast cancer patients respond to conventional chemotherapy with a pathologic complete response, good outcomes, including long-term survival, can be achieved.

Nonresponse, on the other hand, is associated with poor outcomes.

Platinums are “natural candidates” for triple-negative breast cancer treat-

PARP inhibitors in triple-negative breast cancer, which can overcome the disabling of the homologous combination repair mechanism in patients with BRCA-mutated disease. BRCAdeficient cells should be particularly sensitive to PARP inhibitors, and these drugs may sensitize cancer cells to DNA-damaging agents.

While a phase II study in 130 triplenegative breast cancer patients demonstrated the robust effect of adding a PARP inhibitor to gemcitabine/carboplatin,7 a subsequent phase III trial was negative.5 Nevertheless, there are a number of PARP inhibitors in development.

There are numerous potential targets in triple-negative breast cancer, which are being addressed by inhibitors of receptor tyrosine kinases, PI3K, AKT, mTOR, MEK, and other compounds, but no “home runs” yet. Immunotherapy may also be active in this tumor type. Multiple redundancies and

We now accept the heterogeneity of [triple-negative breast cancer], and it’s natural that we think of these groups differently in terms of treatment.

—Mohammad Jahanzeb, MD

ment, since they are DNA-damaging agents. Triple-negative breast cancer patients already have diminished capacity to repair DNA, especially those with basal-like tumors. Response rates of around 30% can be expected as firstline therapy with a platinum agent, with patients who have BRCA-mutated disease responding better (55%) than those with wild-type disease (26%).5,6 The tnAcity study is comparing nabpaclitaxel/gemcitabine, nab-paclitaxel/ carboplatin, and gemcitabine/carboplatin; the best of the two nab-paclitaxel regimens will be compared to gemcitabine/carboplatin. The TNT/BRCA trial is comparing first-line carboplatin plus second-line docetaxel, vs the opposite sequence, in 400 patients.

“These are not targeted therapy studies, but while we are trying to identify subsets for targeted treatments, we still have to keep treating our patients.

We can generate hypotheses for future studies from these datasets,” he said.

There is also strong rationale for

pathway crosstalk may necessitate combination targeted therapy.

Good Research Platform Since patients who achieve a pathologic complete response have better outcomes, neoadjuvant therapy may be a good research platform in triple-negative breast cancer. “As it stands now, patients who have less than a pathologic complete response should be enrolled on clinical trials,” he said.

In early-stage triple-negative breast cancer, the addition of carboplatin to neoadjuvant chemotherapy produced a pathologic complete response rate of 60% in the phase II CALGB/Alliance 40603 study.8 The rate was 46% for the control arm.

In the I-SPY 2 trial, veliparib plus carboplatin added to standard neoadjuvant chemotherapy improved pathologic complete response rates (52%) over chemotherapy alone (26%).9 The adaptive design of I-SPY 2 offers the chance to eliminate ineffective agents,

“graduate” effective ones to phase III testing, and replace agents over time, he added.

In the phase II PrECOG 0105 trial, 36% of patients achieved a pathologic complete response to a combination regimen of carboplatin, gemcitabine, and iniparib, rising to 47% among ­BRCA-mutated patients and to 56% among triple-negative patients with BRCA mutations.10 Scores from the homologous recombination deficiency assay were significantly higher for responders than nonresponders (whether BRCA-mutated or wild-type), suggesting a potential means of identifying patients for platinum therapy.

A number of studies are underway evaluating treatments (cisplatin and the JAK2 inhibitor ruxolitinib [ Jakafi] are two) in patients with residual disease following neoadjuvant chemotherapy, he added. n Disclosure: Dr. Jahanzeb reported no potential conflicts of interest.

References 1. Mayer IA, Abramson VG, Lehmann BD, et al: New strategies for triple-negative breast cancer—deciphering the heterogeneity. Clin Cancer Res 20:782-790, 2014.

2. Masuda H, Baggerly KA, Wang Y: Differential pathologic complete response rates after neoadjuvant chemotherapy among molecular subtypes of triple-negative breast cancer. 2013 ASCO Annual Meeting. Abstract 1005. Presented June 3, 2013.

3. Rugo HS, Barry WT, Moreno-Aspitia A, et al: CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC).

2012 ASCO Annual Meeting. Abstract CRA1002. Presented June 4, 2012.

4. Rugo HS, Roche H, Thomas E, et al: Ixabepilone plus capecitabine vs capecitabine in patients with triple negative tumors: A pooled analysis of patients from two large phase III clinical studies. Cancer Res 69(2 suppl 1):Abstract 3057, 2009.

5. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. 2011 ASCO Annual Meeting. Abstract 1007. Presented June 6, 2011.

6. Isakoff SJ, Goss PE, Mayer EL, et

ASCOPost.com | AUGUST 15, 2014

PAGE 21

New Orleans Summer Cancer Meeting al: TBCRC009: A multicenter phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p63/p73 as a biomarker of response. Abstract 1025. 2011 ASCO Annual Meeting. Abstract 1025. Presented June 4, 2011.

7. O’Shaughnessy J, Osborne C, Pippen JE, et al: Iniparib plus chemotherapy in

Don’t Miss These Important Reports on Low-Risk Prostate Cancer

metastatic triple-negative breast cancer. N Engl J Med 364:205-214, 2011.

8. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC on pathologic complete response rates in triple-negative breast cancer: CALGB 40603 (Alliance). 2013 San Antonio Breast Can-

cer Symposium. Abstract S5-01. Presented December 13, 2013.

9. Rugo HS, Olopade O, DeMichele A, et al: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the ISPY2 trial. 2013 San B:7.75” Antonio Breast CanT:7” cer Symposium. Abstract S5-02. Presented December 13, 2013. S:6.5”

Now

OAK

10. Telli ML, Jensen KC, Abkevich V, et al: Homologous recombination deficiency score predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and BRCA 1/2 mutation-associated breast cancer. 2012 San Antonio Breast Cancer Symposium.

Abstract PD09-04. Presented December 13, 2012.

Enrolling

A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

Journal Spotlight: Hoffman KE, et al: Physician variation in management of low-risk prostate cancer: A population based cohort study. JAMA Intern Med. July 14, 2014 (early release online), see page 79 in this issue.

MPDL3280A1

(an engineered anti-PDL1 antibody)

Patients with locally advanced or metastatic NSCLC who have failed platinum-containing chemotherapy

N=850

Randomized 1:1

Docetaxel

Primary Endpoint: Plus: Commentary by Anthony L. Zietman, MD, see page 83 Active surveillance in low-risk prostate cancer: When will we pay it more than just lip service?

• Overall survival

• Progression-free survival • Duration of response

• Locally advanced or metastatic NSCLC • • •

For more on prostate cancer, visit ASCOPost.com

• Safety: incidence of adverse events • Overall response rate

Key Inclusion Criteria2:

Commentary by John A. Fracchia, MD, see page 84 Low-risk prostate cancer and principles of active surveillance

Secondary Endpoints:

•

(stage IIIB, stage IV, or recurrent) Representative FFPE tumor specimens Disease progression during or following platinum-containing treatment regimen Measurable disease, defined by RECIST v1.1 ECOG performance status of 0-1

Key Exclusion Criteria2: • History of autoimmune disease • Active hepatitis B or hepatitis C • Prior treatment with docetaxel, CD137 agonists,

anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002476000 Printed in USA.

The ASCO Post | AUGUST 15, 2014

PAGE 22

5th World Congress on Head and Neck Cancer 90 Countries Participate in the 5th World Congress of the International Federation of Head and Neck Oncologic Societies in New York

By Jo Cavallo

A

spectacular parade of nations from 90 countries led by the Emerald Society Pipes and Drums from the New York City Police Department opened the 5th World Congress of the

if detected early. However, millions suffer from delayed diagnosis, inadequate treatment, inappropriate rehabilitation, and palliation,” said Dr. Shah. “We call upon the World

The vast majority of these cancers can be prevented or can be cured if detected early. However, millions suffer from delayed diagnosis, inadequate treatment, inappropriate rehabilitation, and palliation.

—Jatin P. Shah, MD, FACS

International Federation of Head and Neck Oncologic Societies (IFHNOS) on July 27 in New York City. The 4-day event was held in conjunction with the Annual Meeting of the American Head and Neck Society (AHNS) and coincided with the centennial anniversary of the first head and neck cancer surgery service at Memorial Sloan Kettering Cancer Center (MSKCC) in New York.

The conference drew more than 3,100 specialists in head and neck cancer from around the world to share advancements and research in their field and included presentations of over 500 oral papers and 1,300 posters.

Health Organization and the Union for International Cancer Control to also recognize July 27 as World Head and Neck Cancer Day and to join the international movement to increase

awareness and promote education and training in the diagnosis, treatment, outcomes, and research in head and neck cancer.”

Political and Film Luminaries Address the World Congress The opening session of the 5th World Congress included a video presentation by former President Bill Clinton, who said the event marked an important milestone of 100 years of dedicated research and advocacy in head and neck health. “Every year, nearly 350,000 lives are lost to head and neck cancer and almost twice that amount in new cases are diagnosed,” said President Clinton.

President Clinton’s remarks were followed by a speech by Academy Award-winning actor and cancer survivor Michael Douglas (see “Michael Douglas Speaks Out About Having

Head and Neck Cancer a Global Burden Declaring July 27 World Head and Neck Cancer Day, Jatin P. Shah, MD, FACS, Chief, Head and Neck Service at MSKCC, Congress Chairman of ­IFHNOS, and Past President of AHNS, spoke about the need to reduce the global burden of head and neck squamous cell carcinoma.

“The vast majority of these cancers can be prevented or can be cured

Fig. 1: Parade of flags is led by the Emerald Society Pipes and Drums from the New York City Police Department. Photo courtesy of the American Head and Neck Society.

a Life-Threatening Cancer,” on page 123). Diagnosed with stage IV oropharyngeal cancer in 2010, Mr. Douglas spoke about his personal experience with the disease, the delay in getting an accurate diagnosis, and the importance of scientific research to further treatment advances in the cancer.

Public Knows Little About Head and Neck Cancers According to a study1 published in the Journal of the American Medical Association Otolaryngology–Head and Neck Surgery, few Americans know about the symptoms and risk factors associated with head and neck cancer and only about one in eight is able to identify human papillomavirus (HPV) infection as a risk factor for mouth and throat cancer. According to Patrick Gullane, MD, Chair of Otolaryngology-Head and Neck Surgery at the University of Toronto, who gave the Hayes Martin Lecture at the 5th World Congress, the incidence of head and neck cancer from HPV infection increased 225% between 1988 and 2004. Educating the public about HPV-related cancer and the importance of HPV vaccines to protect against head and neck cancer will reduce new cases of the disease.

“The future is in prevention,” said Dr. Gullane.

For additional information on the 5th World Congress, visit www. ahns2014.org. For dates of upcoming meetings of the American Head & Neck Society, visit http://www.ahns. info/meetings. n Reference 1. Luryi AL, Yarbrough WG, Niccolai LM, et al: Public awareness of head and neck cancers: A cross-sectional survey. JAMA Otolaryngol Head Neck Surg 140:639-646, 2014.

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PAGE 23

MASCC/ISOO International Symposium Mucositis Remains a Challenge in Head and Neck Cancer

By Caroline Helwick

C

hemoradiotherapy for head and neck cancer requires intensive supportive care by a knowledgeable and proactive multidisciplinary team, according to Avraham Eisbruch, MD, Professor of Radiation Oncology at the University of Michigan, Ann Arbor.

“Aggressive chemoradiotherapy has improved the cure rates of head and neck cancer, but these improvements have been associated with increased rates and severity of acute and late treatment side effects. Adequate supportive care can reduce these and improve the therapeutic index,” said Dr. Eisbruch, who conducts research in the area of mucositis.

Severe mucositis, late fibrosis and dysphagia are not only troublesome to the patient but are the major factors preventing dose escalation for poor-prognosis patients, he noted. Interventions that may reduce the risk or manage mucositis were discussed by Dr. Eisbruch at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer, held recently in Miami.

Mucosal Protectors The pharmacologic radiation protector amifostine binds to free radicals produced by radiation and interferes with their oxygen binding, which is essential to their damage of the DNA. While the drug’s mechanism is good in theory, issues related to amifostine include a short half-life (which requires administration before each treatment), its cost, and its potential for side effects. Furthermore, while amifostine has shown benefit in mice with head and neck or lung tumors, value has not been proven in these settings for humans, Dr. Eisbruch noted.

Antiviral, antibacterial, and mucosal coating agents are often used without evidence. Based on multiple—mostly conflicting—studies, acyclovir, nystatin, fluconazole, chlorhexidine, and sucralfate cannot be recommended to reduce mucositis risk, he said.

On the other hand, data support the use of keratinocyte growth factor (palifermin [Kepivance]), which stimulates the differentiation of mucosal cells and has proven effective in reducing mucositis after high-dose chemotherapy and bone marrow transplantation. That said, although palifermin significantly reduced severe mucositis and its duration in randomized trials in

head and neck cancer, the compound had no effect on narcotic use, patientreported pain, and chemoradiotherapy compliance.1,2 “We may be using something here that helps the physician but not the patient,” he commented.

Newer Radiosensitizers Tumors expressing the epidermal growth factor receptor (EGFR) are more resistant to radiotherapy. Drugs that increase the radiosensitivity of EGFR-positive tumor cells may enhance radiotherapy’s efficacy. Cetuximab (Erbitux) given concurrently with radiotherapy improves tumor control and is considered to be tumor-specific, improving the therapeutic index compared with radiosensitization using che-

Reduced Treatment Intensity

Supportive Measures

Another strategy is to reduce the radiation treatment intensity in patients with good prognosis, such as those with human papillomavirus (HPV)-positive tumors. The Eastern Cooperative Oncology Group (ECOG) 1308 trial recently found that if a complete response is achieved with induction chemotherapy, intensity-modulated radiotherapy (IMRT) with 54 Gy delivered concurrently with cetuximab achieves local control in 95% of HPV-positive patients.4 A comparison of IMRT (mean oral dose, 27 Gy) vs conventional radiotherapy (mean, 43 Gy) found significantly less mucositis grade 3 or higher at virtually all time points, with IMRT.5 Dr. Eisbruch also advocates meticu-

Intensive supportive measures in the areas of nutrition and hydration are important to combat dysphagia, weight loss, thick secretions, and so forth. Dr. Eisbruch advocates the use of acetylcysteine for mucus once patients complete radiotherapy. Zinc sulfate as an approach to taste abnormalities was shown effective in uncontrolled trials, but not in more rigorous studies.

Enteral feeding is necessary for some patients, with caveats, he said. It is debated whether feeding tubes are best used prophylactically or when weight loss is ≥ 10%. Two randomized studies found that prophylactic percutaneous endoscopic gastrostomy resulted in less weight loss, improved patient-reported quality of life, and less long-term dysphagia.6,7 “However,” he added, “the benefit may come at the expense of longer dependence on [percutaneous endoscopic gastrostomy] and increased late esophageal strictures requiring dilatation. Feeding tubes also reduce patient motivation to swallow food, and a complete lack of swallowing increases the rate of strictures.”

Dr. Eisbruch’s policy is as follows: • No prophylactic percutaneous endoscopic gastrostomy unless the patient lost weight or was cachectic preradiotherapy, or is found on videofluoroscopy to aspirate food, as determined by a speech/swallow therapist • Close monitoring by a nutritionist • Insertion of a feeding tube if the patient cannot maintain weight • With enterally fed patients, instruction on eating orally as much as possible • Removal of feeding tube in approximately 2 months In conclusion, he predicted, “The reduction of acute and long-term sequellae of chemoradiotherapy can be further achieved by finding tumor-selective radiosensitizers and tissue-selective radioprotectors, and by customizing treatment intensity to the prognosis of the individual patient.” n

The reduction of acute and longterm sequellae of chemoradiotherapy can be further achieved by finding tumor-selective radiosensitizers and tissue-selective radioprotectors, and by customizing treatment intensity to the prognosis of the individual patient.

—Avraham Eisbruch, MD

motherapy. However, Dr. Eisbruch cautioned that some studies have shown toxicity, including mucositis, to be increased with concurrent cetuximab and radiotherapy.

“This is also my clinical impression.

Some patients develop severe mucositis while others do not, so be careful with this,” he advised.

To better understand the effects of an EGFR inhibitor on mucosal cells in head and neck cancer, Dr. Eisbruch and his team obtained pre- and posttreatment tissue samples and showed that erlotinib inhibited the activation of EGFR and reduced EGFR expression in tumors, but in normal tissue there was substantial heterogeneity in EGFR inhibition.3 “The EGFR therapeutic index (EGFR inhibition in tumor vs normal mucosal cells) seemed to vary greatly among patients,” he said. It may be prudent, therefore, to test the therapeutic index in each patient individually before proceeding with a full course of radiotherapy with cetuximab, he added.

lous prophylactic dental care and protection.

Reducing Mucositis-Related Pain It may be easier to address the pain related to mucositis, he said. These include topical tetracaine, nonsteroidal anti-inflammatory drugs, narcotics, and the long-acting opioid, fentanyl transdermal patch (Duragesic). Dr. Eisbruch commented on the safe use of narcotics.

“The fentanyl patch reduces the need for immediate-release opiates and provides lengthier freedom from pain. Start with the lowest dose to assess response,” he advised. “But remember that fentanyl is more fat-soluble than morphine, so patients with cachexia or significant weight loss have a reduced volume of distribution of fentanyl and are at higher risk of toxicity. Nystatin and fluconazole also reduce the metabolism of narcotics and elevate their blood levels.”

Tricyclic antidepressants reduce patient-reported pain without affecting the severity of mucositis, he added.

Disclosure: Dr. Eisbruch reported no potential conflicts of interest.

References 1. Le QT, Kim HE, Schneider CJ, et al: Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally continued on page 26

MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects, with the most frequent being thrombocytopenia and anemia.

Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary

Jakafi is a registered trademark of Incyte Corporation. © 2014, Incyte Corporation. All rights reserved. RUX-1329a 01/14

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Tuberculosis (TB) has been reported; attention should be given to the possibility of latent or active TB. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis.

If PML is suspected, stop Jakafi and evaluate

The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

50

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

40

Patients (%)

50

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

0

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus-associated kinase.

• Advise patients about early signs and symptoms of herpes zoster and to seek early treatment • The three most frequent non‐hematologic adverse reactions were bruising, dizziness and headache • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast‐feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information.

Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al.

N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

The ASCO Post | AUGUST 15, 2014

PAGE 26

MASCC/ISOO International Symposium Mucositis in Head/Neck Cancer continued from page 23

advanced head and neck cancer: A randomized, placebo-controlled study. J Clin Oncol 29:2808-2814, 2011.

2. Henke M, Alfonsi M, Foa P, et al: Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: A

randomized, placebo-controlled trial. J Clin Oncol 29:2815-2820, 2011.

3. Tsien CI, Nyati MK, Ahsan A, et al: Effect of erlotinib on epidermal growth factor receptor and downstream signaling in oral cavity squamous cell carcinoma. Head Neck 35:1323-1330, 2013.

4. Cmelak A, Shuli L, Shanthi M, et al: E1308: Reduced-dose IMRT in human

papilloma virus-associated resectable oropharyngeal squamous carcinomas after clinical complete response to induction chemotherapy. ASCO Annual Meeting.

Abstract LBA6006. Presented June 2, 2014.

5. Vergeer MR, Doornaert PA, Rietveld DH, et al: Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: Re-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transAdministration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pre- with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations.

Active serious infections should have resolved before starting therapy with Jakafi. Tuberculosis has been reported in patients receiving Jakafi for myelofibrosis. Attention should be given to the possibility of latent or DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib active tuberculosis. Observe patients receiving Jakafi for signs and symptoms of infection and initiate increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminif suspected [see Adverse Reactions]. istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under There was an 8% and 27% increase in the C and AUC of ruxolitinib, respectively, with Jakafi administration max widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacomost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses however, it has not been established whether discontinuation of therapy contributed to the clinical course in of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratothese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanStudy During Randomized Treatment tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for Jakafi Placebo fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest (N=155) (N=151) dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of d myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differUrinary Tract Infections 9.0 0 0 5.3 0.7 0.7 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Weight Gaine 7.1 0.6 0 1.3 0.7 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2013 Incyte Corporation. All rights reserved.

Issued: November 2013 RUX-1326 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

sults of a nonrandomized prospective study using a standardized follow-up program. Int J Radiat Oncol Biol Phys 74:1-8, 2009.

6. Salas S, Baumstarck-Barrau K, Alfonsi M, et al: Impact of the prophylactic gastrostomy for unresectable squamous cell head and neck carcinomas treated with radio-chemotherapy on quality of life: Prospective randomized trial.

Radiother Oncol 93:503-509, 2009.

7. Silander E, Nyman J, Bove M, et al: Impact of prophylactic percutaneous endoscopic gastrostomy on malnutrition and quality of life in patients with head and neck cancer: A randomized study. Head Neck 34:1-9, 2012.

MASCC Awards Honorary Lifetime Membership

T

he Multinational Association for Supportive Care in Cancer ­(MASCC) has awarded Honorary Lifetime Membership status to Hans-Jürg Senn, MD, based on his commitment, vision, and extraordinary service to the Society and its publication Supportive Care in Cancer, according to Society News, the MASCC newsletter. Along with Jean Klastersky and ­ Steven Schimpff, Professor Senn founded MASCC 22 years ago. He served as the

Hans-Jürg Senn, MD

first Editor-in-Chief of Supportive Care in Cancer for 17 years.

MASCC has noted that Professor Senn’s leadership has been fundamental to advancing this supportive care society and that his contributions as a clinician researcher have improved the lives of cancer patients everywhere.

Professor Senn has served as Scientific Director of Tumor and Breast Center ZeTuP, St.Gallen, Switzerland since 1998. He is emerited Professor of Internal Medicine/Oncology at the University of Basel, Switzerland and Founding Chairman of St. Gallen International Oncology Conferences (since 1982).

Professor Senn is also the Founding Member of Swiss Society of Medical Oncology and President of Cancer Research Foundation of Eastern ­Switzerland. n

ASCOPost.com | AUGUST 15, 2014

PAGE 27

MASCC/ISOO International Symposium NEPA for Chemotherapy-Induced Nausea and Vomiting: Key Endpoints and Additional Analyses Show Strong Efficacy

By Caroline Helwick

F

or the prevention of chemotherapy-induced nausea and vomiting, NEPA, a novel combination of a neurokinin-1 (NK1) receptor antagonist and the 5-HT3 receptor antagonist palonosetron (Aloxi), has been studied in three pivotal trials that were recently published in the Annals of Oncology.1-3 Further analyses of these data were presented at the Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology (­ MASCC/ISOO) International Symposium on Supportive Care in Cancer.

NEPA is an oral fixed-dose combina-

chemotherapy cycles, controls not only emesis but also nausea, is protective in patients receiving carboplatin-based chemotherapy (for whom guidelines are not clear), and is not affected by cisplatin’s chemotherapy partner.

Dr. Aapro reported the key results from the registration studies in chemotherapy-naive patients (Table 1). The primary endpoint was complete response, which was defined as no emesis and no use of rescue medications.

In the phase II HEC [highly emetogenic chemotherapy] study and the phase III AC [anthracycline/cyclophos-

The development of NEPA is an opportunity to overcome some barriers interfering with guideline adherence by targeting two critical pathways involved in emesis with a single oral dose.

—Matti S. Aapro, MD

tion containing 300 mg of netupitant (a highly selective NK1 receptor antagonist) and 0.50 mg of palonosetron (a pharmacologically and clinically distinct 5-HT3 receptor antagonist). The combination targets dual antiemetic pathways and thus provides more complete control than 5-HT3 receptor antagonists alone.

The single-capsule oral administration of the combination may improve adherence to the guidelines for prevention of chemotherapy-induced nausea and vomiting, according to Matti S. Aapro, MD, of the Multidisciplinary Oncology Institute, Clinique de Genolier, Switzerland.

“The development of NEPA is an opportunity to overcome some barriers interfering with guideline adherence by targeting two critical pathways involved in emesis with a single oral dose,” Dr. Aapro said. “It further simplifies treatment because of the long effect of palonosetron, which allows us to not use corticosteroids on days 2 and 3.”

Key Findings At the MASCC/ISOO meeting, held recently in Miami Beach, Dr. Aapro and other investigators reported that NEPA is effective across multiple

phamide] MEC [moderately emetogenic chemotherapy] study, the difference between NEPA/dexamethasone and oral palonosetron/dexamethasone was statistically significant (P < .01).

Study Details The phase III, multinational, randomized, double-blind study enrolled 1,455 patients, of whom 1,286 participated in the multiple-cycle extension of the study. NEPA was given to 635 patients, while 651 were treated with oral palonosetron, for a total of 5,969 total chemotherapy cycles.

Dr. Aapro reported that NEPA exerted continued benefit throughout several cycles of chemotherapy. “NEPA showed superior 0- to 120-hour complete response rates compared with oral palonosetron over all cycles. All the differences were statistically significant.… We saw very encouraging persistence of the protection for patients overall,” he said.

At cycle 4, no emesis was reported by 87% of the NEPA arm vs 79% of the control arm (P = .0003). In addition, no significant nausea was reported by 80% and 75%, respectively (P = .042). No significant nausea was defined as maximum < 25 mm on the 100-mm visual analog scale.

NEPA for Chemotherapy-Induced Nausea and Vomiting ■■ Key findings from three pivotal trials of fixed-dose NEPA (netupitant plus palonosetron) showed the novel combination agent to be more effective than oral palonosetron alone in controlling emesis in patients receiving moderately and highly emetogenic chemotherapy.

■■ NEPA is consistently effective across multiple cycles of chemotherapy.

■■ NEPA is effective in preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin, and regardless of which agent is partnered with cisplatin.

“Treatment-related adverse events were quite rare (4% at cycle 4), with no differences between the arms and no indication of an increase in neutropenia.

This is very important, as many patients and physicians ask about potential interactions of NEPA with chemotherapy,” he added.

“We believe a single fixed-dose of NEPA plus dexamethasone on day 1 of chemotherapy offers the potential for guideline-based prophylaxis with a convenient single-dose treatment,” Dr. Aapro concluded.

Nausea Control “We have made tremendous progress in [chemotherapy-induced nausea and vomiting] prevention over 30 years, yet challenges remain. Nausea control, especially, is clearly suboptimal,” said Lee S. Schwartzberg, MD, FACP, of the West Clinic, Memphis.

Debate continues as to whether NK1 receptor antagonists enhance nausea control. The addition of these agents to 5-HT3 receptor antagonists plus dexa-

Lee S. Schwartzberg, MD, FACP

methasone has not shown consistent superiority over 5-HT3 receptor antagonists alone in terms of nausea control; however, the combination has clearly proved its worth in controlling emesis.

The study presented at MASCC by Dr. Schwartzberg evaluated whether NEPA offers better control of nausea than single-agent oral palonosetron.

“We found that the addition of the NK1 receptor antagonist netupitant significantly improved the overall prevention of nausea over palonosetron alone in patients receiving cisplatin or AC,” he reported. “As expected, the absolute benefit was smaller for the prevention of nausea than it was for the prevention of vomiting.”

The analysis is from the multinational, randomized, double-blind registration trials of patients who received cisplatin-based highly emetogenic chemotherapy, which was study 1 (n = 271), and those who received moderately emetogenic chemotherapy with AC, which was study 2 (n = 1,449).

Both compared NEPA to oral palonosetron; patients also received oral dexamethasone (12 mg with NEPA, 20 mg with palonesetron) on days 1 to 4 in study 1 and on day 1 in study 2.

In the primary analysis, rates of “no emesis” were significantly higher in the NEPA arms of both studies for the acute phase, delayed phase, and overall time period. For the current analysis, the proportion of patients reporting no significant nausea was significantly higher, as well, in the NEPA arms.

“With NEPA, we saw a statistically significant improvement in the proportion of patients who had nausea control overall and in the acute and delayed phases,” Dr. Schwartzberg reported.

About 90% of patients receiving NEPA in study 1 (highly emetogenic chemotherapy recipients) reported no significant nausea, compared to 79% with oral palonosetron (P = .021). The odds ratios favoring NEPA ranged from approximately 2.2 (delayed phase and overall) to 4.7 (acute phase).

Mean visual analog scale score (on a 100-mm scale) was also significantly lower in the NEPA arm for the acute, continued on page 28

The ASCO Post | AUGUST 15, 2014

PAGE 28

MASCC/ISOO International Symposium Novel Combination for Nausea and Vomiting continued from page 27

delayed, and overall analyses: 3.0, 7.5, and 8.0, respectively, compared to 6.5, 15.2, and 16.9 for oral palonosetron.

In study 2 (the AC moderately emetogenic chemotherapy population), no differences were observed in the acute phase, but NEPA provided a significant improvement in nausea control in the delayed phase (77% vs 71%, P = .014) and overall analysis (75% vs 69%, P = .020). The numerical improvement in percentage of patients with no significant nausea was somewhat less— approximately 7% overall—and mean visual analog scale scores, which were higher in study 2 than study 1, were numerically lower with NEPA. “The beneficial effect on nausea was greater with cisplatin than for AC,” Dr. Schwartzberg pointed out.

On the Functional Living Index– Emesis questionnaire, significantly more patients on NEPA reported no impact on daily living for both the vomiting and nausea domains, he added.

Use With Carboplatin Karin Jordan, MD, of the University of Halle, Germany, reported on the use of NEPA plus dexamethasone in patients receiving moderately emetogenic chemotherapy, noting that clinical guidelines for its use in this setting are not consistent.

Karin Jordan, MD

“NK1 receptor antagonists are a standard of care in the treatment of patients with [highly emetogenic chemotherapy], but in the [moderately emetogenic chemotherapy] setting their use is not presently recommended by ­MASCC,” she indicated. “With ASCO, it’s kind of a ‘may consider’ situation.

The National Comprehensive Cancer Network guidelines recommend them in selected patients.”

Dr. Jordan and colleagues performed a post hoc analysis from a prospective phase III trial of 413 patients to assess NEPA’s effectiveness in the subset of 140 patients receiving carboplatin. The endpoint during the overall phase (0– 120 h) was the proportion of patients

with no emesis.

“High rates of ‘no emesis’ were seen following a single dose of NEPA plus dexamethasone in the carboplatin subset, and the antiemetic efficacy was maintained over the cycles,” she reported.

The proportions of patients reporting no emesis were 83% in cycle 1, 91% in cycle 2, 92% in cycle 3, and 95% in cycle 4. The benefit with carboplatin was similar to that seen with cisplatin in other studies; it is more than 10% greater than the historical control rate of 70% and at least as good as what has been observed with the aprepitant three-drug regimen in both the cisplatin and carboplatin settings. Dr. Jordan cautioned, however, that while this is the largest prospective cohort study to evaluate the contribution of NK1 receptor antagonists in patients receiving carboplatin, it is a post hoc analysis and the data are descriptive only.

Nevertheless, she suggested, “Given the consistent evidence in almost 300 patients treated with NEPA/dexamethasone and previously with the aprepitant triplet, guidelines should consider the addition of an NK1 receptor antagonist in patients receiving carboplatin.”

Impact of Cisplatin’s Chemotherapy Partner Paul J. Hesketh, MD, of Lahey Hospital & Medical Center, Burlington, Massachusetts, reported that NEPA was equally effective whether cisplatin was partnered with an agent of lower or higher emetogenic potential.

Cisplatin is the most emetogenic of the commonly used agents, and data suggest that whatever chemotherapy is added to cisplatin can affect antiemetic control. For example, the triplet of aprepitant, ondansetron, and dexamethasone proved less efficacious when anthracyclines and/or cyclophosphamide were added to cisplatin.

Dr. Hesketh, therefore, led a post hoc analysis of the phase II dose-ranging trial to further explore this question in 265 patients who received cisplatin plus an agent of lower emetogenic potential (most often fluorouracil, etoposide, or none) generally received by patients

Paul J. Hesketh, MD

Table 1: Complete Response Rates Observed During Cycle 1 (0–120 h) in Registration Studies of NEPA

Study Phase II dose-ranging HEC study Phase III AC MEC study Phase III multiple cycle non-AC MEC + HEC study

NEPA + dexamethasone

Oral palonosetron + dexamethasone

Aprepitant + 5-HT3 receptor antagonist + dexamethasonea

90% (n = 136)

77% (n = 136)

87% (n = 134)

74% (n = 724)

67% (n = 725)

NA

81% (n = 309)

NA

76% (n = 104)

a Aprepitant-containing regimen was exploratory only, with no formal efficacy comparison vs study arms; data from the registration trials.

AC = anthracycline/cyclophosphamide; HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy; NA = not available.

Courtesy of Matti S. Aapro, MD.

with lung, respiratory tract, and head and neck cancers, and 142 patients receiving cisplatin plus an agent of higher risk (cyclophosphamide, doxorubicin), typically ovarian and breast cancer ­patients.

The overall response rate was 89% for the lower-risk group and 87% for the higher-risk group. The pattern was repeated across all phases and for nausea control as well, he said.

“In patients receiving cisplatin-based chemotherapy, NEPA plus dexamethasone resulted in very good [chemotherapy-induced nausea and vomiting] control that was comparable between the two risk categories.… This was admittedly a post hoc analysis, but to me the bottom line is that regardless of the chemotherapy agent used in combination with cisplatin, emetic control will not deteriorate as a consequence of adding a highly emetogenic agent to cisplatin,” Dr. Hesketh concluded. n

Disclosure: Dr. Aapro has received study grants and has been a consultant or speaker for Helsinn, Eisai, Merck, Roche, and Janssen. Dr. Schwartzberg reported no potential conflicts of interest. Dr. Jordan is on the speakers bureau and advisory board of Helsinn and Merck. Dr. Hesketh is a noncompensated consultant for Helsinn.

References 1. Aapro M, Rugo H, Rossi G, et al: A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 25:1328-1333, 2014.

2. Hesketh PJ, Rossi G, Rizzi G, et al: Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced

nausea and vomiting following highly emetogenic chemotherapy: A randomized dose-ranging pivotal study. Ann Oncol 25:1340-1346, 2014.

3. Gralla R, Bosnjak S, Hontsa A, et al: A phase 3 study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol 251:13281333, 2014.

4. Aapro M, Karthaus M, Schwartzberg L, et al: Multiple, cycle CINV control and safety of NEPA, a capsule containing netupitant and palonosetron administered once per cycle of moderately emetogenic chemotherapy. MASCC/ISOO International Symposium on Supportive Care in Cancer.

Abstract 64. Presented June 26, 2014.

5. Schwartzberg L, Aapro M, Hesketh PJ, et al: Do NK1 receptor antagonists contribute to nausea control? Evaluation of the novel NEPA fixed-dose combination of NK1 RA + 5-HT3 RA from pivotal trials.

MASCC/ISOO International Symposium on Supportive Care in Cancer. Abstract 81.

Presented June 26, 2014.

6. Jordan K, Gralla R, Rossi G, et al: Is the addition of an NK1 receptor antagonist beneficial in patients receiving carboplatin?

Supplementary data with NEPA, a fixeddose combination of netupitant and palonosetron. MASCC/ISOO International Symposium on Supportive Care in Cancer Abstract 82.

7. Hesketh PJ, Gralla RJ, Rossi G, et al: NEPA, a fixed-dose antiemetic combination of netupitant and palonosetron: Results of effectiveness in 407 patients receiving cisplatin plus chemotherapy of various emetic risk. MASCC/ISOO International Symposium on Supportive Care in Cancer Abstract 80. Presented June 26, 2014.

ASCOPost.com | AUGUST 15, 2014

PAGE 29

MASCC/ISOO International Symposium Supportive Care in Pediatric Patients With Cancer: Recent Developments in Treating Febrile Neutropenia

By Meg Barbor

R

ecent developments in supportive care for children with cancer can be broken down into three categories: doing the simple things well, applying evidence-based medicine to daily practice, and extending the benefits to everyone, according to Scott C. Howard, MD, of St. Jude Children’s Research Hospital, Memphis.

At the 2014 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer, Dr. Howard applied these principles to the management of febrile neutropenia in pediatric cancer patients.1

From Principle to Practice “We know exactly what to do, yet there is often a gap in how we do it,” said Dr. Howard, a specialist in pediatric hematology-oncology. “For example, the number of lives saved by hand-washing are far more than almost anything we could imagine,” he said. However, in study after study, following the implementation of hand-washing programs, hand-washing practices improve only temporarily.

Within the realm of applying evidence-based medicine to daily practice, Dr. Howard outlined four important categories. First, it is important to establish a solid evidence base. “We know how to treat febrile neutropenia,” he said. Evidence guides the clinician in choice of antibiotics for patients with fever.

Secondly, there is the issue of education. “Just because we know what to do doesn’t mean we always do it,” explained Dr. Howard. New doctors, nurses, and pharmacists are constantly

coming on board in need of continuous education. Finally, there are the matters of application and evaluation.

Reducing Morbidity and Mortality According to Dr. Howard, the best way to reduce morbidity and mortality in patients with febrile neutropenia is by more rapid administration of the first dose of antibiotic.

The patient with 4,000 bacteria per microliter of blood typically presents with a fever. Because some bacteria double every half-hour, in 2 more hours, this patient will have 16 times the concentration of bacteria and will develop sepsis. Two hours after sepsis, if left untreated, the patient will go into septic shock, and 2 hours after septic shock the patient will die.

pital. “We tell patients we want a phone call within 30 seconds and we want you there within 30 minutes,” said Dr. Howard. At St. Jude, if a patient calls ahead, the antibiotic is already prescribed and prepared when the patient arrives, he explained.

However, particularly in lower- and middle-income countries, a number of factors contribute to why children with febrile neutropenia never make it to the hospital. First, many individuals do not believe it is truly an emergency. “Some parents say, ‘The last time he got a fever we came 2 days later and he’s not dead.

Now you’re telling us it’s an emergency?’” he explained.

“Since 10% to 20% of fevers are caused by bacteremia, four out of five times the patient won’t die; it’s not an emergency,” he continued. The prob-

Instead of competing on who can get the paper out first, let’s put the patients first. If we work together and encourage each other, we’re that much more likely to succeed.

—Scott C. Howard, MD

“We can do an ICU intervention,” explained Dr. Howard, “or we can catch the patient 6 hours earlier and not need an ICU intervention after all.” Such patients should be treated almost immediately, he stressed.

Causes of Treatment Failure In order to effectively manage febrile neutropenia in pediatric cancer patients, the patient must get to a hos-

lem lies in the inability to know upfront whether the fever is caused by bacteremia or something else (usually viral infections), he added.

Other reasons patients never make it to the hospital include conflicts with issues they deem as more important, as well as logistical issues, including distance to the hospital. “If it takes 12 hours to get to the hospital and you have bacteremia, that’s at least 6 hours

too long,” Dr. Howard noted.

Sometimes, risks of travel exceed the risks of delayed management of febrile neutropenia. Toxic death from infection is a much more dire concern in lower- and middle-income countries than in high-income countries, he reiterated.

Extending Benefits to Everyone According to Dr. Howard, extending the benefits to patients everywhere entails learning from mistakes and publishing the results, ensuring continuous quality improvement, and working together.

“We have people at this meeting from all over where the issues are similar, and I suspect that decision time, transport time, and antibiotic time are the three key components that should be measured in all countries—high income, middle income, and low income,” he said.

“Working together should be common practice and should involve recognizing and encouraging our colleagues, Dr. Howard suggested. “Instead of competing on who can get the paper out first, let’s put the patients first,” he said.

“If we work together and encourage each other, we’re that much more likely to succeed.” n

Disclosure: Dr. Howard reported no potential conflicts of interest.

Reference 1. Howard S: Supportive cancer care in children: Recent developments. Special Parallel Session: Global Development of Supportive Care. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 27, 2014.

Visit The ASCO Post website at ASCOPost.com

Does your ovarian cancer patient have a BRCA mutation?

Only testing will tell.

Screening based on family history or age misses a substantial number of ovarian cancer patients with a BRCA mutation.

Approximately 15% of women with ovarian cancer have a deleterious BRCA mutation.1 Testing for a BRCA mutation provides powerful information for patients with ovarian cancer, their families, and their physicians. Yet most patients with ovarian cancer are not tested, leaving their BRCA status unknown.

positive ovarian cancer patients are aged 50 or older, and about one-third are aged 60 or older.8,9 BRCAm Ovarian Cancer Patients by Age at Diagnosis8

NCCN, SGO, and ASCO guidelines recommend that all patients with epithelial ovarian cancer be considered for BRCA testing, regardless of family history, age, or ethnicity.2-4

39% 29

%

The Society of Gynecologic Oncology encourages the medical community to offer hereditary cancer risk assessment to all women with ovarian, fallopian tube and peritoneal carcinoma.”

- SGO Clinical Practice Statement, March 2014 3 In clinical practice, however, the decision to recommend genetic testing is too often based on certain patient and disease characteristics.5 Despite guidelines, every year less than a quarter of patients with ovarian cancer are tested for a BRCA1/2 mutation.6,7

Family history and age at diagnosis are poor predictors of BRCA status in ovarian cancer patients. 8,9 Nearly half of patients with ovarian cancer and a BRCA1/2 mutation have no significant family history of ovarian or breast cancer. In addition, more than two-thirds of BRCABRCAm Ovarian Cancer Patients by Family History Status8

53%

47% No relevant family history Relevant family history

32%

71%

of patients with ovarian cancer and a BRCA mutation are aged 50 or older at diagnosis.8 <50 50-59 >60

Moreover, the prevalence of a BRCA mutation has been shown to be remarkably similar regardless of ethnicity, yet BRCA testing is not as common in women of non-European descent.10 Even sophisticated predictive models, which attempt to use a number of factors (including family history and age) to determine who should be tested for a BRCA mutation, fail to identify a significant proportion of patients who carry a BRCA mutation.11,12

Ovarian cancer cells with a BRCA mutation have DNA repair deficiencies and therefore are particularly sensitive to DNA-damaging agents.13 Germline BRCA mutations are associated with improved survival and generally favorable response to platinum-based chemotherapy in ovarian cancer.9,13 Additionally, there is evidence to suggest that BRCA expression is predictive of a clinical benefit for the use of IP-administered chemotherapy compared with IV-administered chemotherapy.14

Testing ALL of your ovarian cancer patients for their BRCA status provides powerful information for you, your patient, and her family.

REFERENCES: 1. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 4;2013. 3. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. March 2014. http://www.sgo.org/clinical-practice/ guidelines/genetic-testing-for-ovarian-cancer/. Accessed June 13, 2014. 4. Lu KH, Wood ME, Daniels M, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 5. Norquist BM, Pennington KP, Agnew KW, et al. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing. Gynecol Oncol. 2013;128(3):483-487. 6. Myriad Genetics. http://www.myriadpro.com. 7. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities.

Obstet Gynecol. 2010;115(5):945-952. 8. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 9. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. 10. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 11. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 12. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 13. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 14. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237. ©2014 AstraZeneca. All Rights Reserved. 3011508 Last Updated 07/14

The ASCO Post | AUGUST 15, 2014

PAGE 32

Journal Spotlight Head and Neck Cancer

No Overall Survival Improvement but Some Palliative Benefit With Gefitinib in Esophageal Cancer Progressing Postchemotherapy

By Matthew Stenger

I

n what may be the first randomized trial of systemic therapy in this setting, Susan J. Dutton, MSc, of University of Oxford, United Kingdom, and colleagues evaluated the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib vs placebo in patients with esophageal cancer progressing after chemotherapy.1 As reported in the Lancet Oncology, the COG trial showed no survival benefit with gefitinib but provided evidence of palliative benefit of the drug in odynophagia and other patient-reported outcomes.

EGFR is expressed in most esophageal cancers, and increased EGFR copy number is found in 5% to 10% and is more common in esophageal cancer than in other gastrointestinal cancers.

Both of these characteristics are associated with poor survival in esophageal cancer. Further, activating EGFR mutations have been identified in esophageal cancer.

Phase II trials of EGFR tyrosine kinase inhibitors have shown objective responses in approximately 8% of patients including those with adenocarcinoma and squamous cell carcinoma.

In contrast, no responses to such treatment have been observed in gastric cancer. These observations formed the rationale for the phase III COG trial.

Study Details In this double-blind trial, 449 adults at 48 UK centers with advanced esophageal cancer or type I/II Siewert junctional tumors and histologically confirmed squamous cell carcinoma or adenocarcinoma who had progressed after chemotherapy were randomly

treatment. The primary endpoint was overall survival in the intention-to-treat population.

The gefitinib and placebo groups were generally balanced for age (median, 65 years in both), sex (82% and 84% men), original diagnosis (adenocarcinoma in 77% and 75%, squamous cell carcinoma in 22% and 25%), disease site (esophageal in 76% and 80%,

Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients.

—Susan J. Dutton, MSc, and colleagues

type I junctional (distal part of esophagus) in 12% and 9%, type II junctional (adenocarcinoma of the real cardia, within 1 cm above and 2 cm below the esophagogastric junction) in 12% and 10%), World Health Organization performance status (0 in 25% in both, 1 in 52% and 56%, 2 in 22% and 20%), previous treatments (3 in 5% and 4%, 2 in 35% and 33%, 1 in 61% in both), brain metastases (no in > 99% and 96%), and body mass index (median, 24.01 kg/m2 in both).

Survival and Disease Control Median overall survival was 3.73 months (95% confidence interval [CI] = 3.23–4.50) in the gefitinib group vs 3.67 months (95% CI = 2.97–4.37) in the placebo group (hazard ratio [HR] =

Gefitinib in Esophageal Cancer ■■ Gefitinib provided no overall survival benefit vs placebo but was associated with prolonged progression-free survival and a higher rate of stable disease.

■■ Gefitinib was associated with a significant improvement in odynophagia and several exploratory patient-reported outcomes.

assigned between March 2009 and November 2011 to receive gefitinib at 500 mg/d (n = 224) or placebo (n = 225). Patients had to have measurable or evaluable disease on computed tomography. All patients received best supportive care in addition to study

Median progression-free survival was significantly but minimally prolonged with gefitinib (1.57 vs 1.17 months, HR = 0.80, P = .020). In subgroup analyses, hazard ratios consistently favored gefitinib, with significant or borderline significant benefit observed in subgroups with performance status of 0 (HR = 0.67), those with esophageal disease site (HR = 0.80),

0.90, P = .29). Patients were not stratified by performance status; performance status was a significant predictor of overall survival, with median overall survival of 6.1, 3.9, and 2.2 months in patients with performance status of 0, 1, and 2 (P < .0001 for trend).

males (HR = 0.82), those with one previous treatment (HR = 0.79), and those with adenocarcinoma (HR = 0.81).

Disease control at 8 weeks was present in 24% of patients in the gefitinib group (including 6 partial responses) and in 16% of the placebo group (including 1 partial response; P = .02).

Among gefitinib patients, disease control rates were 23% in those with adenocarcinoma and 28% in those with squamous cell carcinoma. Objective response to gefitinib was rapid, with 7 of 8 observed by week 4. Responses persisted for 1.2 to 7.3 months.

In total, 22% of patients received further treatment, including chemotherapy in 9% of the gefitinib group vs 10% of the placebo group, palliative radiotherapy in 8% vs 11%, and stents in 6% vs 8%.

Patient-Reported Outcomes Health-related quality of life was assessed by the generic European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the esophageal, junctional, and gastric cancer–specific EORTC QLQ-OG25.

Questionnaires for prespecified patient-reported outcomes were completed at baseline and 4 weeks by 110 gefitinib patients and 121 placebo patients.

Among these patients, gefitinib patients had significantly improved odynophagia (P = .004), with improvement from

baseline observed in the gefitinib group.

No significant differences were found in the other prespecified outcomes, consisting of global quality of life, dysphagia, and eating restriction, although all changes favored gefitinib.

Among exploratory patient-reported outcomes, the gefitinib group had significantly better outcomes in social functioning (P = .013), pain (P = .035), constipation (P = .0001), cough (P = .013), and speech function (P = .0004), with improvement or no worsening from baseline in each, whereas the placebo group reported less worsening of diarrhea (P < .0001). Virtually all other changes (eg, in hair loss, dyspnea, anxiety, sleep, saliva, reflux) favored gefitinib.

Adverse Events The most common adverse events of any grade in the gefitinib group were diarrhea (16% vs 3% in the placebo group) and skin toxicity (21% vs 1%). The most common grade 3 or 4 adverse events were fatigue (11% vs 6%) and diarrhea (6% vs 1%). In total, grade 3 or 4 gastrointestinal adverse events occurred in 21% vs 23%, and grade 3 or 4 respiratory adverse events occurred in 14% vs 13%.

Serious adverse events were reported in 49% and 45% of patients. Three fatal serious adverse events (2 in the placebo group and 1 in the gefitinib group) were considered possibly related to study treatment. Dose reduction from 500 mg to 250 mg occurred in 4% and 1% of patients.

The investigators concluded, “The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients.” n

Disclosure: The study was funded by Cancer Research UK. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Dutton SJ, Ferry DR, Blazeby JM, et al: Gefitinib for oesophageal cancer progressing after chemotherapy (COG): A phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 15:894-904, 2014.

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PAGE 33

Perspective

EGFR as a Therapeutic Target for Gastroesophageal Cancer—or Is It Really?

By Elena Elimova, MD, Shumei Song, MD, PhD, and Jaffer A. Ajani, MD

T

he epidermal growth factor receptor (EGFR) gene is often amplified and its protein overexpressed in upper gastrointestinal cancers— and overexpression has prognostic value. With the advent of monoclonal antibodies and tyrosine kinase inhibitors against EGFR, we have witnessed a rash of randomized clinical trials in patients with advanced or localized gastroesophageal cancers (squamous cell carcinoma and adenocarcinoma).

The results have been uniformly disappointing.

Here, we highlight a recently reported UK trial (COG) in patients with Siewert-type I/II advanced gastroesophageal cancers (adenocarcinoma or squamous cell carcinoma) in the second-line setting.1 The report,

by Dutton and colleagues in Lancet Oncology, is summarized in this issue of The ASCO Post.

The COG trial randomly assigned 449 patients to receive gefitinib (Iressa) or placebo. The primary endpoint was overall survival, and secondary endpoints included progression-free survival. The median overall survival was 3.73 months for patients who received gefitinib and 3.63 months for those who received a placebo (hazard ratio [HR] = 0.9, P = .29). There was a minor prolongation of progressionfree survival by 0.4 months for patients who received gefitinib (HR = 0.80, P = .02).

imab (Erbitux). This study did not achieve its primary endpoint, with the median progression-free survival for capecitabine/cisplatin plus cetuximab being 4.4 months compared to 5.6 months for capecitabine/cisplatin alone (HR = 1.09, 95% confidence interval [CI] = 0.92–1.29, P = .32).2 The REAL-3 study was terminated prematurely because a statistically significantly lower overall survival was noted in patients who received EOC (epirubicin,j oxaliplatin, and capecitabine) and panitumumab (Vectibix). Median overall survival of patients allocated to EOC was 11.3

Drs. Elimova, Song, and Ajani are in the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

have been a few successes (KRAS, ERRB2, ALK-rearrangement, and BRAF), there are many more failures.

It is quite likely that EGFR is not the primary driver in esophageal cancers.

The sheer complexity of the genome is staggering, and structural alterations do not necessarily translate into functional/protein aberrations.

Vogelstein et al recently suggested that the whole idea of eradicating cancer by targeting metastatic disease seems improbable.11 The carcinogenesis takes decades to transform a normal (stem) cell into cancer. Cancer cells use approximately 12 pathways for survival. Driver mutations are difficult to decipher, and the cure of cancer is unlikely to come from focusing on advanced cancer; the advantage might come from focusing on early detection (eg, blood biomarker testing).

Multiple Mechanisms

In-depth functional and structural studies of the gastroesophageal cancer genome are needed.

Simultaneously, we should be harnessing the prowess of the immune system, through vaccines, antibodies, cell therapy, and/or programmed cell death inhibitors.

—Elena Elimova, MD, Shumei Song, MD, PhD, and Jaffer A. Ajani, MD

Related Trials Before we speculate as to why gefitinib failed to prolong overall survival in these patients in whom EGFR is often overexpressed and thought to impart resistance to therapy, it is useful to review other studies that have assessed EGFR inhibition in gastroesophageal cancer patients. Equally disappointing results were reported from two EGFR-targeting trials (EXPAND and REAL-3) in patients with metastatic gastric or gastroesophageal cancer.2,3 The EXPAND trial randomly assigned patients to receive capecitabine and cisplatin with or without cetux-

of cetuximab.5 The SCOPE1 study randomized both adenocarcinoma and squamous cell carcinoma patients who were candidates for definitive chemoradiation therapy to cisplatin, capecitabine, and radiation with or without cetuximab. This trial was stopped based on the results of an interim analysis that crossed the bounds for futility. The cetuximab group had a median overall survival of 22.1 months (95% CI = 15.1–24.5) compared to 25.4 months (95% CI = 20.5–37.9) for those who did not get cetuximab (adjusted HR = 1.53, 95% CI = 1.03–2.27, P = .035).6

months (95% CI = 9.6–13.0) compared with 8.8 months (95% CI = 7.7–9.8) in patients allocated to modified EOC and panitumumab (HR =1.37, 95% CI = 1.07–1.76, P = .013).

An exploratory molecular analysis of tumors of patients in the trial did not identify any predictive biomarkers for panitumumab.4 A similar strategy of using an antiEGFR antibody in combination with chemoradiation was evaluated in two randomized trials in patients with localized gastroesophageal cancers. The Radiation Therapy Oncology Group (RTOG) 0436 phase III trial evaluated the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with unresectable esophageal cancer; no prolongation of overall survival was observed with the addition

Driver Mutations Squamous cell carcinomas seem to overexpress EGFR at a high frequency (60%–70%) and have a fairly high rate of EGFR amplification (28%).7,8 These changes are associated with poor response to chemoradiotherapy and shorter overall survival.9 However in the COG study, squamous cell carcinoma patients formed a minority, and there was a trend for improved overall survival in adenocarcinoma patients, highlighting the fact that overexpression of EGFR may not represent a therapeutic target. In gastric cancer, although EGFR amplification has been low, EGFR expression is similar to that in esophageal cancers, and it is prognostic.10 Exploiting biomarkers in the clinic is very challenging and although there

One possibility for the findings in studies in this area is that the EGFR pathway is upregulated through multiple mechanisms, and therefore the direct blockage of the EGFR pathway alone would be expected to be ineffective or insufficient, as appears to be borne out by these trials. The Hippo signaling pathway regulates organ size and cell proliferation. YAP1 is a key downstream effector of the Hippo signaling pathway and is tightly regulated by a number of upstream kinases and their adaptors—eg, Mst1/2, Sav1, and Lats1/2, which are tumor suppressors in several tumor types.12 Conditional deletion of these genes in mice led to a dramatic increase in organ size and tumor formation in a process largely dependent on YAP1.12 In transgenic mice, tissue-specific expression of YAP results in tissue overgrowth and tumor formation.13 EGFR activation occurs frequently in Hippo pathway–defective mouse liver tumors.14 A recent study from Reddy et al demonstrated that the EGFR-RAS-MAPK branch of EGFR signaling activates YAP1 by promoting phosphorylation of the Ajuba family protein WTIP and enhancing WTIP binding to Lats1/2.15 Therefore, it may be that a therapeutic combination to inhibit one or continued on page 34

The ASCO Post | AUGUST 15, 2014

PAGE 34

Perspective

Elena Elimova, MD Shumei Song, MD, PhD Jaffer A. Ajani, MD continued from page 33

more pathways would be advantageous. The trials we discussed have not selected patients based on EGFR or other biomarkers; however, a predictive biomarker for a given inhibitor is difficult to figure out. It is entirely possible that YAP1 is upregulating EGFR and that YAP1 should be inhibited in EGFR-overexpressing tumors.

In summary, we believe that indepth functional and structural studies of the gastroesophageal cancer genome are needed. Simultaneously, we should be harnessing the prowess of the immune system, through vaccines, antibodies, cell therapy, and/or programmed cell death inhibitors. n

Disclosure: Drs. Elimova and Song reported no potential conflicts of interest.

Dr. Ajani has received research grants from Amgen, Genentech, BMS, Taiho, Novartis, and DFP, and is a paid consultant for Lilly and Celgene.

References 1. Dutton SJ, Ferry DR, Blazeby JM, et al: Gefitinib for oesophageal cancer progressing after chemotherapy (COG): A phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 15:894-904, 2014.

2. Lordick F, Kang YK, Chung HC, et al: Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol 14:490-499, 2013.

3. Waddell T, Chau I, Cunningham D, et al: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol 14:481-489, 2013.

4. Okines AF, Gonzalez de Castro D, Cunningham D, et al: Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials. Eur J Cancer 49:2116-2125, 2013.

5. Suntharalingam M, Winter K, Ilson DH, et al: The initial report of RTOG

0436: A phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery. J Clin Oncol 32(3 suppl):Abstract LBA6, 2014.

6. Crosby T, Hurt CN, Falk S, et al: Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): A multicentre, phase 2/3 randomised trial. Lancet Oncol 14:627637, 2013.

7. Hanawa M, Suzuki S, Dobashi Y, et al: EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer 118:1173-1180, 2006.

8. Gibault L, Metges JP, Conan-Charlet V, et al: Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer. Br J Cancer 93:107-115, 2005.

9. Wang KL, Wu TT, Choi IS, et al: Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: Association with poor outcome. Cancer 109:658-667, 2007.

10. Galizia G, Lieto E, Orditura M, et al: Epidermal growth factor receptor (EGFR) expression is associated with a worse prognosis in gastric cancer patients undergoing curative surgery. World J Surg 31:1458-1468, 2007.

11. Vogelstein B, Papadopoulos N, Velculescu VE, et al: Cancer genome landscapes. Science 339:1546-1558, 2013.

12. Lu L, Li Y, Kim SM, et al: Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA 107:1437-1442, 2010.

13. Camargo FD, Gokhale S, Johnnidis JB, et al: YAP1 increases organ size and expands undifferentiated progenitor cells.

Curr Biol 17:2054-2060, 2007.

14. Bard-Chapeau EA, Nguyen AT1, Rust AG, et al: Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model. Nat Genet 46:24-32, 2014.

15. Reddy BV, Irvine KD: Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev Cell 24:459-471, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Kathy D. Miller, MD, on adjuvant endocrine therapy in breast cancer see page 50

Larissa Nekhlyudov, MD, MPH, on collaboration between oncologists and primary care physicians see page 55

Richard J. Boxer, MD, using technology to bring health care to patients see page 132

Ethan Basch, MD, on patientreported outcome measures in palliative care see page 112

Michael Douglas on his experience with stage IV oropharyngeal cancer see page 123

Alan R. Marks, MD, on the Florida Society of Clinical Oncology see page 134

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | AUGUST 15, 2014

PAGE 36

Journal Spotlight Genitourinary Oncology

PREVAIL Trial: Enzalutamide Before Chemotherapy Prolongs Survival in Metastatic Prostate Cancer

By Matthew Stenger

T

he androgen-receptor inhibitor enzalutamide (Xtandi) has been shown to prolong survival in men with metastatic castration-resistant prostate cancer with progressive disease after chemotherapy. In the phase III PREVAIL trial reported in The New England Journal of Medicine, Tomasz M. Beer, MD, of OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, and colleagues found that enzalutamide treatment prior to chemotherapy was associated with significantly prolonged progression-free survival, overall survival, and time to chemotherapy compared with placebo in patients with metastatic disease progressing despite androgen-deprivation therapy.1 The trial was stopped after demonstration of benefit at the first overall survival interim analysis.

Study Details In the double-blind trial, 1,717 patients with minimally symptomatic or asymptomatic metastatic prostate cancer who had not received chemotherapy were randomly assigned to receive oral enzalutamide at 160 mg/d (n = 872) or placebo (n = 845). The coprimary endpoints were radiographic progressionfree survival and overall survival.

The enzalutamide and placebo groups were balanced for age (median, 72 and 71 years; 21% < 65 years in both), ethnicity (77% white in both, 10% Asian in both), Eastern Cooperative Oncology Group performance status (0 in 67% and 69%, 1 in 33% and 31%), prostate-specific antigen (PSA) level (median, 54 vs 42 µg/L), history of cardiovascular disease (21% vs 20%), Gleason score (≤ 7 in 49% and 48%, ≥ 8 in 51% and 52%), time from diagnosis or first treatment (median, 63 and 65 months), and type of disease progression at study entry (PSA only in 43% and 44%, PSA and radiographic in 40% and 41%, radiographic only in 15% and 13%).

The two group were similarly balanced for disease localization (bone only in 40% in both, soft tissue only in 14% and 18%, bone and soft tissue in

45% and 42%), distribution of disease (bone in 85% and 82%, lymph nodes in 50% and 51%, lung or liver visceral disease in 11% and 13%), use of prior antiandrogens (87% and 86%), number of prior antiandrogens (1 for 66% in both, 2 in 19% and 18%), and number of bone metastases (0 in 15% and 18%, 1–9 in 52% and 49%, 10–20 in 16% and 14%, > 20 in 17% and 18%).

Survival Benefits At 12 months, the rate of radiographic progression-free survival was 65% in the enzalutamide group vs 14% in the placebo group (hazard ratio [HR] = 0.19, P < .001). Median radiographic progression-free survival was not reached vs 3.9 months. Hazard ratios for radiographic progression-free survival were significant in favor of enzalutamide in all subgroup analyses, consisting of those

was 22 months. Death had occurred in 28% of enzalutamide patients vs 35% of placebo patients (HR = 0.71, P < .001).

Median overall survival was estimated at 32.4 vs 30.2 months.

The treatment effect of enzalutamide was consistent across all prespecified subgroups for overall survival, with hazard ratios being significant in favor of enzalutamide for most. The overall survival benefit was also not affected by previous exposure to antiandrogens.

In an updated overall survival analysis (including 116 additional deaths), 82% vs 73% of patients in the enzalutamide and placebo groups, respectively, remained alive at 18 months; median overall survival was estimated at not reached vs 31.0 months (HR = 0.73, P < .001).

Subsequent anticancer therapy was taken by 44% of the enzalutamide group and 76% of the placebo group, including

Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.

—Tomasz M. Beer, MD, and colleagues

according to ECOG performance status 0 and 1, age < 75 and ≥ 75 years, geographic region, and Gleason score at diagnosis of ≤ 7 and ≥ 8, PSA progression only and radiographic progression with or without PSA progression at study entry, presence and absence of visceral disease, PSA value above and below median, lactate dehydrogenase level above and below median, hemoglobin level above and below median, and presence and absence of baseline bisphosphonate or denosumab (Xgeva) use. Risk reduction with enzalutamide was not affected by prior exposure to antiandrogens.

At the planned interim analysis of overall survival (after 540 deaths), median duration of follow-up for survival

Prechemotherapy Enzalutamide in Metastatic Prostate Cancer ■■ Enzalutamide significantly prolonged radiographic progression-free and overall survival.

■■ Enzalutamide significantly prolonged time to cytotoxic chemotherapy, first skeletal-related event, and PSA progression.

treatments associated with survival benefit in metastatic prostate cancer by 40% and 70%, respectively; the most commonly used of the latter were docetaxel (33% and 57%), abiraterone (Zytiga, 21% and 46%), and cabazitaxel (Jevtana, 6% and 13%). This difference was largely a reflection of the difference in the percentage of participants still receiving their assigned study treatment at the time of the analysis, Dr. Beer explained to The ASCO Post.

Improved Secondary Endpoints Enzalutamide treatment was associated with significant reduction in the risk of all secondary endpoints (P < .001 for all), as reflected in prolongation of median time to initiation of cytotoxic chemotherapy, median time to first skeletal-related event, and median time to PSA progression. The drug was also associated with significantly greater rates (P < .001 for all) of complete or partial soft-tissue response in patients with measurable disease at baseline (59%, including complete re-

sponse in 20%, vs 5%, including complete response in 1%) and achievement of PSA decline of ≥ 50% (78% vs 3%) and ≥ 90% (47% vs 1%).

In an exploratory quality of life analysis using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale, enzalutamide treatment was associated with a significantly greater time to decline in FACT-P global score (median, 11.3 vs 5.6 months, HR = 0.63, P < .001).

Adverse Events The median duration of study drug treatment was 16.6 months in the enzalutamide group and 4.6 months in the placebo group, and the median reporting period for adverse events was 17.1 vs 5.4 months. Adverse events of grade 3 or higher occurred in 43% vs 37% of patients, with the median time until the first grade 3 event being longer in the enzalutamide group (22.3 vs 13.3 months).

Adverse events of any grade occurring in ≥ 20% of enzalutamide patients and at a rate ≥ 2% higher than in placebo patients consisted of fatigue, back pain, constipation, and arthralgia. After adjustment for length of exposure, events with a higher rate per 100 patient-years in the enzalutamide group were hot flush (14 vs 12), hypertension (11 vs 7), and falls (11 vs 9).

Hypertension was the most common adverse event of ≥ grade 3 in the enzalutamide group (7%), and the most common cardiac event was atrial fibrillation (2% vs 1% in placebo group). Serious adverse events occurred in 32% vs 27% of patients in the enzalutamide and placebo groups, respectively, and adverse events led to treatment discontinuation in 6% vs 6% and to death in 4% vs 4%.

There was no evidence of enzalutamideassociated hepatotoxicity.

The investigators concluded, “Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.” n

Disclosure: The study was funded by Medivation and Astellas Pharma. Dr. Beer has received research grants from Astellas Pharma, and Medivation. For full disclosures of all study authors, visit www.nejm.org.

Reference 1. Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. June 1, 2014 (early release online).

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Postmenopausal women with HR+/HER2– advanced breast cancer No prior systemic anticancer therapy for advanced disease

Randomization (1:1)

ECOG performance status 0 or 1 Additional inclusion/exclusion criteria apply.

Letrozole 2.5 mg QD + LEE011 600 mg QD

For more information • Contact your local Novartis medical representative • Call Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (US only)

Letrozole 2.5 mg QD + placebo QD

Primary end point: Progression-free survival Key secondary end point: Overall survival

Abbreviations: CDK4/6, cyclin-dependent kinase 4/6; ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; QD, once daily.

• Visit www.clinicaltrials.gov (NCT01958021)

LEE011 is an investigational drug. Efficacy and safety have not been established. There is no guarantee that LEE011 will become commercially available.

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.

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The ASCO Post | AUGUST 15, 2014

PAGE 38

Perspective

Enzalutamide and the Landscape of Castration-Resistant Prostate Cancer: Integrating New Indications With Existing Agents

By Daniel P. Petrylak, MD

T

he androgen receptor axis is a validated target for the treatment of castration-resistant prostate cancer. Several perturbations in this pathway are postulated to lead to androgen-independent growth, including androgen receptor mutation and amplification as well as the autocrine production of testosterone.

Two drugs targeting this pathway in castration-resistant prostate cancer—abiraterone acetate (Zytiga) and enzalutamide (Xtandi)—are approved for use in patients who have already received chemotherapy. Mechanistically, abiraterone exerts antitumor activity by inhibition of the 17,20-lyase pathway, crucial to testosterone synthesis. Enzalutamide binds to the androgen receptor and prevents its translocation into the nucleus. Abiraterone is also approved for patients in the prechemotherapy setting based on results of the Cougar 302 trial.1

Two Key Studies The PREVAIL trial, reported

by Beer and colleagues in The New England Journal of Medicine and reviewed in this issue of The ASCO Post, compared enzalutamide to placebo in 1,717 men with metastatic castration-resistant prostate cancer who had not received prior chemotherapy.2 The trial was terminated early after a planned interim analysis at 540 deaths found a statistically significant therapeutic benefit in men treated with enzalutamide, with a 29% reduction in risk of death being observed in the enzalutamide group (hazard ratio = 0.71, 95% confidence interval = 0.60–0.84, P < .001).

There are important differences between the PREVAIL and Cougar 302 trials. In contrast to Cougar 302, patients in PREVAIL were permitted to have visceral metastases at entry, and these were present in 12% of patients. PREVAIL used a placebo Dr. Petrylak is Director, Genitourinary Oncology Research Program, and CoDirector, Signal Transduction Program, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut.

control arm, whereas COUGAR 302 used oral prednisone at 5 mg twice daily as its control treatment.

Androgen Receptor Targeting The PREVAIL trial raises several important questions regarding the initial management of castration-resistant prostate cancer. The challenge in patient management and future clinical trials will be how to best sequence and combine enzalutamide and abiraterone, particularly in light of the fact that we have alternatives

suade sequential use of the agents.

Moreover, those patients who develop the mutation while on treatment with abiraterone or enzalutamide may not be appropriate to be crossed over to the other drug.

Role of Testosterone Steroid synthetic pathways also may yield important information for drug sequencing. 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) is crucial to the conversion of dehydroepiandrosterone (DHEA) into dihydrotestosterone (DHT). A mutation

A panel of markers appears to be emerging that characterizes the androgen receptor pathway; our task is to design rational clinical trials that take into account the biology of the disease. This will have important implications not only for patient care, but for health-care costs.

—Daniel P. Petrylak, MD

for asymptomatic patients (sipuleucel-T [Provenge]) and symptomatic patients (docetaxel and radium-223 [Xofigo]) that have efficacy in the in the initial treatment setting.

The patient’s clinical characteristics alone are not sufficient for drug selection. Critical to this task will be a better understanding of the mechanisms of resistance and response to androgen receptor– targeted therapy. Several potential resistance mechanisms and targets have already been identified.

A recent presentation at ASCO

by Antonarkis et al demonstrated that the presence of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells is associated with primary and acquired resistance to both enzalutamide and abiraterone in castration-resistant prostate cancer patients.3 Although this marker does not help us in the choice between abiraterone or enzalutamide, identification of AR-V7 in patients initially treated with enzalutamide or abiraterone could potentially dis-

in 3βHSD1 has been identified in a subset of human castration-resistant prostate cancer tumors that prevents degradation of this enzyme, and the increased levels of 3βHSD1 have been shown to confer resistance to abiraterone in a mouse model. It has been demonstrated that upregulation of testosterone occurs in the bone marrow of castration-resistant prostate cancer patients treated with enzalutamide, thus making abiraterone a reasonable drug to consider in these patients since it lowers testosterone.

The practical use of this test is limited by the necessity of performing sequential bone marrow biopsies.

Moreover, this resistance pathway points toward the use of androgen receptor–targeted therapy in combination with inhibitors of steroidogenesis. This may come at the expense of increased fatigue; the combination of enzalutamide, abiraterone, and prednisone was associated with a 73% rate of grade 1 to 3 fatigue in a phase I trial compared with 36% and 40% in

the PREVAIL and Cougar 302 trials, respectively. The Alliance is currently accruing patients to a randomized trial of enzalutamide combined with abiraterone vs enzalutamide in the prechemotherapy castration-resistant prostate cancer setting.

Another important question is whether enzalutamide or abiraterone renders subsequent therapies less effective. Retrospective data suggest that patients treated with abiraterone have lower progression-free survival and overall survival than reported in patients treated with docetaxel in the TAX 327 as well as the SWOG 99-16 trial. This may in part be due to the fact that docetaxel also targets the androgen receptor axis by preventing its translocation into the nucleus. No such sequential data have been generated with enzalutamide followed by docetaxel.

Conclusions In conclusion, the PREVAIL trial represents a major advance in the treatment of castration-resistant prostate cancer. In contrast to 2004, when docetaxel was the only agent demonstrating a survival benefit in castrationresistant prostate cancer, we now have five agents that we can use. A panel of markers appears to be emerging that characterizes the androgen receptor pathway; our task is to design rational clinical trials that take into account the biology of the disease. This will have important implications not only for patient care, but for health-care costs. n

Disclosure: Dr. Petrylak is a consultant to Johnson & Johnson and Astellas, and he receives research support from Astellas.

References 1. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy.

N Engl J Med 368:138-148, 2013.

2. Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. June 1, 2014 (early release online).

3. Antonarakis ES, Lu C, Wang H, et al: Androgen receptor splice variant AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration resistant prostate cancer.

2014 ASCO Annual Meeting. Abstract 5001. Presented June 1, 2014.

ASCOPost.com | AUGUST 15, 2014

PAGE 39

Clinical Recommendations Genitourinary Oncology

College of American Pathologists Publishes Recommendations for Prostate Cancer Active Surveillance

R

ecommendations from the United States Preventive Services Task Force and randomized trials have drawn attention to overtreatment of localized, low-risk prostate cancer. PSA screening and changing consensus on PSA testing practices are among the many factors that contribute to the overdiagnosis and overtreatment of prostate cancer.

Active surveillance offers low-risk prostate cancer patients a means to avoid the potentially harmful side effects from treatment. Pathologists help determine patient eligibility for active surveillance, and recently a multispecialty team published their recommendations for making such determinations.1

Active Surveillance With active surveillance, patients undergo regular visits with prostate-specific antigen (PSA) tests and repeated prostate biopsies rather than aggressive treatment.

It is distinguished from watchful waiting, in which treatment for localized disease is withheld and palliative treatment for systemic disease is initiated.

“Active surveillance is an important management option for men with low-risk prostate cancer,” says lead author Mahul Amin, MD, FCAP, Chair, Department of Pathology & Laboratory Medicine, CedarsSinai Medical Center, Los Angeles. “Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for active surveillance.”

Pathologic Parameters

pathologists, radiation oncologists, surgeons, and urologists from Australia, Canada, Italy, New Zealand, Sweden, and the United States.

For a full list of study authors, visit www. archivesofpathology.org

Supported by the College of American Pathologists, International Society of Urological Pathology, Association of Directors of Anatomic and Surgical Pathology, the New Zealand Society of Pathologists,

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Dr. Amin spearheaded the team that highlighted the pathologic parameters key for the successful identification of patients likely to succeed with active surveillance. The key parameters, at a general level, address: • Sampling, submission, and processing issues in needle biopsies used to diagnose prostate cancer • Tumor extent in needle biopsies • Biopsy reporting for all and special cases • Gleason scores, the system for grading prostate cancer tissue based on how it looks under a microscope • Precision medicine markers • Other pathologic considerations The team further concluded that the key parameters to be reported by the surgical pathologists: (1) need to be reproducible and consistently reported and (2) highlight the importance of accurate pathology reporting. n Disclosure: Dr. Amin reported no potential conflicts of interest. The article’s authors include CM-0006-0814

and the Prostate Cancer Foundation.

Reference 1. Amin, MB, Lin DW, Gore JL, et al: Arch Pathol Lab Med. August 5, 2014 (early release online).

The ASCO Post | AUGUST 15, 2014

PAGE 40

Expert’s Corner Surgical Oncology

The Evolving Role of Surgery in Germ Cell Tumors

By Ronald Piana

Stephen B. Riggs, MD

O

ver the past several decades, the role of postchemotherapy surgery for advanced testicular cancer has evolved with regard to patient selection, surgical planning, lymph node dissection, and surgical technique. To add clarity to this complex clinical setting, The ASCO Post recently spoke with urologic oncologist Stephen B. Riggs, MD, of Levine Cancer Institute, ­McKay Department of Urology, Carolinas Healthcare System, Charlotte, North Carolina.

Patient Selection Please shed light on the selection process used to determine which patients with advanced testicular cancer should be considered for surgery following chemotherapy.

It takes a team and a process that involves careful consideration within a multidisciplinary approach among experienced surgeons, medical oncologists, radiologists, as well as experts in pathology. Testicular cancer essentially comes in two histologic variations: seminomatous and nonseminomatous tumors. The paradigm by which we select patients for postchemotherapy treatment is different based on which histology a patient has in addition to their pre- and postchemotherapy tumor marker status.

In patients with seminoma, we observe tumors that, after chemotherapy, are less than 3 cm because the chance of viable tumor is exceedingly low.

Secondly, for reasons still unknown, seminomatous tumors develop a desmoplastic reaction after chemotherapy, which can make the surgery more difficult and increases the potential for morbidity.

However, if after chemotherapy a retroperitoneal mass is ≥ 3 cm, then positron-emission tomography (PET with 18 F-fluorodeoxyglucose (FDG) imaging is now utilized to assess the clinical situation. PET is very good in this setting because not all patients with tumors greater than 3 cm will need surgery (even

though the inherent chance of viable germ cell tumor is greater).

In addition to the percentage change of tumor size from pre- to postchemotherapy, a negative PET scan gives us evidence that surgery is probably not necessary.

Finally, our ability to utilize PET after chemotherapy is unique to patients with seminoma because the residual mass will contain either fibrosis/necrosis or viable germ cells. Fibrosis or necrosis tends not to have a large affinity for the radiotracer but viable germ cells do, so we can determine histology based on PET scan results.

Nonseminomatous Tumors How does the treatment approach differ in nonseminoma?

There are two schools of thought in patients with nonseminomatous histology and a residual mass (with normalized beta-hCG and AFP) following chemotherapy, and at the epicenter is the concern for teratoma or viable cancer.

The first approach is to observe all patients with residual masses smaller than 1 cm, a paradigm that we currently endorse at our institution. This concept is based on robust data from the University of Indiana as well as observational data from the British Columbia Combined Regis-

unless there is a good medical or surgical reason not to do so.

Much of the data supporting observation are based on a large group of patients with a very favorable prognosis to begin with. So this is still a debate within the community.

Improved Surgical Techniques Please briefly discuss the evolution of lymph node dissection in these patients and any advances in nerve-sparing ­techniques.

Testes cancer gives us good insight into how surgical oncology has evolved in terms of cancer outcomes and morbidity.

In retroperitoneal lymph node dissection, we know the flow of lymphatic drainage for each testicle.

Because of this knowledge, we’ve been able to tailor our surgical margins in lymph node dissections, which form our basis for a modified approach. Pioneers utilized this knowledge in addition to the location and understanding of the sympathetic nerve channels located in the retroperitoneum to reduce both the extent of disease and retrograde ejaculation. This modified approach is accomplished by staying above the hypogastric plexus located right below the interior mesenteric artery. Of course, we can also prospec-

Our knowledge has allowed us to reduce morbidity in the more challenging postchemotherapy setting, where patients can be carefully considered for the extent and technique of surgery.

—Stephen B. Riggs, MD

try, suggesting that patients with pristine postchemotherapy scans, or minute residual disease, have very good outcomes on observation. However, in fact, the overwhelming patients in these studies had a good risk profile.

Nevertheless, there are other institutions that advocate that nearly all postchemotherapy patients should undergo a retroperitoneal lymph node dissection, especially those patients considered intermediate or high risk by International Germ Cell Consensus Group Classification I think there is fair uncertainty, regarding the long-term outcomes of small amounts of residual teratoma, as well as concern over higher-risk patients so there remains some anxiety (and debate) associated with the observational approach. My own approach is to do a postchemotherapy retroperitoneal lymph node dissection

tively spare sympathetic nerves in a full bilateral dissection but, unfortunately, nerve sparing is not always possible in the postchemotherapy setting.

There remains some debate in the postchemotherapy realm about whether every patient should get bilateral dissection or if it is appropriate to utilize a more directed modified approach. I believe that patients with less bulky disease (stage IIA or IIB) in the predicted site of drainage can be managed with a more targeted modified approach. When employed, this approach offers a patient a very good chance at preserving his ejaculatory status without compromising cancer control.

Ultimately, the decision with regard to extent of the dissection really comes down to how bulky the initial and remaining disease is. For large tumors, it is much more difficult to spare the nerves and preserve antegrade ejaculation and

most importantly, bulky disease can result in crossover drainage (eg, right to left) as well as retrograde drainage out of predicted drainage sites.

What has led to better surgical techniques resulting in less morbidity?

Most importantly, it is our understanding of the anatomy, specifically the location of drainage with in the lymph nodes as well as the vascular and nerve structures within the retroperitoneum. Our knowledge has allowed us to reduce morbidity in the more challenging postchemotherapy setting, where patients can be carefully considered for the extent and technique of surgery.

Looking Ahead What’s next in the surgical approach to germ cell tumors?

Laparoscopy is certainly gaining traction. But to be fair, we do not have a lot of data on long-term outcomes in laparoscopy in the postchemotherapy setting which makes it hard to fully endorse this approach. A postchemotherapy retroperitoneal lymph node dissection is a technically demanding operation in its current form, and although robotics may improve our ability, this remains to be seen. Moreover, the adoption of a newer technique is challenged by the paucity of cases seen within some practices, which limits the iterative process that is required to master the technique.

Most importantly, as a surgeon, incomplete resection can potentially do harm to the patient. We know that patients who require “redo” retroperitoneal lymph node dissection do not do as well. Ultimately, you cannot salvage a poor surgery with systemic chemotherapy. So those of us who choose to use a laparoscopic approach need to be very skilled—you only have one shot, as this may be the only factor in a patient’s disease state that we can actually control. In fact, I believe that any surgeon who takes on a postchemotherapy dissection really needs to know what he is doing, as there are many traps for young and inexperienced players.

Is robotic surgery the next leap forward in this clinical setting?

Most likely yes, and this trend has begun. That said, it is the skill behind the robot and an understanding of the nuances of this disease that matters, because no matter how you do this procedure, the cost to the patient of not doing it well is very high. n Disclosure: Dr. Riggs reported no potential conflicts of interest.

ASCOPost.com | AUGUST 15, 2014

PAGE 41

Journal Spotlight Gastrointestinal Oncology

Study Finds New Genetic Risk Markers in Pancreatic Cancer

A

large DNA analysis of people with and without pancreatic cancer has identified several new genetic markers that signal increased risk of developing the disease, report scientists from ­Dana-Farber Cancer Institute and other institutions worldwide. The markers are variations in the inherited DNA code at particular locations along chromosomes. Several of these variations in the DNA code were identified that influence an individual’s risk for pancreatic cancer.

The discovery of these markers along with four that were previously identified is important for several reasons, said Brian Wolpin, MD, MPH, first author of the report published online by Nature Genetics.1 One is that further study of these DNA variants may help explain on the molecular level why some people are more or less susceptible to pancreatic cancer than the average person. A second is the potential to identify people at increased risk who then might be candidates to undergo MRI or ultrasound scanning to look for early, treatable pancreatic tumors.

“Currently there is no population screening program for pancreatic cancer, which in 80% of cases is discovered when it’s too late to allow curative surgery,” said Dr. Wolpin. The only healthy

individuals currently screened for pancreatic cancer are members of high-risk families due to multiple family members with pancreatic cancer. “But the field has been struggling to find factors that can identify people at highest risk in the general population, when a strong family history is not present,” Dr. Wolpin said.

Genome-Wide Association Study The study findings represent analyses of DNA from 7,683 patients with

genome known to have single nucleotide polymorphisms (SNPs), differing versions of a single letter of DNA code.

These variations can alter the expression of a gene or the content of its message, and the researchers looked for variants that were associated with the risk of having pancreatic cancer.

Dr. Wolpin said the results confirmed the presence of four risk-associated SNPs that had been identified in a previous, smaller genome-wide association study. In addition, five new risk markers were discovered and a

The field has been struggling to find factors that can identify people at highest risk in the general population, when a strong family history is not present.

—Brian Wolpin, MD, MPH

pancreatic cancer and 14,397 control patients without this cancer, all of European descent, from the United States, Europe, Canada, and Australia. The scientists used sequencing technology to examine more than 700,000 sites of the

sixth that was of borderline statistical ­significance.

The risks linked to each SNP or marker were largely independent and additive, so that they may have utility in future attempts to identify indi-

viduals in the general population at higher risk for pancreatic cancer. The average lifetime risk of pancreatic cancer is 1.5%.

The long-term goal is to create a “risk-stratification tool” that could be used in primary care practice to identify individuals who should undergo screening for pancreatic cancer with tests such as ultrasound or magnetic resonance imaging.

The report includes authors from around the world, and includes several senior authors, including Charles Fuchs, MD, MPH, and corresponding authors Rachael S. Stolzenberg-Solomon, MD, and Laufey T. Amundadottir, MD. The project, known as PanScan III, was funded by numerous sources, including the National Cancer Institute of the National Institutes of Health under contract number HHSN261200800001E and the Lustgarten Foundation. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Wolpin BM, Rizzato C, Kraft P, et al: Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nature Genetics. August 3, 2014 (early release online).

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Continue treatment.* 1-4 Extend survival.

For patients with advanced nonsquamous† NSCLC Median Overall Survival: 13.9 months with ALIMTA® (pemetrexed for injection) single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02 * Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA continuation maintenance showed extended overall survival with a safety profile consistent with previously reported ALIMTA single-agent trials

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

Select Important Safety Information Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and Precautions Premedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

Clinically relevant differences in survival probability as compared with placebo in certain patients* with advanced nonsquamous† NSCLC 1,4,5

a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy. b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety Information Warnings and Precautions ALIMTA can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Frequent blood monitoring is required with ALIMTA therapy. Dose adjustments, modifications, or suspension of therapy may be necessary based on hematologic and nonhematologic toxicities.

Monitor renal function during ALIMTA therapy. ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

See the complete data at ALIMTAhcp.com/data See the Important Safety Information and Brief Summary for ALIMTA on the following pages.

References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013.

2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597.

4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Data on file, Eli Lilly and Company. ONC20120911A.

Indications for ALIMTA® (pemetrexed for injection) ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information for ALIMTA Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and Precautions Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities.

Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC) The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/ desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page.

Drug Interactions See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency.

PM_HCP_ISI_NSCLC1M_17OCT2012

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

PM90247

04/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. ALIMTA® is a registered trademark of Eli Lilly and Company.

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2 Nonsquamous Non-Small Cell Lung Cancer — Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.

2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen and Concurrent Medications Vitamin Supplementation Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].

Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].

Corticosteroids Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle.

Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3.

75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 without bleeding 75% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 with bleedinga, 50% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA Dose of Cisplatin (mg/m2) (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous 75% of previous dose dose Any diarrhea requiring hospitalization (irrespective 75% of previous 75% of previous of Grade) or Grade 3 or 4 diarrhea dose dose ALIMTA® (pemetrexed for injection)

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Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.)

Grade 3 or 4 mucositis

50% of previous dose

100% of previous dose

a

NCI Common Toxicity Criteria (CTC).

Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity b

Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/ Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

5 WARNINGS AND PRECAUTIONS 5.1 Requirement for Premedication and Concomitant Medication to Reduce Toxicity Vitamin Supplementation Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

Corticosteroids Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see Dosage and Administration (2.3)].

5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation.

Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the ALIMTA® (pemetrexed for injection)

ALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5

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PAGE 46

FDA Update

FDA Grants Bevacizumab Priority Review for Certain Types of Cervical Cancer

T

he U.S. Food and Drug Administration (FDA) has accepted Genentech’s supplemental Biologics License Application and granted Priority Review for bevacizumab (Avastin) plus chemotherapy in the treatment of women with persistent, recurrent, or metastatic cervical cancer.

The designation of Priority Review status is granted to drugs that the FDA believes have the potential to provide “significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.” The

supplemental Biologics License Application for bevacizumab plus chemotherapy in cervical cancer is based on data from the phase III GOG-0240 trial.

GOG-0240 Study GOG-0240 is an independent, Na-

tional Cancer Institute (NCI)-sponsored phase III study assessing the efficacy and safety profile of bevacizumab plus chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) in women with persistent, recurrent, or metastatic cervical cancer.

3 3 platelet is ≥100,000 cells/mm , and creatinine clearance is ≥45 mL/min [see platelet count is ≥100,000 cells/mm , andcount creatinine clearance is ≥45 mL/min [see Dosage Incidence 1%Dosage to 5% Incidence 1% to 5% Body as a Whole — febrile neutropenia, pyrexia Body asinfection, a Whole — febrile neutropenia, infection, pyrexia and Administration (2.4)]. and Administration (2.4)]. lacrimatio General Disorders — dehydrationGeneral Disorders — dehydration Inc 5.6 Pregnancy Category D 5.6 Pregnancy Category D Metabolism and Nutrition — increased AST, increased ALT — increased AST, increased ALT Metabolism and Nutrition Based on its action, ALIMTA can cause fetal harm when administered Based on its mechanism of action, ALIMTA canmechanism cause fetalofharm when administered — creatinine failureclearance decrease, renal failure Renal —renal creatinine to a pregnant woman.

Pemetrexed administered intraperitoneally Renal to mice during clearance decrease, to a pregnant woman. Pemetrexed administered intraperitoneally to mice during Special — conjunctivitis Special Senses — conjunctivitis was embryotoxic, andthan teratogenic thanSenses 1/833rd organogenesis was embryotoxic,organogenesis fetotoxic and teratogenic in micefetotoxic at greater 1/833rd in mice at greater Incidence Less than 1% Incidence Less than 1% recommended If ALIMTA used during pregnancy, or if the patient the recommended human dose.theIf ALIMTA is usedhuman duringdose. pregnancy, or ifisthe patient Cardiovascular — arrhythmia Cardiovascular — arrhythmia while taking drug, ofthethepatient should be apprised of the potential becomes pregnant while taking becomes this drug,pregnant the patient should be this apprised potential General Co hazard to the fetus. Women of childbearing potential should be advised to avoid Disorders becoming — chest pain General Disorders — chest pain hazard to the fetus. Women of childbearing potential should be advised to avoid becoming Metabolism and Nutrition — increased GGT and Nutrition — increased GGT Metabolism Ind pregnant.

Women should be advisedmeasures to use effective contraceptive measures to prevent pregnant. Women should be advised to use effective contraceptive to prevent Tab during treatment ALIMTA (8.1)]. [see Use in Specific PopulationsNeurology (8.1)]. — motor neuropathy Neurology — motor neuropathy pregnancy during treatment withpregnancy ALIMTA [see Use in Specificwith Populations Non-Small Cell Lung Cancer (NSCLC) – Maintenance Non-Small Cell Lung Cancer (NSCLC) – Maintenance of the 500 ADVERSE REACTIONS 6 ADVERSE REACTIONS 6 ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based maintenanI Therapy Therapy Th 6.1 Clinical Trials Experience6.1 Clinical Trials Experience provides the frequency and severity of adverse reactionsand reported in >5% of reactions reported Table 5 provides the frequency severity of adverse doses ofin Becauseunder clinical trialsvarying are conducted under widely varying Table 5 conditions, adverse Because clinical trials are conducted widely conditions, adverse 438 patients NSCLC ALIMTAwith maintenance the 218 patients with 438 patients NSCLC whoand received ALIMTA maintenance and thereductions 218 patie reactions ratesto cannot directly compared to rates in otherthe clinical trials andwith may not whothereceived reactions rates cannot be directly compared rates inbeother clinical trials and may not NSCLC who received placebo following platinum-based induction therapy.

NSCLC awho received placebo following a platinum-based induction therapy. the placeb reflect the rates observed in clinical practice. reflect the rates observed in clinical practice.

All patients received following platinum-based patients received study4 cycles therapyofimmediately following 4 cycles arm of platinum and 1 In clinical trials, the most common≥20%) adverseduring reactions (incidence ≥20%) duringstudy therapyAllimmediately In clinical trials, the most common adverse reactions (incidence treatment for locally advanced ortreatment metastaticforNSCLC. study arms werePatients fully in both study locally Patients advancedin orboth metastatic NSCLC. acidarms andwv therapy with a single-agent were fatigue, and anorexia.

Additional therapy with ALIMTA as a single-agent wereALIMTA fatigue,asnausea, and anorexia.

Additionalnausea, supplemented with folic vitamin B12. with folic acid and vitamin B12. common≥20%) adverse reactions ≥20%) during with ALIMTA when usedacid in andsupplemented common adverse reactions (incidence during therapy(incidence with ALIMTA when usedtherapy in Table combination cisplatin leukopenia, included vomiting, anemia, stomatitis/ combination with cisplatin included vomiting,with neutropenia, anemia,neutropenia, stomatitis/ leukopenia,Table Table 5: Adverse in Patients Receiving ALIMTA versus Placebi 5: Adverse Reactions in Patients ReceivingReactions ALIMTA versus Placebo ALIMTA a a pharyngitis, thrombocytopenia, and constipation. pharyngitis, thrombocytopenia, and constipation. in NSCLC in NSCLC Following Platinum-Based Following Platinum-Based Induction Therapy Induction Therapy Non-Small Cell inLung Cancer (NSCLC) – ALIMTA in Combination with Cisplatin Non-Small Cell Lung Cancer (NSCLC) – ALIMTA Combination with Cisplatin ALIMTA Placebo ALIMTA Placebo Adverse 4 provides the frequency andthat severity of adverse reactions that have been Table 4 provides the frequency Table and severity of adverse reactions have been (N=438) (N=218) (N=438) (N=218) Reactionb Reactionb Syst in >5% 839 randomized patients withtoNSCLC whoreceived were randomized to study and received reported in >5% of 839 patientsreported with NSCLC whoofwere study and Grades Grade Grade3-4 3-4 All Grades Grad ALIMTA plus and were 830 patients withtoNSCLC ALIMTA plus cisplatin and 830 patients with cisplatin NSCLC who randomized study who and were randomized to study and All Grades Grade 3-4 AllAllGrades Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxic received gemcitabine plusstudy cisplatin.

All as patients received gemcitabine plus cisplatin.

All patients received therapy initial received treatmentstudy therapy as initial treatment Toxicity (%) Toxicity (%) Toxicity All Adve locallyand advanced NSCLCgroups and patients in both treatment groups were fully for locally advanced or metastaticforNSCLC patientsorinmetastatic both treatment were fully All66Adverse Reactions 37 All Adverse Reactions 16 3766 416 Laborat supplemented with folic acid andsupplemented vitamin B12. with folic acid and vitamin B12.

Laboratory Laboratory Hemat TableSupplemented 4: Adverse Reactions in Fully Supplemented Table 4: Adverse Reactions in Fully Hematologic Hematologic Anem a a Receiving NSCLC Patients Receiving ALIMTA plusPatients Cisplatin in NSCLCALIMTA plus Cisplatin in Anemia 13 6 615 3 15 Anemia Neutro 03 0 06 3 6 Neutropenia Neutropenia ALIMTA/cisplatin Gemcitabine/cisplatin ALIMTA/cisplatin Gemcitabine/cisplatin Clinical 12 1 16 2 6 Leukopenia Leukopenia (N=839) (N=830) (N=839) (N=830) Reactionb Reactionb Constit Hepatic Hepatic Sympto Grades Grade Grade3-4 3-4 All Grades Grade 3-4 All Grades Grade 3-4 AllAllGrades Increased ALT 0 4 Increased ALT (%) 10 410 00 Fatigu Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxicity Toxicity (%) Toxicity (%) Toxicity Increased AST 0 4 Increased AST 8 48 00 Gastro All 91 53 All Adverse Reactions 90Adverse Reactions 37 9190 5337 Clinical Clinical Nause Laboratory Laboratory Constitutional Constitutional Vomit Hematologic Hematologic Symptoms Symptoms Mucos 10 106 46 4633 6 33 Anemia Anemia Fatigue 11 Fatigue 25 5 1125 15 Genera 27 2715 38 3829 15 29 Neutropenia Neutropenia Gastrointestinal Gastrointestinal Edem 8 85 21 2118 5 18 Leukopenia Leukopenia 11 6 a 619 1 19 Nausea Nausea 13 134 27 2710 4 10 Thrombocytopenia Thrombocytopenia Adverse 02 5 519 2 19 Anorexia Anorexia adverse Renal Renal 00 1 19 0 9 Vomiting Vomiting Creatinine elevation 7 1 Creatinine elevation 10 1 710 11 01 2 b to those 27 1 7 Mucositis/stomatitis Mucositis/stomatitis NCI CTC 01 3 35 1 5 Diarrhea Diarrhea Clinical Clinical Ad Constitutional Constitutional Infection 2 Infection 5 2 25 02 erythropoi Symptoms Symptoms Neurology Neurology factors (6% Fatigue 45 5 Fatigue 43 7 4543 57 Neuropathy-sensory 4 Neuropathy-sensory 9 1 49 01 Th Gastrointestinal Gastrointestinal frequently Dermatology/Skin Dermatology/Skin 4 47 53 5356 7 56 Nausea Nausea Inc Rash/Desquamation 3 Rash/Desquamation 10 0 310 00 6 66 36 3640 6 40 Vomiting Vomiting a a 24 12 2427 2 27 Anorexia Anorexia Foroffthe purpose of thisfortable a cut off of events 5% waswhere used the for inclusion of all events w For the purpose of1this table a cut of 5% was used inclusion of all 0 a possible relationship 01 20 considered 2021 1 21 Constipation Constipation reporter considered reporter to ALIMTA.a possible relationship to ALIMTA. Inc b b 12 01 1214 1 14 Stomatitis/Pharyngitis Stomatitis/Pharyngitis Refer CTCAE Criteria version 3.0 for each Grade of toxicity.

Refer to NCI CTCAE0 Criteria version 3.0toforNCI each Grade of toxicity.

2 21 13 No clinically relevant 1312 1 12 Diarrhea Diarrhea NoGrade clinically differenceswere in Grade 3/4patients adverse reactions were seen in differences in 3/4 relevant adverse reactions seen in 0 ethnic origin, 00 6 on age, gender, 65 0 5 Dyspepsia/Heartburn Dyspepsia/Heartburn basedoronhistology age, gender, origin, or histology except based exceptethnic a higher incidence of Grade 3/4a higher incidence of G fatigue for patients compared non-Caucasian fatigue for Caucasian patients compared to Caucasian non-Caucasian patients (6.5%toversus 0.6%). patients (6.5% versus 0 Neurology Neurology Safety was assessed by exposure for one patients by exposure for patients who received at least dosewho of received at least one Neuropathy-sensory Neuropathy-sensory 9 0 12 Safety was assessed 1 129 10 (N=438).

The incidence of adverse reactions ALIMTA of adverse reactions was evaluated for patients whowas evaluated for patie Taste Taste disturbance 8 disturbance 0c 9 (N=438). The 0c incidenceALIMTA 98 0c0c ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of received ≤6 cycles of ALIMTA, andreceived compared to patients who received >6 cycles of ALIMTA. No Dermatology/Skin Dermatology/Skin in adverse reactions (all grades) werehowever observednowith longer exposure; how Increases in adversecreactions (allIncreases grades) were observed with longer exposure; Alopecia Alopecia 12 0c 21 1 2112 1c0c clinically in Grade clinically relevant differences in Grade 3/4relevant adversedifferences reactions were seen.3/4 adverse reactions were seen. increased Rash/Desquamation Rash/Desquamation 7 8 Consistent with 1 the higher incidence 0 87 10 Ada Consistent with(all thegrades) higher incidence of anemia (all grades) on the ALIMTA of anemia on the ALIMTA arm, use Sep a a For purpose of thisfortable a cut off of events 5% waswhere used the for inclusion of all events(mainly where RBC) the andof erythropoiesis For the purpose of this table a cut offthe of 5% was used inclusion of all transfusions (mainly RBC) agents and erythropoiesis stimulating agents (ESAs; eryth of transfusions stimulating (ESAs; erythropoietin Eso reporter considered reporter considered a possible relationship to ALIMTA.a possible relationship to ALIMTA. andALIMTA darbepoetin) were higher in the ALIMTA compared to the placebo arm (tran and darbepoetin) were higher in the arm compared to the placebo armarm (transfusions b NCI CTC Criteria version 2.0 for each Grade of toxicity.9.5% versus 3.2%, ESAs 5.9% versus Refer to NCI CTC Criteria versionb Refer 2.0 fortoeach Grade of toxicity.

6.2 Po 9.5% versus 1.8%). 3.2%, ESAs 5.9% versus 1.8%). c c According to NCI CTC Criteria version 2.0,only thisbe adverse event term should only be reported According to NCI CTC Criteria version 2.0, this adverse event term should reported following reactions were observed in patients withThno The following additional adverse The reactions wereadditional observedadverse in patients with non-small ALIMTA. B as Grade 1 or 2. as Grade 1 or 2. cell lung cancer who received ALIMTA. cell lung cancer who received ALIMTA. size, it is relevant differences in patients No clinically relevant differencesNoin clinically adverse reactions were seen in adverse patients reactions based were seen Incidence 1% to 5% Incidence 1% based to 5% relationsh on histology. on histology.

Dermatology/Skin — alopecia, pruritus/itching Dermatology/Skin — alopecia, pruritus/itching Gastrointestinal — constipation Gastrointestinal — constipation Th to thetoxicity lower incidence of hematologic toxicity on the ALIMTA and cisplatin In addition to the lower incidenceInofaddition hematologic on the ALIMTA and cisplatin General edema, fever (in the absence of neutropenia) General (in theDisorders absence — of neutropenia) combinati arm, use ofand transfusions (RBC growth and platelet) wasDisorders lower in — edema, fever arm, use of transfusions (RBC and platelet) hematopoietic factorsand washematopoietic lower in growth factors Hematologic — thrombocytopenia — thrombocytopenia Blo the ALIMTA andgemcitabine cisplatin arm the gemcitabine and cisplatin Hematologic arm. the ALIMTA and cisplatin arm compared to the andcompared cisplatin to arm.

— decreased de Renal decreased creatinineRenal clearance, increasedcreatinine creatinine,clearance, decreasedincreased creatinine, Ga following reactions were observed in patients with— non-small The following additional adverse The reactions wereadditional observedadverse in patients with non-small glomerular filtration rate glomerular filtration rate Ge celltolung cancer randomly cell lung cancer randomly assigned receive ALIMTA plus assigned cisplatin. to receive ALIMTA plus cisplatin.

ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection)

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ASCOPost.com | AUGUST 15, 2014

PAGE 47

FDA Update

Study data from 452 women showed that the study met its primary endpoint of overall survival with a statistically significant 29% reduction in the risk of death for women who received bevacizumab plus chemotherapy vs chemotherapy alone. Median overall survival for women receiving bevacizumab plus chemotherapy was 17.0 months, compared to 13.3

months for chemotherapy alone (hazard ratio [HR] = 0.71, P = .004).

Women in the bevacizumab-plus-chemotherapy arm also lived longer without disease worsening compared to those who received chemotherapy alone, with a median progression-free survival of 8.2 months vs 5.9 months (HR = 0.67, P = .002).

Hypertension of grade 2 or higher was

significantly more common with bevacizumab-containing regimens (25% vs 2%), but did not result in the discontinuation of the drug. Gastrointestinal or genitourinary

Injury, poisoning, and proceduralrecall complications Injury, poisoning, and procedural complications — Radiation has been — Radiation recall has been Special Senses — ocular surface disease (including conjunctivitis), increased Special Senses — ocular surface disease (including conjunctivitis), increased reported received in patients who have previously received radiotherapy. reported in patients who have previously radiotherapy. lacrimation on Respiratory — interstitial pneumonitis Respiratory — interstitial pneumonitis Incidence Less than 1% cidence Less than 1% SkinStevens-Johnson — Bullous conditions, including Stevens-Johnson Skin — Bullous conditions, including syndrome and toxic epidermal syndrome and toxic epidermal Cardiovascular Cardiovascular — supraventricular arrhythmia — supraventricular arrhythmia necrolysis. Some cases were fatal.necrolysis. Some cases were fatal.

Dermatology/Skin — erythema multiforme Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity General Disorders — febrile neutropenia, allergic reaction/hypersensitivity DRUG INTERACTIONS 7 DRUG INTERACTIONS 7 Neurology — motor neuropathy Neurology — motor neuropathy 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Renal — renal failure Renal — renal failure Although (400 mg fourthetimes a day)ofcan decrease the clearance of Although times ibuprofen a day) can decrease clearance ALIMTA ALIMTA as Maintenance Following ALIMTA Plus ibuprofen Platinum(400 mg four ontinuation of ALIMTA as Continuation Maintenance ofFollowing Plus Platinum pemetrexed, it caninbepatients administered with ALIMTA in patients with normal renal function pemetrexed, it can be administered with ALIMTA with normal renal function Induction Therapy duction Therapy clearance ≥80 mL/min).

No dosewith adjustment of ALIMTA is needed with concomitant (creatinine clearance ≥80 mL/min).(creatinine No dose adjustment of ALIMTA is needed concomitant Table 6 provides the frequency severityinof>5% adverse reactions reported in >5% ble 6 provides the frequency and severity of adverse reactionsand reported NSAIDs in patients with normal renal function NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)].[see Clinical Pharmacology (12.3)]. of the 500 patients non-squamous who received at least one cycle of ALIMTA 0 patients with non-squamous NSCLC whowith received at least oneNSCLC cycle of ALIMTA should NSAIDs be usedconcurrently when administering NSAIDs concurrently with ALIMTA Caution should be used when Caution administering with ALIMTA Induction (n=333) or placebo (n=167) ontrial. the continuation maintenance trial. mild to moderate nce (n=333) or placebomaintenance (n=167) on the continuation maintenance to patients with mild to(creatinine moderate clearance renal insufficiency to patients with renal insufficiency from 45 to(creatinine clearance from 45 to Theadministered median of maintenance cycles administered receiving one or more he median of maintenance cycles to patients receiving one or moreto patients 79 mL/min).

79 mL/min). nmaintenance >5% of doses4 of therapy was on botharms. the pemetrexed and NSAIDs placebo with arms.short Doseelimination NSAIDs therapy was on maintenance both the pemetrexed and 4placebo Dose short elimination half-lives (e.g., half-liveswith (e.g., diclofenac, indomethacin) shoulddiclofenac, indomethacin) should ents reductions for adverse events occurred 3.3%andof 0.6% patients ALIMTA arm and 0.6% in s forwith adverse events occurred in 3.3% of patients in the ALIMTAinarm in in the a period 2 daysfollowing before, the day of, and 2 days following administration be avoided for a period of 2 daysbe avoided before, theforday of, andof2 days administration placebo arm.occurred Dose delays for adverse events of patients in the ALIMTA bo arm. Dose delays forthe adverse events in 22% of patients in theoccurred ALIMTA in 22% of ALIMTA. of ALIMTA. m-based and 16% in the placebo in bothwith studyfolic arms were supplemented withof folic 16% in the placebo arm.arm Patients in both study arms arm. werePatients supplemented In the absence of data regarding potential interaction In the absence data regarding potential interaction between ALIMTA and NSAIDs withbetween ALIMTA and NSAIDs with were fully acid and vitamin B12. vitamin B12. half-livespatients (e.g., meloxicam, patients taking these NSAIDs should interrupt longer half-lives (e.g., meloxicam,longer nabumetone), taking thesenabumetone), NSAIDs should interrupt least2 days 5 daysfollowing before, the day of, and 2 days following ALIMTA administration. If for at Receiving least 5 days before,dosing the dayforof,atand ALIMTA administration.

If Table 6:b Occurring Selecteda in e 6: Selecteda Adverse Reactions Adverse Occurring in ≥5%dosing of Patients ≥5% ofReactions Patients bReceiving bo concomitant administration of NSAIDs is necessary, patients concomitant administration is necessary, patients should be monitored closely for should be monitored closely for ALIMTA in Nonsquamous Following ALIMTA Plus Cisplatin Induction Therapy of NSAIDs in Nonsquamous NSCLC Following ALIMTA Plus NSCLC Cisplatin Induction Therapy toxicity, especially myelosuppression, toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.renal, and gastrointestinal toxicity.

ALIMTA Placebo ALIMTA Placebo 7.2 Nephrotoxic Drugs 7.2 Nephrotoxic Drugs (N=333) (N=167) (N=333) (N=167) e Reaction Organ Adverse Reaction Organ ALIMTA is renally primarilyaseliminated ALIMTA is primarily eliminated unchanged a result of unchanged glomerular renally filtrationas a result of glomerular filtration a tem and Term System and Term All Grades Gradesa a Grades Grade3-4 3-4aa All Gradesa Grades 3-4a Grade 3-4a AllAllGrades and tubular secretion.

Concomitantdrugs administration of nephrotoxic drugs could result in and tubular secretion. Concomitant administration of nephrotoxic could result in de 3-4 Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity delayed clearance of ALIMTA. Concomitantthat administration delayed clearance of ALIMTA. Concomitant administration of substances are also of substances that are also city (%) All53Adverse Reactions 34 secreted 4.8 erse Reactions 17 3453 4.817 tubularly (e.g., probenecid) potentially result in delayed clearance of ALIMTA. tubularly (e.g., probenecid) couldsecreted potentially result in delayedcould clearance of ALIMTA. 4 Laboratory tory 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS Hematologic tologic 8.1 Pregnancy 8.1 Pregnancy Anemia 4.8 4.8 0.6 mia 15 4.8 4.815 0.6 Teratogenic Effects - Pregnancy Category D(5.6)]. [see Warnings and Precautions (5.6)].

Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions 1 Neutropenia 0.6 0 openia 9 3.9 0.69 03.9 Based on its action, ALIMTA can cause fetal harm when administered Based on its mechanism of action, ALIMTA canmechanism cause fetalofharm when administered 0 Clinical a pregnant are nostudies adequate and wellin controlled studies of ALIMTA in to a pregnant woman. There areto no adequatewoman. and wellThere controlled of ALIMTA 1 Constitutional tutional pregnant women. fetotoxic, Pemetrexed embryotoxic, fetotoxic, pregnant women. Pemetrexed was embryotoxic, andwas teratogenic in mice.

In and teratogenic in mice. In Symptoms oms mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis 0 Fatigue 4.5 11 fetal malformations 0.6 ue 18 4.5 1118 0.6 caused ossification fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd caused (incomplete of talus and skull bone; about 1/833rd 0 2 the recommended intravenous dosepalate on a (1/33rd mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m basis),human and cleft Gastrointestinal ointestinal recommended human dose on a was mg/m2 basis). Embryotoxicity was the2.4recommended 0intravenous the human dose on aintravenous mg/m2 basis).

Embryotoxicity 00.3 2.412 0.3 12 Nausea ea characterized increased characterized by increased embryo-fetal deathsbyand reducedembryo-fetal litter sizes. Ifdeaths ALIMTAandis reduced used litter sizes. If ALIMTA is used 0 00 1.8 1.86 0 6 Vomiting ting during pregnancy, or if while the patient while taking this drug, the patient during becomes pregnant taking becomes this drug,pregnant the patient 0 if the patient 00.3 2.4 pregnancy, or 2.45 0.3 5 Mucositis/stomatitis sitis/stomatitis 1 should be apprised of theWomen potential hazard to thepotential fetus. Women of childbearing potential should be apprised of the potential hazard to the fetus. of childbearing General Disorders al Disorders be advised to use effective contraceptive measures should be advised to use effectiveshould contraceptive measures to prevent pregnancy during the to prevent pregnancy during the Edema 3.6 with ALIMTA. 0 ma 5 0 3.65 00 treatment with ALIMTA. treatment 1 a reactions of any severity (all grades) more frequently (≥5%) orMothers Grade 3-4 reactions of any severityAdverse (all grades) occurring more frequently (≥5%) occurring or Grade 3-4 0 8.3 Nursing Mothers 8.3 Nursing reactions more frequently in ALIMTA-treatedIt patients reactions occurring moreadverse frequently (≥2%)occurring in ALIMTA-treated patients(≥2%) compared 0 It is ornotitsknown whetherareALIMTA metabolites are excreted in human is not compared known whether ALIMTA metabolites excretedor inits human to those receiving placebo receiving placebo 0 milk. Because manymilk, drugs excreted milk, milk. Because many drugs are excreted in human andarebecause of inthehuman potential forand because of the potential for b CAE 0 Criteria version 3.0 NCI CTCAE Criteria version 3.0 serious adverse ALIMTA, serious adverse reactions in nursing infants fromreactions ALIMTA, ina nursing decisioninfants should from be made to a decision should be made to of RBC (13%versus versus0.6%) 4.8%)transfusions, and platelet (1.5% versus 0.6%) transfusions, dministration of RBC (13% versusAdministration 4.8%) and platelet (1.5% discontinue nursinginto or discontinue drug, taking intodrug account the importance of the drug discontinue nursing or discontinue the drug, taking account the the importance of the 0 (12%colony versusstimulating 7%), and granulocyte colony stimulating for the mother. iesis stimulating agentserythropoiesis (12% versusstimulating 7%), and agents granulocyte for the mother.

(6% versus were higher in the ALIMTA % versus 0) were higherfactors in the ALIMTA arm0)compared to the placebo arm.arm compared to the placebo arm.

8.4 Pediatric Use 8.4 Pediatric Use additional or 4 adverse he0 following additional Grade The 3 orfollowing 4 adverse reactionsGrade were3 observed more reactions were observed more Efficacy of in pediatric patients has not Efficacy of ALIMTA in pediatric patients hasALIMTA not been demonstrated.

ALIMTA wasbeen demonstrated. ALIMTA was y in the ALIMTA arm. frequently in the ALIMTA arm. intravenous 10 cycle minutes administered as an intravenous administered infusion over as 10anminutes on Dayinfusion 1 of a over 21 day to on Day 1 of a 21 day cycle to Incidence 1% to 5% cidence 1% to 5% 0 patients with recurrent solidpatients) tumors and in a aPhase pediatric patients with recurrent pediatric solid tumors in a Phase 1 study (32 Phase1 study (32 patients) and a Phase Blood/Bone Marrow — thrombocytopenia Blood/Bone Marrow — thrombocytopenia 2 study (72 pretreatment patients). All with patients received pretreatment 2 study (72 patients). All patients received vitamin B12 and folic acid with vitamin B12 and folic acid where the General Disorders — febrile neutropenia General Disorders — febrile neutropenia supplementation and dexamethasone. dosedetermined escalation in the Phase 1 study determined supplementation and dexamethasone.

The dose escalation in the PhaseThe 1 study Incidence Less than 1% cidence Less than 1% 2 the1910 maximum 1910 mg/mfor2 and the maximum tolerated dose was mg/mtolerated this dose (or 60 mg/kg for patients and thisdose dosewas (or 60 mg/kg patients Cardiovascular — ventricular tachycardia, syncope <12 months old) was evaluated in<12 months Cardiovascular — ventricular tachycardia, syncope wasofevaluated in therelapsed Phase 2orstudy of patients with relapsed or refractory the Phase 2old) study patients with refractory n patients General Disorders — pain General Disorders — pain osteosarcoma,PNET, Ewing sarcoma/peripheralneuroblastoma, PNET, rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing sarcoma/peripheral rhabdomyosarcoma, Grade 3/4 Gastrointestinal Gastrointestinal — gastrointestinal obstruction — gastrointestinal obstruction ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma.

0.6%).

Neurologic — depression Neurologic — depression No responses were observed among theThe 72 patients in this Phase 2 trial. The most common No responses were observed among the 72 patients in this Phase 2 trial. most common e dose of Renal — renal failure Renal — renal failure toxicities reported were hematological (leukopenia,anemia, neutropenia/granulocytopenia, anemia, toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, ents who thrombocytopenia, lymphopenia), liver function abnormalities (increased ALT/AST), thrombocytopenia, and lymphopenia), liver functionandabnormalities (increased ALT/AST), fVascular ALIMTA. — pulmonary embolismVascular — pulmonary embolism No relevant effect for ALIMTA due toexcept gender was identified, except an fatigue, and nausea. owever relevant due to gender or race wassafety identified, anor race fatigue, and nausea. no effect for ALIMTA safety increasedcompared incidence to of women (16%). rash in men (24%) compared to women (16%).The single dose pharmacokinetics d incidence of rash in men (24%) The single dose administered pharmacokinetics of ALIMTA of ALIMTA in doses rangingadministered in doses ranging Additional dditional Trials Experience Across Clinical Trials from 400 to 2480 mg/m from 400 to 2480 mg/m2 were evaluated were themales Phaseand 1 trial in 22 patients (13 males and in the Phase 1 2trial in evaluated 22 patientsin(13 arm, useExperience Across Clinical which in insome cases was 1% fatal,ofoccurred of patients. psis, which in some cases wasSepsis, fatal, occurred approximately patients. in approximately females)age aged to 18 Pemetrexed years (average age 12(AUC years).

9 females)1% aged 4 to 18 years 9(average 12 4years). exposure and Pemetrexed exposure (AUC and hropoietin Esophagitis occurred in less than 1% of patients. ophagitis occurred in less than 1% of patients.

Cmax) appeared Cmax) appeared to increase proportionally to increase proportionally with dose.

The average pemetrexed clearance with dose.

The average pemetrexed clearance nsfusions 2 (2.30 L/h/m2) and half-life (2.3 (2.30 ) and half-life in pediatric patients were comparable to values hours)L/h/m in pediatric patients(2.3 werehours) comparable to values 6.2 Postmarketing Experience ostmarketing Experience reported in adults. use of reported in adults. adverse during reactions have been use identified post-approval heon-small following adverse reactionsThe havefollowing been identified post-approval of during Because these reactions are reportedof voluntarily uncertain 8.5 Geriatric Use Because these reactionsALIMTA. are reported voluntarily from a population uncertain from8.5a population GeriatricofUse it is not alwaystheir possible to reliably estimate their frequency orALIMTA establish a causal not always possible tosize, reliably estimate frequency or establish a causal ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse is known to be substantially excreted by the kidney, and the risk of adverse hip to drug exposure. relationship to drug exposure. reactions to thiswith drugimpaired may be greater in patients with impaired renal function. Renal function reactions to this drug may be greater in patients renal function.

Renal function occurred ALIMTA when as a single-agent and in withmonitoring hese reactions occurred withThese ALIMTAreactions when used as awith single-agent and inused monitoring is recommended administration of ALIMTA. is recommended administration of ALIMTA. Nowith dose reductions other than No dose reductions other than combination therapies. ion therapies. those all patients areofnecessary for patients those recommended for all patients arerecommended necessary for for patients 65 years age or older [see 65 years of age or older [see Dosage and Administration (2.4)].Dosage and Administration (2.4)].

Blood and Lymphatic Systemanemia – Immune-mediated hemolytic anemia ood and Lymphatic System – Immune-mediated hemolytic ecreased 3,946across patients ≥65) trials studied[see across the five clinical trials [see Clinical Of 3,946 patients (34.0% ≥65) Of studied the(34.0% five clinical Clinical Gastrointestinal — colitis, pancreatitis astrointestinal — colitis, pancreatitis Studies 14.2, 14.3,onand 14.4)],was the similar effect ofinALIMTA the (14.1, effect of ALIMTA survival patientson survival was similar in patients General and—Administration Site Conditions —Studies edema (14.1, 14.2, 14.3, and 14.4)], eneral Disorders and Administration SiteDisorders Conditions edema

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fistulas of grade 3 or higher were significantly increased with the bevacizumabcontaining regimens (6% vs 0%), as were thromboembolic events of grade 3 or higher (8% vs 1%).

There was no increase in treatmentrelated deaths in the bevacizumab-pluschemotherapy arm, as compared to the chemotherapy-alone arm. n

The ASCO Post | AUGUST 15, 2014

PAGE 48

FDA Update

FDA Grants Bevacizumab Priority Review for Recurrent Platinum-Resistant Ovarian Cancer

T

he U.S. Food and Drug Administration (FDA) has accepted Genentech’s supplemental Biologics License Application and granted Priority Review for bevacizumab (Avastin) plus chemothera-

py for the treatment of women with recurrent platinum-resistant ovarian cancer.

“The majority of women with ovarian cancer will become resistant to platinum therapy, and a quarter of women

will have platinum-resistant disease at the time of a first recurrence. New treatment options are needed,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development.

<65 compared to ≥65 years of age. There were no differences in safety with the exception <65 compared to ≥65 years of age. There were ofnothe differences safety3-4 withadverse the exception followinginGrade reactions, which were noted in at least one of the five of the following Grade 3-4 adverse reactions, which least one65ofyears the five trials were to be noted greaterininatpatients of age and older as compared to younger patients: trials to be greater in patients 65 years of age and older, fatigue, as compared to younger patients: anemia thrombocytopenia, hypertension, and neutropenia. anemia , fatigue, thrombocytopenia, hypertension, and neutropenia.

8.6 Patients with Hepatic Impairment 8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics There was no effect of elevated AST, ALT,oforpemetrexed. total bilirubin However, on the pharmacokinetics no formal studies have been conducted to examine the of pemetrexed. However, no formal studies pharmacokinetics have been conducted to examine of pemetrexed in the patients with hepatic impairment [see Clinical pharmacokinetics of pemetrexed in patientsPharmacology with hepatic(12.3)]. impairment [see Clinical Pharmacology (12.3)].

8.7 Patients with Renal Impairment 8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function ALIMTA is known to be primarily excretedwillby result the kidneys.

Decreased renaland function in reduced clearance greater exposure (AUC) to ALIMTA compared with will result in reduced clearance and greater exposure (AUC)normal to ALIMTA with Dosage and Administration (2.4) and Clinical patients with renalcompared function [see patients with normal renal function [see Dosage and Administration (2.4)fullandPrescribing Clinical Information]. Cisplatin coadministration with Pharmacology (12.3) in the Pharmacology (12.3) in the full Prescribing Information].

ALIMTA hasCisplatin not beencoadministration studied in patientswith with moderate renal impairment.

ALIMTA has not been studied in patients with moderate renal impairment.

8.8 Gender 8.8 Gender Of 3,946 patients (Male 70.5% ) studied across the five registration studies for Of 3,946 patients (Male 70.5% ) studied acrossindications the five registration ALIMTA [see Clinical studies Studies for (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, effect ofand ALIMTA on survival and was14.4)], similarthe in female male patients. on survival was similar in female and male patients.

8.9 Race 8.9 Race Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for Of 3,946 patients (Caucasian 78.6%) studied across the five[see registration ALIMTA indications Clinical studies Studies for (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, effect of ALIMTA on survival and was14.4)], similarthe in the Caucasian and non-Caucasian patients. on survival was similar in the Caucasian and non-Caucasian patients.

10 OVERDOSAGE 10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included There have been few cases of ALIMTA overdose. anemia, Reportedthrombocytopenia, toxicities includedmucositis, and rash. Anticipated complications neutropenia, neutropenia, anemia, thrombocytopenia, mucositis, and rash.include Anticipated of overdose bonecomplications marrow suppression as manifested by neutropenia, of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia.

In addition, infection with or without fever, diarrhea, and thrombocytopenia, and anemia. In addition, infection withmay or without mucositis be seen.fever, If andiarrhea, overdoseandoccurs, general supportive measures should be mucositis may be seen. If an overdose occurs,instituted general as supportive measures by should be physician. deemed necessary the treating instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia In clinical trials, leucovorin was permitted CTCCTCGrade lasting ≥3fordays, Grade4 4 leukopenia neutropenia lasting ≥3 days, and immediately for CTC lasting ≥3 days, CTC Grade 4 neutropenia lasting and immediately for CTC Grade ≥34 days, thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 4 thrombocytopenia, bleeding associated withorGrade 3 thrombocytopenia, or Grade 3 4 mucositis.

The following intravenous doses and schedules of leucovorin were Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin recommended for intravenous use: 100were mg/m2, intravenously once, followed by leucovorin, 2 intravenously once, followed recommended for intravenous use: 100 mg/m , 50 everyby6leucovorin, hours for 8 days. mg/m2, intravenously 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.1 Carcinogenesis, Mutagenesis, Impairment ofNo Fertility carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was No carcinogenicity studies have been conducted withinpemetrexed.

Pemetrexed assay was in mouse bone marrow but was not mutagenic clastogenic the in vivo micronucleus clastogenic in the in vivo micronucleus assay in mouse boneinmarrow but(Ames was not mutagenic in multiple vitro tests assay, CHO cell assay). Pemetrexed administered at i.v. doses in multiple in vitro tests (Ames assay, CHO cell assay). administered at i.v.mice doses(about 1/1666 the recommended human dose on of 0.1Pemetrexed mg/kg/day or greater to male 2 the recommended human dose on of 0.1 mg/kg/day or greater to male mice (abouta1/1666 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. mg/m a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATION 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (PPI) See FDA-Approved Patient Labeling (PPI) Instruct patients to read the patient package insert before initiating ALIMTA. Instruct patients to read the patient package insert initiating ALIMTA. • before Instruct patients on the need for folic acid and vitamin B 12 supplementation to to • Instruct patients on the need for folic acid and vitamin B 12 supplementation reduce treatment-related hematologic and gastrointestinal toxicity and of the reduce treatment-related hematologic and gastrointestinal toxicity and toofreduce the treatment-related dermatologic toxicity [see need for corticosteroids need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

Dosage and Administration (2.3) and Warnings Precautions • and Inform patients (5.1)]. of the risk of low blood cell counts and instruct them to • Inform patients of the risk of low blood cell immediately counts and contact instruct their them physician to for signs of infection, including fever, immediately contact their physician for signsbleeding of infection, including fever, or symptoms of anemia. bleeding or symptoms of anemia.

• Instruct patients to contact their physician if persistent vomiting, diarrhea, or • Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear. signs of dehydration appear.

• Instruct patients to inform their physician of all concomitant prescription • Instruct patients to inform their physician of orall concomitant prescription over-the-counter medications they are taking, particularly those for pain or over-the-counter medications they are taking, particularly those or inflammation such for as pain non-steroidal anti-inflammatory drugs [see Drug or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company 1-800-LillyRx or http://www.fda.gov/medwatch.

(1-800-545-5979) or FDA atat1-800-FDA-1088, (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch.

Additional information can be found at www.AlimtaHCP.com Additional information can be found at www.AlimtaHCP.com

Marketed by: Lilly USA, LLC Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Indianapolis, IN 46285, USA Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PM HCP BS NSCLC1M 18Nov2013 PM HCP BS NSCLC1M 18Nov2013 ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP

The designation of Priority Review status is granted to medicines that the FDA believes have the potential to provide “significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.” The supplemental Biologics License Application for bevacizumab plus chemotherapy for recurrent platinum-resistant ovarian cancer is based on data from the phase III AURELIA trial.

AURELIA Study AURELIA is a company-sponsored, multicenter, randomized, open-label, phase III study in 361 women with platinum-resistant recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer who had received no more than two anticancer regimens prior to enrollment in the trial. Participants were randomly assigned to one of six treatment arms (paclitaxel, topotecan, or liposomal doxorubicin with or without bevacizumab).

The study met its primary endpoint and showed that bevacizumab plus chemotherapy reduced the risk of disease progression by 52% compared to chemotherapy alone; the median progression-free survival was 6.7 months for bevacizumab plus chemotherapy vs 3.4 months for chemotherapy alone (hazard ratio [HR] = 0.48, P < .001). No statistically significant difference was seen in the secondary endpoint of overall survival (P < .174).

Women in the bevacizumab-plus-paclitaxel arm (n = 60) experienced a 54% improvement in progression-free survival (10.4 vs 3.9 months; HR = 0.46, 95% confidence interval [CI] = 0.30–0.71) and a 35% improvement in overall survival (22.4 vs 13.2 months; HR = 0.65, 95% CI = 0.42–1.02).

The study showed women who received bevacizumab plus chemotherapy had a significantly higher objective response rate compared to chemotherapy alone when evaluated by the RECIST criteria (27.3% vs 11.8%, respectively; P = .001).

Grade 3 to 5 adverse events occurring at a higher incidence in women receiving bevacizumab plus chemotherapy compared to women receiving chemotherapy alone were hypertension (7% vs 1%), proteinuria (2% vs 0 %) and gastrointestinal perforations (2% vs 0%). n

ALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5

PRINTER VERSION 4

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Journal Spotlight Guidelines

Adjuvant Endocrine Therapy for Hormone Receptor–Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update

By Matthew Stenger

A

SCO has released a focused update of its clinical practice guideline on adjuvant endocrine therapy in women with hormone receptor–positive breast cancer.1 The focused update, formulated

by Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues in the ASCO Update Committee and published in Journal of Clinical Oncology, was warranted by emergence of data on optimal duration of treatment, particularly with adjuvant tamoxifen. The update includes review of evidence on duration of tamoxifen treatment of > 5 years. Recommendations regarding duration of adjuvant endocrine therapy < 5 years, sequencing of therapy, and aromatase inhibitor treatment appear in the 2010 ASCO guideline update on adjuvant endocrine therapy.2 The focused update was developed by a multidisciplinary group of experts (the update committee), who conducted a systematic review of randomized clinical trials from January 2009 to June 2013 and analyzed three historical trials. The recommendations are based on the clinical trial evidence and clinical experience.

What’s New In brief, five studies of tamoxifen treatment of > 5 years were identified, with the two largest studies with longest follow-up showing a breast cancer survival advantage with a 10-year duration of tamoxifen treatment. In addition, extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer.

Previous ASCO guidelines recommended treatment with 5 years of tamoxifen in premenopausal women with hormone receptor–positive breast cancer and a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor (in sequence) in postmenopausal women. The guideline update recommends that pre- or perimenopausal women who have received 5 years of adjuvant tamoxifen should be offered 10 years total duration of tamoxifen. Postmenopausal women who have received 5 years of adjuvant tamoxifen should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy.

Recommendations The central question for the focused update was: What is the recommended duration of adjuvant endocrine monotherapy? The recommendations are summarized below, along with notations for type of evidence, evidence quality, and strength of recommendation.

Pre- or Perimenopausal Women Women with hormone receptor– positive breast cancer who are pre- or perimenopausal should be offered adjuvant endocrine therapy with tamoxifen

tamoxifen for a duration of 10 years (type = evidence-based, evidence quality = high, strength of recommendation = strong); (2) an aromatase inhibitor for 5 years; there are insufficient data to recommend an aromatase inhibitor for a duration > 5 years (type =evidence-based, evidence quality = high, strength of recommendation = strong); (3) tamoxifen for an initial duration of 5 years with a switch to an aromatase inhibitor for up to 5 years, for a total duration of therapy of up to 10 years (type = evidence-based, evidence quality = high, strength of recommendation = strong); or (4) Tamoxifen for a dura-

The guideline panel encouraged longer durations of therapy based on the emerging data, understanding that the benefits of longer durations of treatment are small and may not justify the side effects of treatment for many women. Usually, clinicians and patients can find common ground based on the patient’s preferences and the risks of cancer recurrence.

—Harold J. Burstein, MD, PhD

women should be offered continued tamoxifen for a total duration of 10 years or a switch to aromatase inhibitor treatment for up to 5 years, for a total duration of up to 10 years of therapy (type = evidence-based, evidence quality =high, strength of recommendation = strong). Pre- or perimenopausal women and women in whom menopausal status cannot be ascertained should be offered 5 additional years of tamoxifen, for a total duration of 10 years (type = evidence-based, evidence quality = high, strength of recommendation = strong).

Benefits and Risks Prospective benefits of implementation of the new recommendations include increased overall survival and distant disease-free survival and reduced breast cancer–specific mortality, risk of recurrence, and risk of contralateral breast cancer.

Potential harms include risk of endometrial cancer (in women continuing tamoxifen), hot flashes and other menopausal symptoms (with either tamoxifen or aromatase inhibitors), deep-vein thrombosis or pulmonary embolism (with tamoxifen), ischemic heart disease (with aromatase inhibitor), osteopenia/ osteoporosis (with aromatase inhibitor), and uterine cancer (with tamoxifen).

Qualification for an initial duration of 5 years. After 5 years, women should receive additional therapy based on menopausal status.

Pre- or perimenopausal women and those in whom menopausal status is unknown or cannot be determined should be offered continued tamoxifen for a total duration of 10 years (type = evidence-based, evidence quality = high, strength of recommendation = strong).

Women who have become definitively postmenopausal should be offered continued tamoxifen for a total duration of 10 years or a switch to up to 5 years of aromatase inhibitor therapy, for a total duration of treatment of up to 10 years (type = evidence-based, evidence quality for tamoxifen = high, evidence quality for aromatase inhibitor = high, strength of recommendation = strong.)

Postmenopausal Women Postmenopausal women with hormone receptor–positive breast cancer should be offered adjuvant endocrine therapy with one of the following: (1)

tion of 2 to 3 years with a switch to an aromatase inhibitor for up to 5 years, for a total duration of up to 7 to 8 years (type = evidence-based, evidence quality = high, strength of recommendation = strong).

Appropriate Sequence Women who are postmenopausal and are intolerant of either tamoxifen or an aromatase inhibitor should be offered the alternative type of endocrine therapy.

Women who have discontinued aromatase inhibitor treatment at < 5 years may be offered tamoxifen for a total of 5 years (type = informal consensus, evidence quality = low, strength of recommendation = weak).

Women who have received tamoxifen for 2 to 3 years should be offered a switch to an aromatase inhibitor for up to 5 years, for a total duration of up to 7 to 8 years of therapy (type = evidence-based, evidence quality = high, strength of recommendation = strong).

Women who have received 5 years of tamoxifen as adjuvant therapy should be offered additional adjuvant endocrine treatment. Postmenopausal

There are no specific patient populations or subgroups, except for menopausal status subgroups that appear to derive differing degrees of benefit from an aromatase inhibitor vs tamoxifen or for the adjuvant treatment durations recommended.

Clinicians and patients should discuss a patient’s individual risk-benefit profile.

Patient information on this topic can be found at www.cancer.net. n

Disclosure: Dr. Burstein reported no potential conflicts of interest. For full disclosures of all the guideline authors, visit jco.ascopubs.org.

References 1. Burstein HJ, Temin S, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol 32:2255-2269, 2014.

2. Burstein HJ, Prestrud AA, Seidenfeld J, et al: American Society of Clinical Oncology clinical practice guideline: Update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 28:3784-3796, 2010.

The ASCO Post | AUGUST 15, 2014

PAGE 50

Perspective

Patience Remains a Virtue: The Ongoing Quest to Optimize Adjuvant Endocrine Therapy in Breast Cancer

By Kathy D. Miller, MD

T

he most recent ASCO Clinical Practice Guideline update— summarized in this issue of The ASCO Post—represents the latest chapter in the ongoing evolution of adjuvant endocrine therapy for hormone-sensitive breast cancer.1 Rather than including a comprehensive review of the 2010 guidelines, this update focuses on the duration of tamoxifen therapy.

With each change in guidelines, clinicians are likely to ask three important questions: (1) What happened? (2) How should my practice change? and (3) Are we done yet?

What Happened?

Long ago, patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial who were completing 5 years of therapy were offered re-randomization to an additional 5 years of tamoxifen vs placebo. Disease-free survival, relapse-free survival, and overall survival all favored placebo, though only the difference in disease-free survival reached statistical significance.2 Though the efficacy results were surprising, the toxicity results were entirely predictable—longer duration of therapy brought more toxicity. In the absence of any suggestion of benefit and with the real and documented increased toxicity, guidance at the time appropriately recommended that tamoxifen therapy be limited to 5 years’ duration.

Many researchers urged caution, pointing out that NSABP B-14 was a relatively small trial limited to patients with a low risk of recurrence (~1,150 patients enrolled, 243 disease-free events reported). They suggested that B-14 provided, at best, a preliminary estimate rather than a definitive answer.

While much of the focus of hormone therapy investigations over the ensuing decade shifted to the aromatase inhibitors, the ATLAS and aTTom trials soldiered on, re-addressing the tamoxifen duration question and contributing more than 10 times the number of patients enrolled in B-14 to the analysis.3,4 The result was clear: Dr. Miller is Professor of Medicine at Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.

longer treatment (at least up to 10 years) does increase the risk of significant toxicity, but also reduces the risk of recurrence. Importantly, longer duration of tamoxifen decreased the risk of death from any cause, providing irrefutable confirmation that the benefit outweighs the risk.

How Should My Practice Change?

The change in guidelines is most directly applicable to those patients who remain premenopausal after 5 years of tamoxifen therapy. If observation off therapy was an uncomfortable option, patients and their treating physicians

in trials with limited follow-up or a small number of events will always require caution. The benefit of therapeutic interventions may not be apparent until 7 to 8 years after diagnosis,7 and may take even longer to reach statistical significance.

Questions remain regarding the optimal duration (and schedule) of the aromatase inhibitors and the role of ovarian suppression. Since the guideline panel met to review the ATLAS and ATTom trial data, the combined analysis of the TEXT and SOFT trials suggested that ovarian suppression and exemestane reduced recurrence compared to ovarian sup-

Perhaps the ‘optimal’ hormone therapy might be described most simply as ‘the hormone therapy the patient can and will continue to take.’

—Kathy D. Miller, MD

faced a difficult choice of continuing tamoxifen or pursuing ovarian suppression (either alone or with an aromatase inhibitor), recognizing that both choices brought toxicity and had no proven benefit. Those patients should be offered the option of continuing tamoxifen for another 5 years.

We should also be mindful of the broader implications. Patients who become amenorrheic during tamoxifen therapy also now have a choice for extended therapy—either continue tamoxifen or change to an aromatase inhibitor. Many postmenopausal patients find the aromatase inhibitors difficult to tolerate, with up to 25% discontinuing therapy due to toxicity in some studies.5 Postmenopausal patients unable to tolerate the aromatase inhibitors should be offered extended-duration tamoxifen.

Are We Done Yet? We are clearly not done yet. Hormone-sensitive breast cancer has an extremely long natural history with a low but constant rate of recurrence over at least 15 years.6 Quick answers

pression and tamoxifen.8 Additional analyses of the SOFT trial to clarify the impact of ovarian suppression are expected within the next year. The understanding of the impact of breast cancer molecular subtype on the benefit of various hormone therapy strategies is in its infancy.

In short, patience will remain a virtue when it comes to the management of hormone-sensitive early breast cancer. Since up to 40% of patients discontinue hormone therapy before completing even 5 years (often without the knowledge of their treating physician),9,10 the benefit from enhancing adherence is likely to far outweigh the incremental benefits reported in any of the trials reported thus far. Perhaps the “optimal” hormone therapy might be described most simply as “the hormone therapy the patient can and will continue to take.” n Disclosure: Dr. Miller reported no potential conflicts of interest.

References 1. Burstein HJ, Temin S, Anderson H, et al: Adjuvant endocrine therapy for women

with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol 32:2255-2269, 2014.

2. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93:684690, 2001.

3. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381:805-816, 2013.

4. Gray R, Rea D, Handley K, et al: ATTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 31(suppl):Abstract 5, 2013.

5. Henry NL, Skaar TC, Dantzer J, et al: Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer. Breast Cancer Res Treat 138:807-816, 2013.

6. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738-2746, 1996.

7. Albain KS, Barlow WE, Ravdin PM, et al: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet 374:2055-2063, 2009.

8. Pagani O, Regan M, Walley BA, et al: Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials.

J Clin Oncol 32(suppl):Abstract LBA1, 2014.

9. Partridge AH, Wang PS, Winer EP, et al: Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:602-606, 2003.

10. Partridge AH, LaFountain A, Mayer E, et al: Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol 26:556-562, 2008.

FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.

Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% confidence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

EXTEND SURVIVAL WITH ZELBORAF Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)† 100

HR=0.47 (95% CI, 0.35-0.62), P<0.0001

Percentage surviving

80 60 40 20 0

0

1

2

3

4

5

6

7 8 OS (months)

9

10

ZELBORAF (n=337)

11

12

13

Dacarbazine (n=338)

14

*Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2 † At the time of FDA approval, median follow-up was 6.2 months for ZELBORAF patients.

53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (HR=0.47; 95% CI, 0.35-0.62; P<0.0001) —78 (23%) deaths and 122 (36%) deaths in the ZELBORAF and dacarbazine arms, respectively In an updated analysis, median OS was reached at 13.6 months with ZELBORAF: 3.3-month improvement over median OS of 10.3 months with dacarbazine (95% CI, 12.0-15.3 months vs 9.1-12.8 months) —Updated based on 478 deaths (ZELBORAF median follow-up 13.4 months)

Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.

Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms.

Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies.

Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

© 2014 Genentech USA, Inc. All rights reserved. BRF0000653206

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued.

QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.

Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval.

Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.

Significant improvement in PFS ≈4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).

Hepatotoxicity Liver laboratory abnormalities can occur.

Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation.

Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid).

Photosensitivity Mild to severe photosensitivity can occur.

Advise patients to avoid sun exposure and use adequate sun protection.

Institute dose modifications for intolerable grade 2 or greater photosensitivity.

Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm.

Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011.

Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | AUGUST 15, 2014

PAGE 54

Awards

Fred Hutchinson Cancer Research Center Researcher Veena Shankaran, MD, to Receive ‘40 Under 40’ Award

T

he Puget Sound Business Journal (PSBJ) has recognized Veena Shankaran, MD, a Medical Oncologist and Health Economist at Fred Hutchinson Cancer Research Center,

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF* Trial 1: Treatment Naïve Patients

ADRs

Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

ZELBORAF n= 336 Grade All Grades 3a (%) (%)

Trial 2: Patients with Failure of at Least One Prior Systemic Therapy Dacarbazine ZELBORAF n= 287 n= 132 Grade Grade All All Grades 3a Grades 3 (%) (%) (%) (%)

37 33 45 23 24 9 8 19 5 14

8 3 <1 1 1 2 0 0 <1 0

2 4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

5

3

1

0

15

6

18

0

8

<1

21

0

8

0

7

0

12

0

10

0

0

0

14

0

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.

Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0 * For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

honoring all 40 recipients later this fall.

Dr. Shankaran, who has appointments in the Clinical Research and Public Health Sciences divisions at Fred Hutchinson, specializes in caring

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)].

7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)].

Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.

7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates.

If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].

ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.

Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established.

8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment.

10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)].

• ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)].

• Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)].

• Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)].

• ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)].

• Liver laboratory abnormalities can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)].

• ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)].

• Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)].

• ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422005 Initial U.S. Approval: August 2011 © 2014 Genentech, Inc

for patients with gastrointestinal malignancies. She’s also an Investigator in the Hutchinson Institute for Cancer Outcomes Research (HICOR), where she studies health economics and

Veena Shankaran, MD

comparative effectiveness with a focus on patterns of care and risk factors for financial hardship among cancer patients.

Dr. Shankaran’s work is motivated largely by a recent HICOR study that found close to 40% of colon cancer patients in the western Washington/ Puget Sound region have experienced major financial hardship related to their diagnosis and treatment. So-called “financial toxicity” is, unfortunately, an issue that often goes unassessed and unmeasured until patients already face serious financial challenges.

“Beyond the critically important step of understanding the risk factors for financial toxicity in our patients, I recognize the importance of developing strategies to mitigate this toxicity,” Dr. Shankaran said. “One such strategy includes educating patients about the financial impact of cancer and providing access to copayment assistance, social work resources, and financial counselors.”

Dr. Shankaran recently received a Career Development Award from the ASCO’s Conquer Cancer Foundation. She and her HICOR colleagues are now working on one of the largest population-based studies of financial toxicity among colon cancer patients starting from the time of diagnosis. n

Safety:10"

ZELBORAF ® (vemurafenib) tablet for oral use Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information.

1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure.

In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)].

5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)].

5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)].

5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.

Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.

Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).

5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated.

Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation.

Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)].

5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.

Institute dose modifications for intolerable Grade 2 or greater photosensitivity.

5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.

5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.

There are no adequate and well-controlled studies in pregnant women.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily.

Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash.

The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

as one of 40 individuals under age 40 who have demonstrated extraordinary leadership within their field. Dr. ­Shankaran will accept the award, now Safety:7" in its 16th year, at a PSBJ reception

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

ASCOPost.com | AUGUST 15, 2014

PAGE 55

Expert’s Corner Survivorship

More Collaboration Needed Between Oncologists and Primary Care Physicians

By Ronald Piana

Making the Transition

Larissa Nekhlyudov, MD, MPH

O

ne of the most important cancer survivorship issues is the transition from oncologist to the primary care setting. With a growing population of cancer survivors, patients need to feel secure about their primary care provider having the tools to address their special needs. To shed light on this important issue, The ASCO Post spoke with ­Larissa Nekhlyudov, MD, MPH, Associate Professor in the Department of Population Medicine, Harvard Medical School, Boston. Dr. Nekhlyudov is a primary care provider specializing in caring for cancer survivors.

Dual Focus Please tell the readers a bit about your background and your current position.

After medical school, I did my residency and internship in internal medicine and then pursued a research fellowship focusing on breast cancer screening.

After my fellowship, I joined the faculty at Harvard Medical School, where I primarily did research across the entire spectrum of cancer care, while still practicing general internal medicine.

More recently, I’ve have taken on a role as a medical provider for adult survivors of childhood cancer at the Dana-Farber Cancer Institute’s David B. Perini, Jr. Quality of Life Clinic. In this consultative role, I address patients’ long-term survivorship needs, which include surveillance for recurrences, monitoring for late and long-term effects of cancer therapies, psychosocial issues, and health promotion.

What sparked your interest in the transition of cancer patients from the oncology setting to the primary care setting?

I’ve been a practicing primary care physician at Harvard Vanguard Medical Associates in Boston since 1999. I care for adult patients with a variety of medical conditions. About 10 years ago, my cancer care research began to focus more on treatment and survivorship.

As I gained expertise in cancer survivorship, I began getting referrals from our local oncologists of patients who had successfully undergone cancer therapy.

In some ways, I became the designated primary care provider for cancer survivors, since the local oncologists felt very comfortable transitioning their patients to me.

Not-So-Seamless Transition In theory, the interaction between oncologist and primary care physician should be a seamless transition with valuable interaction. As one who has successfully bridged the gap between the two disciplines, what have you found?

tinuum, there is very little communication between the oncology provider and the primary care doctor. Many times, it’s up to the patient to make sure that all the parties involved are on the same page.

Models for Continuity In your recent paper in The Oncologist,1 you describe models for involving primary care in cancer survivorship. Please describe them.

The ideal model is one in which the primary care provider is affiliated with a cancer center and engages in the care of the patient from time of diagnosis and into the survivorship phase of care. In this model, the primary care physician needs an in-depth understanding of the implications of cancer and also of the treatments that are given.

Moreover, the primary care physician must have knowledge of surveillance for recurrence and skills for monitoring and managing issues in late-stage disease.

Working together, the oncologist and primary care doctor can also put together individualized survivorship care plans, which includes the interaction of cancer-

Given the growing survivorship population and the workforce challenges in both oncology and primary care, it becomes increasingly important for the two disciplines to communicate and help each other care for the multiple needs involved in cancer survivorship.

—Larissa Nekhlyudov, MD, MPH

One would think that the interaction between oncology and primary care, given the delicate transition needs of the patients, would be seamless, but that’s not the case. Once the cancer diagnosis is made and the patient is referred to an oncology team, there is usually some back and forth among the oncology team and the primary care provider.

As time goes on, the patient gets totally drawn into the oncology setting, which has multiple providers, so the primary care doctor begins to fall out of the care loop. At that point in the care con-

related and comorbid medical conditions. Although this is the optimal model for integrating primary care into cancer care, it isn’t feasible in most settings.

The other model also includes an expert primary care provider with training in survivorship care, but instead of being embedded in the continuity of care, the provider acts more as a consultant as patients complete therapy and transition to survivorship. As part of the consultative model, the primary care provider maintains communication with the oncologist.

That said, there is a role for the primary care physician who has no training in cancer care but has an interest in patients who are transitioning into the survivorship phase. When transitioning from active care, patients can choose such primary care providers, which will help ease the anxiety of transitioning from the oncologist. These relationships can begin a shared organic process during which the primary care doctor learns about survivorship needs as the process evolves.

Given the growing survivorship population and the workforce challenges in both oncology and primary care, it becomes increasingly important for the two disciplines to communicate and help each other care for the multiple needs involved in cancer survivorship.

Moving forward, it is probably a good idea to add more oncology courses into the general internist and primary care curriculum. Primary care doctors will never get involved in oncologic therapy decisions, but a deeper awareness of how cancer and its treatments affect their patients is needed.

Looking Ahead Please give the readers a last thought or two about this valuable issue, and where you see this important continuum-of-care issue progressing.

The growing population of cancer survivors presents a challenge to the cancer care delivery system, which, in many areas of practice, is understaffed and overworked. Moving forward, the oncology community will need a concerted effort to ensure that their patients receive the high-quality care they deserve. One way to handle this challenge is to have a more active involvement of primary care physicians in cancer survivorship programs. n Disclosure: Dr. Nekhlyudov reported no potential conflicts of interest.

Reference 1. Nekhlyudov L: Integrating primary care in cancer survivorship programs: Models of care for a growing patient population.

Oncologist 19:579-582, 2014.

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | AUGUST 15, 2014

PAGE 56

Philanthropy Spotlight

Direct From ASCO

Our First Charge: Fostering the Next Generation of Oncologists and Cancer Researchers ASCO Board Member Gary H. Lyman, MD, MPH, FASCO, Focuses Philanthropy on Early-Career Research

G

ary H. Lyman, MD, MPH, FASCO, is Co-Director of the Hutchinson Institute for Cancer Outcomes Research, a Full Member of the Divisions of Public Health Sciences and Clinical Research at the Fred Hutchinson Cancer Research Center, and Professor of Medicine, Public Health, and Pharmacy at the University of Washington. He’s been an ASCO member since 1977, and his membership has been an active one, including service on numerous committees and working groups and culminating in his current term on ASCO’s Board of Directors.

Supporting Young Investigators Dr. Lyman recalled that when ASCO created the Conquer Cancer Foundation in 1999 to support the broad interests of the Society in research and education, he and others thought it “made a good deal of sense.”

“The Foundation has provided an important focus on what many of us feel is right at the top of ASCO’s charge and role,” he said. “A primary mission of ASCO has always been training, encouraging, and supporting the next generation of oncologists and cancer researchers.”

The Conquer Cancer Foundation Grants & Awards Program fuels a broad spectrum of programs designed to support the next generation of oncologists.

They range from awards and fellowships designed to support early-career oncologists in low- and middle-income countries, to awards helping introduce

physicians from backgrounds underrepresented in medicine to oncology as a career, to its flagship Young Investigator Award (YIA) and Career Development Award (CDA) grants, which have launched the research careers of hundreds of young oncologists.

“The Foundation has proven its ability to foster the development and careers of promising young investigators who have received funding and gone on

The shortage of funding for cancer research continues. Even in years when the Conquer Cancer Foundation is able to award a large number of awards—such as in 2014, when 56 YIAs were awarded—promising work goes unfunded.

“It’s so hard in today’s research environment,” Dr. Lyman continued.

“Cutbacks at the NIH and other funding agencies have made it increasingly difficult, not only for young investigators, but even for senior investigators.” According to ASCO, as of 2014,

A primary mission of ASCO has always been training, encouraging, and supporting the next generation of oncologists and cancer researchers.

—Gary H. Lyman, MD, MPH, FASCO

to already outstanding careers,” said Dr. Lyman. “I can’t tell you how many have come up to me and said their first grant or the grant that got them started was a YIA or CDA or both from the Conquer Cancer Foundation.”

Dr. Lyman also has a personal link to the successes enabled by the Grants & Awards Program. His wife, Nicole Kuderer, MD, also of the University of Washington, received a Conquer Cancer Foundation of ASCO Young Investigator Award. “My wife had the opportunity to receive a Young Investigator Award and that helped accelerate her research career and formed the basis for her receiving a K Award,” he said. “I know she valued that support enormously.”

Funding Cutbacks a Real Concern Dr. Lyman had the opportunity to see the inner workings of the Conquer Cancer Foundation Grants & Awards Program first hand when he served on the Foundation’s Grants Selection Committee. He cited the incredible array of proposals submitted—and the breadth of expertise on the committee to evaluate those proposals—but, above all, what stuck out as the greatest challenge was simply the number of outstanding proposals.

“There are so many! You rank them, you score them, and you try to distinguish degrees of excellence and that can be very challenging and often you just say ‘These should all be funded!’” he said.

“Or the ones that don’t quite make the cut because there is not enough money to distribute, you really feel bad because you know that those studies, those proj-

ects and young researchers should be supported, but there’s just not enough to go around.”

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY

continued on page 58

5 most-accessed Top 10 Top most-accessed articles recentlyinpublished articles published 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

Official Journal of the American Society of Clinical Oncology

What’s Hot in

JCO

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

JCO.org Pain in Patients With Cancer

by Pamela J. Goodwin, et al

Second-Line Therapy in Non–Small-Cell Lung Cancer: The DELTA Between Different Genotypes Widens

by Alona Zer, et al

Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Rectal Cancer: Surgical End Points From National Surgical Adjuvant Breast and Bowel Project Trial R-04

by Michael J. O’Connell, et al

Impact of Oophorectomy on Cancer Incidence and Mortality in Women With a BRCA1 or BRCA2 Mutation

by Amy P.M. Finch, et al

That’s the GIST of It: Use of Adjuvant Imatinib After Resection of a Primary GI Stromal Tumor

by William D. Tap, et al

ASCOPost.com | AUGUST 15, 2014

PAGE 57

Direct From ASCO

Center for Medicare and Medicaid Services Approves QOPI® as Pathway for Federally Required Quality Reporting

T

he Centers for Medicare and Medicaid Services (CMS) has approved ASCO’s Quality Oncology Practice Initiative (QOPI®) as a pathway for oncologists to meet the agency’s quality reporting requirements. Starting in the

possible,” said ASCO Immediate Past President Clifford A. Hudis, MD, FACP. “Hence, we are excited that we can offer them the opportunity to meet their CMS requirements while simultaneously reporting through QOPI.” A provision in the American Taxpayer Relief Act of 2012 allows clinical data registries approved by the U.S. Department of Health and Human Services (HHS) to provide pathways for physicians to meet their federal quality reporting requirement.

ASCO worked with other Clifford A. Hudis, MD, FACP Douglas W. Blayney, MD, FASCO medical specialty societies to achieve bipartisan support for fall of 2014, oncology practices regis- this key provision, and then worked to tered with QOPI will have the oppor- ensure that QOPI met HHS’ requiretunity to fulfill CMS’ Physician Quality ments for approval.

Reporting System (PQRS) or Qualified Clinical Data Registry (QCDR) report- Improving the Quality of Care Launched in 2006, QOPI is the first ing requirements through QOPI. “Oncology practices are striving to national program to help practices imdemonstrate their increasing quality prove the quality of care they deliver. The of care using the most efficient system program enables practices to examine

the quality of care they are providing to patients based on how well they are performing across all aspects of cancer care.

QOPI’s rigorous set of more than 160 quality measures were developed by practicing oncologists and quality experts and span the continuum of cancer care. The quality metrics are based on best practices derived from clinical guidelines, published measures, and collective expert consensus. More than 900 practices are registered with QOPI. Practices receive detailed reports demonstrating their performance level compared with the QOPI national average. The reports provide information to guide improvement efforts.

In addition, practices will have the opportunity to submit their data

electronically via eQOPI, a reporting pathway that accepts structured data elements output from their electronic health record, which will be available during the 2014 fall reporting round.

“This is the latest step in QOPI’s evolution, and we recognize all of the volunteers who participate in ASCO’s quality improvement activities on our patients’ behalf,” said Douglas W. Blayney, MD, FASCO, Chair of the QOPI Steering Group. “ASCO will continue to expand QOPI to make quality reporting as seamless as possible for practices.”

To learn more about QOPI, please visit qopi.asco.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

Proposed 2015 Medicare Physician Fee Schedule and Hospital Outpatient Prospective Payment System Rules Released

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n July 3, 2014, the Centers for Medicare & Medicaid Services (CMS) released its proposed rules for the Medicare Physician Fee Schedule and the Hospital Outpatient Prospective Payment System for 2015. The Medicare Physician Fee Schedule rule, which is titled “Medicare Program: Revisions to Payment Policies under the Physician Fee Schedule, Clinical Laboratory Fee Schedule, Access to Identifiable Data for the Center for Medicare and Medicaid Innovation Models & Other Revisions to Part B for CY 2015,” became available for public review and can be viewed at https:// s3.amazonaws.com/public-inspection. federalregister.gov/2014-15948.pdf.

CMS also released the Hospital Outpatient Prospective Payment System

proposed rule, titled “Medicare and Medicaid Programs: Hospital Outpatient Prospective Payment and Ambulatory Surgical Center Payment Systems and Quality Reporting Programs; Physician-Owned Hospitals: Data Sources

for Expansion Exception, Physician Certification of Inpatient Hospital Services; Medicare Advantage Organizations and Part D Sponsors: Appeals Process for Overpayments Associated with Submitted Data.” It can be viewed at

https://s3.amazonaws.com/public-inspection.federalregister.gov/ 2014-15939.pdf. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCO Launches Online Resource to Help Oncologists Understand the Impact of the Affordable Care Act

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his year, major provisions of the Patient Protection and Affordable Care Act of 2010 are being implemented, with far-reaching impacts on health-care providers and patients. In addition to implementing requirements under the new law, oncology practices are treating considerably more patients with new exchangebased insurance plans and adapting to changes in numerous existing plans.

To help inform its members about the effects of Affordable Care Act implementation on oncology practices, ASCO has established the online Affordable Care Act Resource Center at www.asco.org/aca, which provides details about the law, new requirements for practices, and effects on patients and patient coverage. It also provides information regarding ASCO’s ongo-

ing advocacy efforts on implementation of the health-care law, useful information about the law for patients with cancer, available at Cancer.Net, and an opportunity for oncology practices to share personal experiences in adapting to Affordable Care Act requirements. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | AUGUST 15, 2014

PAGE 58

Direct From ASCO Gary H. Lyman, MD, MPH, FASCO continued from page 56

funding for the National Institutes of Health (NIH) is down 23% since 2003 after adjusting for inflation, and the challenges caused by the decrease in available funding weigh the most heavily on early-career researchers who are

at a crossroads in their careers.

“You only have so many years relatively early in your career to kind of make it or break it,” said Dr. Lyman.

“Over the years, we have lost many very promising, brilliant young investigators who might have gone on to just do outstanding cancer research.”

In the current challenging research

environment, Dr. Lyman sees continued investment in grants like the Young Investigator Award and Career Development Award as imperative.

“We just need to keep beating the bushes to find the funds to support more of these awards,” he said. “We need to do all we can to try and fill the gap before we lose a greater number of

the next generation of outstanding researchers... It’s never enough, but it has been extraordinarily successful, and I think ASCO and the Foundation can be very proud of what has been accomplished and what will be accomplished in the coming years.” n © 2014. American Society of Clinical Oncology. All rights reserved.

Order ASCO Answers Guides to Cancer for Your Practice

T

Advertisement not displayed in digital edition at advertiser’s request

he ASCO Answers guides to breast, colorectal, lung, and prostate cancers are designed to help patients newly diagnosed with these cancers understand their diagnosis and the treatment options. These comprehensive, patientfriendly booklets contain trusted information about the diagnosis, treatment, side effects, and psychosocial effects of cancer. The guides also provide space for recording details about one’s diagnosis and treatment plans, a feature that allows patients to easily go back and find the most pertinent information when needed. Copies can be purchased from the ASCO University Bookstore at cancer.net/eStore. Shipping is free and ASCO members save 20%. n

© 2014. American Society of Clinical Oncology. All rights reserved.

Save the Date Best of ASCO® Seattle August 22-23, 2014 The Westin Seattle Seattle, Washington

ASCOPost.com | AUGUST 15, 2014

PAGE 59

Direct From ASCO

ASCO Celebrates Oncology Luminaries for 50th Anniversary

I

n the 50 years since the American Society of Clinical Oncology was founded, the treatment of cancer has advanced dramatically, due to the work of researchers making important scientific breakthroughs, physicians responsible for delivering those advances to patients, and countless others who contributed to the improvement of cancer care.

To celebrate the ASCO members

who led many important advances over the past 50 years, several volunteer leaders of ASCO identified more than 50 Oncology Luminaries—individuals who have directly or indirectly advanced scientific progress against cancer and cancer patient care.

Throughout 2014, ASCO’s 50th year, the Society’s CancerProgress.Net website is profiling these individuals. The profiles may be found at http://cancerprogress

.net/celebrating-oncology-luminaries.

The list of luminaries is not exhaustive, and ASCO leaders recognize that many more people throughout history have shaped the field of oncology and advanced progress against cancer. We hope that everyone can join with us in

celebrating the accomplishments of all of these exceptional individuals, and the thousands of others who continue to work each day to advance the field. n © 2014. American Society of Clinical Oncology. All rights reserved.

Oncology Luminaries Profiles have been posted for the following ASCO members: • ASCO Founders • Joseph Burchenal, MD, FASCO • Bruce A. Chabner, MD, FASCO • Francis S. Collins, MD, PhD • Brian J. Druker, MD • Sidney Farber, MD • Bernard Fisher, MD, FASCO • Daniel G. Haller, MD, FASCO • Waun Ki Hong, MD, FASCO • V. Craig Jordan, OBE, PhD, DSc • Henry S. Kaplan, MD • David A. Karnofsky, MD, FASCO • Alfred G. Knudson Jr, MD, PhD • John Mendelsohn, MD • Donald L. Morton, MD

• Donald P. Pinkel, MD • Henry Rappaport, MS, PhD • Steven A. Rosenberg, MD, PhD, FASCO • Janet D. Rowley, MD • Richard L. Schilsky, MD, FASCO • Edward Donnell Thomas, MD • Daniel Von Hoff, MD, FACP, FASCO • Robert A. Weinberg, PhD

Profiles coming soon: • Martin D. Abeloff, MD, FASCO • Karen H. Antman, MD, FASCO • James O. Armitage, MD, FASCO • Joseph R. Bertino, MD, FASCO

Conquering

• Clara D. Bloomfield, MD, FASCO • Gianni Bonadonna, MD • Paul A. Bunn Jr, MD, FASCO • Paul P. Carbone, MD, FASCO • Charles A. Coltman Jr, MD, FASCO • George Crile Jr, MD • Nancy E. Davidson, MD, FASCO • Vincent T. DeVita, Jr, MD, FASCO • John R. Durant, MD, FASCO • Lawrence H. Einhorn, MD, FASCO • Judah Folkman, MD • Emil Frei, MD, FASCO • John H. Glick, MD, FASCO • James F. Holland, MD, FASCO

• Gabriel N. Hortobagyi, MD, FACP, FASCO • Rakesh K. Jain, PhD • David H. Johnson, MD, FACP, FASCO • Mary-Claire King, PhD • Richard Klausner, MD • Miodrag Kukrika, MD • Robert J. Mayer, MD, FASCO • Larry Norton, MD, FASCO • Sydney E. Salmon, MD, FASCO • Dennis J. Slamon, MD, PhD • Harold E. Varmus, MD • Umberto Veronesi, MD • Robert C. Young, MD, FASCO

Cancer.

Together, anything is possible.

The Conquer Cancer Foundation. Our name says a lot.

Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supportingthe world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

DonATe ToDAY! ConquerCancerFoundation.org

The ASCO Post | AUGUST 15, 2014

PAGE 60

Inside the Black Box FDA Approval of Ceritinib for the Treatment of ALK-Positive Non–Small Cell Lung Cancer

A Conversation With Sean Khozin, MD, MPH, and Dikran Kazandjian, MD INSIDE THE BLACK BOX is an occasional column providing insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, FDA oncologists Sean Khozin, MD, MPH, and Dikran Kazandjian, MD, discuss anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC) and the recent approval of ceritinib. Drs. Khozin and Kazandjian are Clinical Reviewers in the Division of Oncology Products 2, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research.

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n April 29, 2014, the FDA granted accelerated approval to ceritinib (Zykadia) capsules for the treatment of patients with ALK-positive metastatic NSCLC who have shown disease progression on or are intolerant to crizotinib (Xalkori).

Ceritinib Background What is ceritinib and how does it fit into the new paradigm of personalized cancer therapy?

Dr. Khozin: The treatment of lung cancer has traditionally been based on histology. In recent years, however, the discovery of driver mutations has created a new paradigm where treatment is tailored, or personalized, to the specific mutations that are thought to be oncogenic and responsible for the initiation and maintenance of cancer.

Potentially targetable driver mutations have been discovered in over half of all NSCLCs. ALK gene rearrangements represent one example and are found in about 5% of NSCLC cases.

This oncogenic event leads to an ALK gene fusion product with a constitutively active tyrosine kinase domain.

Ceritinib is an ALK kinase inhibitor that inhibits the proliferation of ALKdependent cancer cells.

Role of ALK in Lung Cancer Tell us about the discovery of ALK in lung cancer and why it is so important.

Dr. Kazandjian: Interestingly, ALK genetic alterations were first discovered in 1994, when ALK fusion translocation events were identified in non-Hodgkin lymphoma. Morris and colleagues showed that a translocation event in-

volving chromosomes 2 and 5 created a fusion protein juxtaposing the tyrosine kinase part of ALK to nucleophosmin (NPM-ALK fusion). Given that the ALK protein is not normally expressed outside of neural development, the expression of the chimeric ALK protein was determined to be an oncogenic driver and implicated in the dysregulation of cell proliferation and apoptosis in anaplastic large cell lymphoma.

The ALK story becomes even more interesting if we fast-forward to 2007, when Soda and colleagues first showed that an ALK alteration—in this case a small chromosomal inversion event— resulted in the expression of a fusion protein with the ability to cause skin tumors in mice. The researchers determined that this chimeric tyrosine kinase fusion protein incorporated a 5ʹ region of the breakpoint partner echinoderm microtubule-associated protein-like 4 (EML4) gene and the 3ʹ intracellular cellular kinase domain of the ALK gene.

Furthermore, they found that 5 of 75 archived samples from patients with NSCLC had this aberration.

Fortuitously, crizotinib had been identified as a lead compound in 2005 and was already in early-phase trials in lung cancer as a c-MET inhibitor. Subsequently, it was found to also inhibit ALK, which quickly led to two patients with ALK-positive NSCLC being enrolled in an ongoing trial. After these two patients were found to have responses in early 2008, an ALK-positive NSCLC cohort was added and additional responses were observed. As a result, in mid-2009, a single-arm phase II trial and a randomized phase III trial

were initiated, and a previously existent fluorescence in situ hybridization (FISH) assay to detect ALK inversion/ translocation events was further refined and validated for use in these trials.

Crizotinib received accelerated approval in 2011. Regular approval was granted in 2013 after confirmatory trials showed objective response rates between 50% to 65% and progressionfree survival rates of about 7 months.

This was deemed to be highly clinically meaningful since traditional chemotherapy delivers response rates of only about 10% and progression-free survival rates of about 3 months.

FDA Clinical Reviewers

Sean Khozin, MD, MPH

Treatment Limitations In the ALK-positive subset of NSCLC, it appears that the oncogenic driver target is clear and that crizotinib clearly inhibits this pathway; why are patients not being cured?

Dr. Kazandjian: As mentioned previously, crizotinib shows impressive antitumor activity in the ALK-positive subset of NSCLC compared to standard chemotherapy and can be considered a tailored medicine. However, with further understanding of the biology of NSCLC, it has become clear that it is a very heterogeneous disease. Early in the development of NSCLC, there may be clones with different genetic alterations, and resistance can occur when clones that are inherently resistant become the majority of the tumor bulk. This phenomenon may occur in both EGFR-positive and ALK-positive NSCLC. Reported mechanisms of resistance for ALK-positive NSCLC include ALK mutations, ALK copy number gains, and oncogenic driver mutations in other genes. Very similar to the “gatekeeper mutations” of T315I in BCR-ABL and T790M in EGFR, the L1196M substitution mutation has been shown to confer resistance to crizotinib in about a third of patents. Other mutations are coming to light, and most of these secondary mutations occur in the kinase domain regions of ALK and affect drug-to-ALK binding. ALK gene copy number gains lead to more chimeric ALK protein than crizotinib can inhibit.

Mutations in other known protooncogenes and oncogenic pathway aberrations have been shown to drive

Dikran Kazandjian, MD

ALK-positive tumors after crizotinib resistance. Interestingly, one such mutation is the well-described EGFR exon 21 L858R mutation, which is the major driver in the EGFR subtype of NSCLC. Other EGFR mutations along with mutations in other oncogenes, including KRAS, have been described.

Crizotinib Resistance Since almost all ALK-positive NSCLCs will eventually stop responding to crizotinib therapy, how can resistance be overcome?

Dr. Kazandjian: One mechanism of acquired resistance to crizotinib may be the development of a second-site mutation that prevents binding of the drug to the ALK-kinase region. This type of resistance could potentially be overcome by newer-generation ALK inhibitors with different three-dimensional chemical structures that may have more favorable binding profiles to these mutated ALK proteins. Secondly, more potent newer-generation ALK inhibitors may help overcome the resistance caused by ALK copy number gains.

Finally, crizotinib resistance caused by activation of other oncogenic pathcontinued on page 66

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.1

LIGHTING A WAY FORWARD Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

• Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

• QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

VOTRIENT demonstrated significant improvement in PFS in a Phase 3 trial1 • VOTRIENT provided a 65% reduced risk of progression or death compared with placebo (HR 0.35; 95% CI 0.260.48; P<0.001)1

Proportion Progression Free

PFS in overall study population (N=369)1

1.6

MONTHS Median PFS

1.0

4.6

VOTRIENT (n=246)

MONTHS Median PFS

Placebo (n=123)

• The efficacy efficacy of VOTRIENT for the treatment of patients with adipocytic STS or GIST has not been demonstrated1

HR 0.35 (95% CI 0.26-0.48) P<0.001

0.8 0.6 0.4 0.2 0.0 0

5

10

15

20

25

Months Randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial to evaluate the efficacy and safety of VOTRIENT in patients (N=369) with advanced STS. The Phase 3 trial population excluded patients with adipocytic sarcoma or GIST. Patients were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.1,2

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo.

One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure.

• Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%).

VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months.

• Arterial Thromboembolic Events: Arterial thromboembolic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months.

• Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, VTEs were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal

pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo.

Monitor for signs and symptoms.

• Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated.

• Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms.

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal.

Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred

by Day 9 and 90% of cases occurred in the first 18 weeks).

Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension.

• Wound Healing: VOTRIENT may impair wound healing.

Interruption of therapy is recommended in patients

undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery.

VOTRIENT should be discontinued in patients with wound dehiscence.

• Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

• Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions.

• Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly.

Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

• Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.

VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Limitation of Use: The efficacy efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.1

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In soft tissue sarcoma, a dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced STS trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced • No dose adjustment is required in patients with mild hepatic impairment • In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials.

Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • The most common adverse reactions (≥20%) in patients with advanced soft tissue sarcoma who received VOTRIENT were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair color changes, vomiting, tumor pain, dysgeusia, headache, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea Please see additional Important Safety Information for VOTRIENT on adjacent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

• For additional information on dosing modifications modifications based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

Important Safety Information for VOTRIENT (cont’d) • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

• Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs. 0% in the placebo group).

• Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm.

• Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice.

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib.

Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours.

• Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions.

Please see additional Important Safety Information for VOTRIENT on adjacent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages. www.GSKSource.com ©2014 GSK group of companies.

All rights reserved. Printed in USA. 66601R0 June 2014

VOTRIENT.com/HCP/aSTS

The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs 48%), diarrhea (59% vs 15%), nausea (56% vs 22%), decreased weight (48% vs 15%), hypertension (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%).

Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in patients receiving VOTRIENT versus placebo included increases in AST (51% vs 22%), ALT (46% vs 18%), glucose (45% vs 35%), alkaline phosphatase (32% vs 23%), total bilirubin (29% vs 7%), and potassium (16% vs 11%); decreases in albumin (34% vs 21%) and sodium (31% vs 20%); and leukopenia (44% vs 15%), lymphocytopenia (43% vs 36%), thrombocytopenia (36% vs 6%), and neutropenia (33% vs 7%).

References: 1. VOTRIENT® (pazopanib) Tablets [package insert].

Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Data on file.

GlaxoSmithKline, 2011.

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials.

Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg.

Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential.

VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively.

Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline.

Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information].

5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.4% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10%

compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)].

Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event.

The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) of patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo.

Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging.

Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)].

5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and

lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established.

VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals.

VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman.

Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient.

There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

Adverse Reactions Fatigue Diarrhea Nausea Weight decreased Hypertension Appetite decreased Hair color changes Vomiting Tumor pain Dysgeusia Headache

VOTRIENT

Placebo

(N=240)

(N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 65 13 1 48 4 1 59 5 0 15 1 0 56 3 0 22 2 0 48 4 0 15 0 0 42 7 0 6 0 0 40 6 0 19 0 0 39 0 0 2 0 0 33 3 0 11 1 0 29 8 0 21 7 2 28 0 0 3 0 0 23 1 0 8 0 0

Musculoskeletal pain

23

2

0

20

2

0

Myalgia

23

2

0

9

0

0

Gastrointestinal pain

23

3

0

9

4

0

Dyspnea Exfoliative rash Cough Peripheral edema Mucositis Alopecia Dizziness Skin disorderb

20 18 17 14 12 12 11 11

5 <1 <1 2 2 0 1 2

<1 0 0 0 0 0 0 0

17 9 12 9 2 1 4 1

5 0 <1 2 0 0 0 0

1 0 0 0 0 0 0 0

Skin hypopigmentation

11

0

0

0

0

0

Stomatitis 11 <1 0 3 0 0 Chest pain 10 2 0 6 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=240)

Parameters Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased Albumin decreased Alkaline phosphatase increased Sodium decreased Total bilirubin increased

Placebo (N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 44 43 36 33

1 10 3 4

0 0 1 0

15 36 6 7

0 9 0 0

0 2 0 0

51 46 45 34

5 8 <1 1

3 2 0 0

22 18 35 21

2 2 2 0

0 1 0 0

32

3

0

23

1

0

31

4

0

20

3

0

29

1

0

7

2

0

Potassium 16 1 0 11 0 0 increased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

T:13”

B:14.25”

S:12.5”

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared to <1% (1/123) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations.

Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs That Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, shortacting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to

avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification.

In addition, there was reduced fetal body weight, and pre- and postimplantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure).

In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/ maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials.

Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist

of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC).

Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing.

Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away.

• Prolonged QT intervals and torsades de pointes have been observed.

Patients should be advised that ECG monitoring may be performed.

Patients should be advised to inform their physicians of concomitant medications.

• Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure.

• Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding.

• Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis.

• Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs.

• Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances).

• Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting.

• GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula.

• VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery.

• Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment.

• Serious infections including some with fatal outcomes have been reported.

Advise patients to promptly report any signs or symptoms of infection.

• Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

• Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs.

• Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements.

• Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of the GSK group of companies.

GlaxoSmithKline Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

Revised: 06/2014 VTR:12BRS ©2014 GSK group of companies.

All rights reserved. Printed in USA. 66601R0 June 2014

The ASCO Post | AUGUST 15, 2014

PAGE 66

Inside the Black Box Cetirinib in ALK-Positive NSCLC continued from page 60

ways by crosstalk or by mutations of other oncogenes poses a more difficult situation. In these resistance types, the biology needs to be further elucidated, and specifically, the pathways and key drivers need to be identified. Currently, a number of therapies targeting these other oncogene products (eg, EGFR, c-MET) are either in clinical trials or will be in the near future. The future will tell whether resistance caused by activation of other oncogenic pathways can be successfully overcome by targetdirected therapies.

Other important questions about resistance are whether it can be prevented in the first place and the optimum timing of treatment with newer-generation ALK inhibitors. For example, should upfront therapy consist of newer-generation ALK inhibitors to prevent the emergence of the L1196M mutation, or should upfront therapy consist of crizotinib followed by newer-generation ALK inhibitors at disease progression?

Future trials will need to address these questions and determine how they ultimately affect survival of patients with ALK-positive NSCLC. One thing is clear: for certain subtypes of NSCLC, targeted therapies have revolutionized treatment options and outcomes for patients compared to a decade ago.

Ceritinib Data Can you describe the data supporting ceritinib’s approval?

Dr. Khozin: The main support for ceritinib’s approval came from a multicenter single-arm trial in 163 patients with metastatic ALK-positive NSCLC who had disease progression on or who were intolerant to crizotinib. All patients received ceritinib orally at a dose of 750 mg once daily.

The primary endpoint of the trial was objective response rate according to RECIST v1.0, as evaluated by both investigator and a blinded independent

central review committee. The trial results showed an objective response rate of 44% and a duration of response of 7.1 months based on review committee–determined tumor assessments.

The analysis by investigator assessment showed similar results, with an objective response rate of 55% and duration of response of 7.4 months.

These results were considered to be clinically meaningful in a population of patients previously treated with crizotinib, and 91% had disease progression on prior crizotinib therapy. Ceritinib therefore appears to overcome resistance to ALK inhibition in about half of patients previously treated with crizo-

in the most efficient manner. We carried the same commitment into the New Drug Application (NDA) review process, which enabled us to perform a thorough benefit-risk analysis and approve the drug 4 months ahead of the goal date for priority review.

Optimized Review Process What challenges did FDA face in helping to expedite the development program and the review process for ceritinib?

Dr. Khozin: After ceritinib was granted Breakthrough Therapy designation, FDA took a proactive approach, which required flexibility on the part of FDA staff and the sponsor to facilitate rapid

The use of technologies such as next-generation sequencing on multiplexed samples and innovative trial designs, coupled with advances in data standardization and computing platforms, have paved the way for a new paradigm that can support an efficient path toward development of new drugs for patients with NSCLC. —Sean Khozin, MD, MPH

tinib. The most common adverse reactions in the trial were gastrointestinal events such as diarrhea, nausea, vomiting, and elevated transaminases.

Breakthrough Therapy Designation On March 6, 2013, FDA granted ceritinib Breakthrough Therapy designation based on preliminary evidence of clinical activity in patients with metastatic ALKpositive NSCLC previously treated with crizotinib. How did that affect the interactions with the sponsor and the review process?

Dr. Khozin: We made a concerted effort to mobilize FDA’s administrative and scientific resources to give the sponsor intensive guidance on their clinical development program, so adequate data for the safe and effective use of ceritinib in the appropriate NSCLC patient population could be generated

GUEST EDITOR

exchange of information via a host of formal meetings and information requests.

This became even more important after NDA submission in order to sustain a tightly coordinated review process.

Special emphasis was placed on the manufacturing aspects of ceritinib’s drug development to avoid delays and to safeguard against potential deficits in the commercial manufacturing process.

Issues surrounding the content and structure of the data for the NDA were also important to facilitate an expedited review. It is clear that the use of interoperable and platform-independent data standards in NDA submissions can create efficiencies in the review process beyond what is feasible with traditional methods of data capture and analysis.

Lessons Learned How can the lessons learned from the experience with ALK inhibitors be ap-

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. plied to other drugs in development for NSCLC? Dr. Khozin: The strategy of molecular enrichment has been the most important factor in the success of not only ALK inhibitors but also EGFR inhibitors in the treatment of patients with metastatic NSCLC. In both cases, patient selection based on the presence of specific genetic alterations allowed for a rational approach to drug development, which in the case of ceritinib, enabled an expedited pathway toward FDA approval.

Enrichment strategies backed by sound scientific evidence are, therefore, of paramount importance and may explain the lag in the development of some of the current investigational agents for advanced NSCLC where no predictive biomarkers have been established. The use of technologies such as next-generation sequencing on multiplexed samples and innovative trial designs such as the Lung Cancer Master Protocol, coupled with advances in data standardization and computing platforms, have paved the way for a new paradigm that can support an efficient path toward development of new drugs for patients with NSCLC. n Disclosure: Drs. Khozin and Kazandjian reported no potential conflicts of interest.

FDA Updates in This Issue of The ASCO Post See pages 1, 12–15, 46–48, and 122 in this issue for more news and announcements from the U.S. Food and Drug Administration.

ASCOPost.com | AUGUST 15, 2014

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Journal Spotlight Breast Cancer

Early Change in Chemotherapy Based on Elevated Circulating Tumor Cells Does Not Improve Outcome in Metastatic Breast Cancer

By Matthew Stenger

E

levated circulating tumor cells are associated with poor prognosis in metastatic breast cancer. In a phase III trial (Southwest Oncology Group [SWOG] S0500) reported in Journal of Clinical Oncology, Jeffrey B. Smerage, MD, PhD, Clinical Associate Professor in Medical Oncology at the University of Michigan Comprehensive Cancer Cen-

meningeal disease were ineligible.

Patients could not have received any prior chemotherapy for metastatic disease; prior and concurrent use of hormone, bisphosphonate, trastuzumab (Herceptin), or bevacizumab (Avastin) therapy was permitted. Adjuvant chemotherapy must have been completed ≥ 12 months prior to the study. Choice

For this population, there is a need for more effective treatment than standard chemotherapy.

—Jeffrey B. Smerage, MD, PhD, and colleagues

ter, Ann Arbor, and colleagues assessed whether changing chemotherapy after one cycle of first-line treatment in patients with persistent circulating tumor cell elevation could improve overall survival.1 They found that change in cytotoxic chemotherapy did not prolong overall survival and their findings confirmed the strong prognostic effect of circulating tumor cell level in this setting.

Daniel F. Hayes, MD, Professor of Medical Oncology at the University of Michigan Comprehensive Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Study Details The study enrolled women with histologically confirmed breast cancer and clinical or radiographic evidence of metastatic disease. Patients could have measurable or nonmeasurable but evaluable bone-only disease with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients were eligible if they had stable brain metastases for ≥ 90 days after completing brain radiotherapy; those with lepto-

of chemotherapy was at the discretion of treating physicians; however, only patients who were to be treated with singleagent chemotherapy were eligible.

Patients were assigned to treatment in four groups. Patients without elevated circulating tumor cells (< 5 circulating tumor cells/7.5 mL whole blood) at baseline remained on initial therapy until progression (group A). Patients with initially elevated circulating tumor cells (≥ 5 circulating tumor cells/7.5 mL) that declined after 21 days of therapy remained on initial therapy (group B).

Patients with persistently elevated circulating tumor cells after 21 days of therapy were randomly assigned to continue initial therapy (group C1) or change to an alternative single-agent chemotherapy selected by physicians (group C2). The primary endpoint was overall survival.

Patient Assignment and Characteristics Of 595 evaluable patients, 276 (46%) did not have elevated circulating tumor cells at baseline (group A). Of those with initially elevated circulating

Circulating Tumor Cells as a Marker in Breast Cancer Treatment ■■ In patients with persistently elevated circulating tumor cells at first measurement, switching to a different cytotoxic agent for first-line treatment did not prolong overall survival.

■■ Patients with no circulating tumor cell elevation at baseline had the longest overall survival, followed by those with elevated circulating tumor cells at baseline but not at follow-up, and by those with persistently elevated circulating tumor cells.

tumor cells, 31 (10%) were not retested due to death, progression, or dropout, 165 were assigned to group B, and 123 were randomized to group C1 (n = 64) or C2 (n = 59).

There were no significant differences among the three groups (A, B, C) or between the two randomized groups (C1 vs C2) in age (59%–62%, 59% vs 66% ≥ 55 years), race (14%–18%, 23% vs 12% black), or measurable disease (79%–83%, 73% vs 85%). Some differences were evident in hormone receptor–positive and HER2-negative disease (54%–72%, 78% vs 66%), triple-negative disease (20%–27%, 17% vs 27%), and HER2-positive disease (6%–22%, 5% vs 7%) status. The likelihood of elevated circulating tumor cells at baseline among these three biologic subtypes was 55%, 45%, and 45% (P = .06). Of patients with elevated circulating tumor cells, 51%, 55%, and 84%

vs 4.2, HR = 0.86, P= .51), triple-negative (2.2 vs 1.9 months, HR = 0.70, P = .38), or HER2-positive disease (7.3 vs 4.7 months, HR = 1.44, P = .69). There was no significant interaction among subtypes for overall survival (P = .21) or progression-free survival (P = .88).

Outcomes Across Groups Median overall survival was 34.8 months in group A (no circulating tumor cell elevation at baseline), 22.9 months in group B (elevated circulating tumor cells at baseline but not after 21 days), and 13.1 months in the total group C (P < .0001 for trend). The hazard ratio for group C vs group B was 2.13 (95% confidence interval [CI ] = 1.63–2.79).

Post hoc pairwise comparisons showed significant differences between groups after adjustment for multiple comparisons (P < .001). Differences among groups remained significant af-

At a recent European meeting, I heard someone say regarding S0500, ‘The technology succeeded, it was the treatment that failed.’ I think that sums up our study nicely.

—Daniel F. Hayes, MD

converted to low circulating tumor cells after 22 days of first-line treatment (P = .001).

Outcome in Randomized Comparison For group C2 (persistently elevated circulating tumor cells, changed treatment) vs C1 (persistently elevated circulating tumor cells, maintained treatment), there were no differences in either median overall survival (12.5 vs 10.7 months, hazard ratio [HR] = 1.00, P = .98) or median progression-free survival (4.6 vs 3.5 months, HR = 0.92, P = .64).

No differences in overall survival were observed among patients with hormone receptor–positive/HER2-negative (17.4 vs 12.4, HR = 0.80, P = .35), triple-negative (7.9 vs 9.1 months, HR = 1.19, P = .67), or HER2-positive disease (7.3 vs 13.3 months, HR = 4.18, P = .16). No differences in progression-free survival were observed among patients with hormone receptor–positive/HER2-negative (5.7

ter adjustment for hormone receptor and HER2 status (P < .0001). Fiveyear overall survival was approximately 25% in group A and < 10% in group C. Median progression-free survival was 11.1, 8.9, and 4.9 months (P < .0001 for trend), and the HR for group C vs group B was 1.94 (95% CI = 1.56–2.47).

According to biologic subtype, median overall survival was 37.3, 28.1, and 15.0 months (P < .0001; HR =1.96 for C vs B, 95% CI = 1.40–2.75) among hormone receptor–positive/HER2-negative patients, 22.1, 12.5, and 9.5 months (P < .0001; HR = 1.73 for C vs B, 95% CI = 1.02–2.95) among triple-negative patients, and not estimable, 33.0, and 14.1 months (P < .0001; HR = 4.62 for C vs B, 95% CI = 1.68–12.76) among HER2positive patients. There was no significant interaction by subtype (P = .30).

Within each group, patients with HER2-negative disease who were hormone receptor–positive had better continued on page 68

The ASCO Post | AUGUST 15, 2014

PAGE 68

Perspective

Circulating Tumor Cells in Metastatic Breast Cancer: Are We Afraid of the Truth?

By Massimo Cristofanilli, MD, FACP “All truths are easy to understand once they are discovered; the point is to discover them.”

—Galileo Galilei

T

here are several “truths” in breast oncology that have been discovered over the years, become widely understood, and changed the way we practice. Prospective randomized studies have shown that breastconserving therapy is associated with similar outcome compared with mastectomy.1 A more conservative surgical approach with the axillary nodes has similar impact on outcome.2 Adjuvant systemic combination therapy improves survival in primary breast cancer,3 and the inclusion of endocrine and biologic therapies is recommended in hormone receptor–positive and HER2-positive disease.4,5 In metastatic breast cancer, targeted therapies have improved progression-free survival and in some cases overall survival in defined subtypes of disease.6,7 Both single-agent and combination-regimen systemic chemotherapy have been evaluated in prospective studies showing evidence of palliative effect.8 These studies suggested some limitations in our systemic treatments and the need for investigations to better understand the metastatic process in order to develop more effective approaches.9 Dr. Cristofanilli is Professor of Medical Oncology, Deputy Director of Translational Research, and Director of the Jefferson Breast Cancer Center, Thomas Jefferson University, Philadelphia.

Metastatic Breast Cancer continued from page 67

overall survival than those who were hormone receptor–negative. Patients in group A with triple-negative disease had the worst overall survival in group A, which was better than overall survival in the hormone receptor–positive/ HER2-negative patients in group C. Patients with HER2-positive vs HER2-negative disease had better overall survival in both groups A and B. Group C had too few HER2 positive patients for analysis. Overall survival was particularly poor in group C patients with triple-negative disease, with 75% of these patients dying within 15 months.

‘Liquid Phase’ of Solid Tumors The detection of circulating tumor cells in the peripheral blood of patients with metastatic breast cancer demonstrated that solid tumors have a “liquid phase” that should always be evaluated and measured in these patients.10 Large prospective studies and retrospective analyses have confirmed that baseline detection of ≥ 5 circulating tumor cells/7.5 mL whole blood in patients with metastatic breast can-

this means that circulating tumor cell detection introduces a new dimension (liquid phase).

Furthermore, the use of systemic chemotherapy as “early” second-line therapy for patients with persistent circulating tumor cells shortly after initiation of systemic treatment is not beneficial and possibly detrimental. In other terms, these patients should be more carefully evaluated for possible use of targeted therapies because “empiric”

The discovery of the liquid phase of solid tumors is an important step forward in understanding the metastatic process and the complexity of the disease. We should not be afraid of embracing this information for routine patient care, disease stratification, and clinical research.

—Massimo Cristofanilli, MD, FACP

cer has a definitive prognostic and predictive value irrespective of line of therapy and disease subtype.11,12 A recent study by Smerage et al, reviewed in this issue of The ASCO Post, further confirms these findings but also adds important new information with implications for patient management.12 The detection of ≥ 5 circulating tumor cells can be used to classify metastatic breast cancer in two biologically different diseases; because the prognostic value is independent of known disease subtype,

choices are unlikely to be effective.

Another important consideration is the use of standard anatomic imaging to assess “tumor shrinkage” as a surrogate for therapeutic benefit.13,14 This approach does not consider the liquid phase of the disease and therefore is imperfect by definition. Chemotherapy as a debulking modality can reduce tumor size without affecting circulating tumor cells, translating to a nonmeaningful response13—that is, patients may be exposed to unnecessary toxicity and prolonged treatment

Nearly 25% of women with triple-negative disease in group A survived 3 years, whereas median survival was only 12.5 months for those in group B, a finding that emphasizes the prognostic significance of circulating tumor cell level.

Median progression-free survival was 12.4, 10.6, and 5.5 months (P < .0001) among hormone receptor–positive/HER2-negative patients, 6.5, 6.5, and 2.8 months (P < .0001) among triple-negative patients and 17.9, 8.8, and 5.5 months (P = .008) among HER2positive patients.

The investigators concluded, “This study confirms the prognostic significance of [circulating tumor cells] in

[metastatic breast cancer] patients receiving first-line chemotherapy. For patients with persistently elevated [circulating tumor cells] after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging [overall survival].

For this population, there is a need for more effective treatment than standard chemotherapy.”

Dr. Hayes told The ASCO Post, “At a recent European meeting, I heard someone say regarding S0500, ‘The technology succeeded; it was the treatment that failed.’ I think that sums up our study nicely.” n Disclosure: The study was supported

without the expected benefit. What are the additional implications of not using this information? Should we consider developing response evaluation criteria in solid tumors (RECIST) version 2?

Clinical Trial Considerations We regard prospective randomized studies as the “holy grail” for assessing the impact of any new therapeutic intervention and potentially proceeding to regulatory approval if a benefit is demonstrated in progression-free and overall survival. We certainly cannot predict if the randomization process will equally distribute among study groups patients with ≥ 5 circulating tumor cells, but it appears unlikely.

As an example, consider the prospective pivotal phase III open-label multicenter trial (NCT00388726, EMBRACE) that resulted in the approval of eribulin (Halaven) in HER2negative metastatic breast cancer.15 The study enrolled 762 patients who received at least two prior chemotherapy regimens for their advanced disease, including anthracyclines and taxanes. Patients were randomly assigned to receive eribulin vs physician’s choice (standard arm). The chemotherapies used in the standard arm included but were not limited to vinorelbine, gemcitabine, capecitabine, taxanes, and anthracyclines.

The median overall survival of the eribulin group (399 days/13.1 months) compared with the standard group (324 days/10.6 months) improved by 75 days/2.5 months (hazard ratio = 0.809, 95% confidence interval continued on page 77

by National Cancer Institute grants and by Immunicon and Veridex. Circulating tumor cell assays were performed by Janssen Diagnostics LLC at no charge to SWOG. Dr. Smearage has received honoraria from Veridex and research funding from Immunicon. Dr. Hayes has received research funding from Veridex/Janssen Diagnostics and has related patents, royalties, or licenses. For full disclosures of all study authors, visit jco.ascopubs.org.

Reference 1. Smerage JB, Barlow WE, Hortobagyi GN, et al: Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol.

June 2, 2014 (early release online).

The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies.

Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

60

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible.

Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

9%

4

%

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

+

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent.

The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749).

RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances.

Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1.

If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent.

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

®

(dabrafenib) 50 mg, 75 mg capsules

®

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications.

Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.

Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective.

Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).

The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).

Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Effects of the Combination of Dabrafenib with Trametinib.

Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al.

N Engl J Med. 2012;367:1694-1703.

TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved.

Printed in USA. MEL156R0 July 2014

®

(dabrafenib) 50 mg, 75 mg capsules

®

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate.

Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent.

The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749).

RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose.

Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.

In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202).

Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.

Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days).

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations.

Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity.

TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman.

Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.

Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.

In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades Adverse Reactions Gradesa 3 and 4 Gradesa General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

0

8

2

0

2

0

0

9

2

0

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.

Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute.

Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

b

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent.

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.

QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].

Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].

Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.

In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].

Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.

Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].

Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].

Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].

The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated.

• TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)].

• TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)].

• TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)].

• TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)].

• TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)].

• MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)].

• TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)].

• TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)].

• TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)].

• TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)].

• MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness.

• MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment.

• TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

• Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)].

• Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)].

• TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.

MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved.

Revised: 01/2014 TFR:4BRS © 2014 GSK group of companies.

All rights reserved. Printed in USA. MEL156R0 July 2014

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PAGE 77

Perspective

Massimo Cristofanilli, MD, FACP

stratification, and clinical research. n

continued from page 68

Disclosure: Dr. Cristofanilli is on the scientific advisory board of Cynvenio.

= 0.660–0.991, P = .041). The Smerage et al study does not specify the drugs used as “early“ second-line therapies, but they likely reflected physician choice and possibly were similar to those used in the EMBRACE study.

What difference in overall survival would have been observed if we were to select a single specific regimen after persistent elevated circulating tumor cells? It is only possible to speculate about indirect comparisons without a confirmation, but it is conceivable that use of a variety of different regimens can dilute any potential (limited) benefit of chemotherapy in metastatic breast cancer.

In conclusion, the discovery of the liquid phase of solid tumors is an important step forward in understanding the metastatic process and the complexity of the disease. We should not be afraid of embracing this information for routine patient care, disease

References 1. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227-1232, 2002.

2. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011.

3. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976.

4. Burstein HJ, Temin S, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. May 27, 2014 (early release online).

5. Romond EH, Perez EA, Bryant J, et

al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005.

6. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:20782099, 2014.

7. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012.

8. Cardoso F, Harbeck N, Fallowfield L, et al: Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(suppl 7):vii11vii19, 2012.

9. Velasco-Velázquez M, Jiao X, De La Fuente M, et al: CCR5 antagonist blocks metastasis of basal breast cancer cells.

Cancer Res 72:3839-3850, 2012.

10. Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast

cancer. N Engl J Med 351:781-791, 2004.

11. Bidard FC, Peeters D, Fehm T, et al: Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of European studies. Lancet Oncol 15:406414, 2014.

12. Smerage JB, Barlow WE, Hortobagyi GN, et al: Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. June 2, 2014 (early release online).

13. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst 92:205-216, 2000.

14. Budd GT, Cristofanilli M, Ellis MJ, et al: Circulating tumor cells versus imaging: Predicting overall survival in metastatic breast cancer. Clin Cancer Res 12:6403-6409, 2006.

15. Cortes J, O’Shaughnessy J, Loesch D, et al: Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study. Lancet 377:914-923, 2011.

Coming in Future Issues of The ASCO Post Coverage of the 2014 Breast Cancer Symposium being held September 4-6, 2014, in San Francisco, including: ■■ A study assessing the impact of Angelina Jolie’s preventive double mastectomy on genetic testing referrals at one academic cancer center (Abstract 44).

■■ A randomized study evaluating the effect of reminder letters from family physicians on screening mammography return rates among women overdue for screening (Abstract 1).

■■ Findings from a survey evaluating the factors associated with a preference for contralateral preventive mastectomy (Abstract 71).

■■ Results from an analysis of locoregional recurrence rates in patients with breast cancer after treatment with neoadjuvant (preoperative) chemotherapy (Abstract 61).

■■ A comparison of 30-day complications after double vs single mastectomy with immediate breast reconstruction (Abstract 62).

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PAGE 78

Announcements

NIH Awards $14.5 Million to Research Groups Studying Newest DNA Sequencing Techniques

A

number of microsized technologies, such as nanopores and microfluidics, are among the approaches researchers will use to develop highquality, low-cost DNA sequencing technology through new grants from the National Institutes of Health (NIH).

The grants, which total approximately $14.5 million to eight research teams over 2 to 4 years as funds become available, are the last to be awarded by the Advanced DNA Sequencing Technology Program of the National Human Genome Research Institute (NHGRI), a part of NIH. The new group of awards, which total more than $4.5 million in the first year, is wide-ranging, and includes several research projects directed at improving the use of nanopores in DNA sequencing or creating nanopore arrays to enable large-scale DNA sequencing efforts.

Nanopore Research For the past several years, nanopore research has been an important focus of the program’s grants. Nanoporebased DNA sequencing entails threading single DNA strands through tiny pores in a membrane. Bases are read one at a time as they squeeze through the nanopore. The different bases are identified by measuring differences in their effect on electrical current flowing through the pore. Nanopores used in DNA sequencing are extremely small, perhaps only about 2 nm wide, and come in several types: protein; solid state (also called synthetic); and even nanopores made of DNA. A nanometer is 1 billionth of a meter; a human hair is 100,000 nm wide.

One of the projects will explore the use of microfluidics in DNA library preparation. Microfluidics can be used to capture small amounts of liquid in hair-thin channels and wells. Another team plans to test a method using an enzyme to amplify a signal that will help identify DNA bases.

“While we continue to support many research projects centered on the development of nanopore technology, some of the new grants focus on additional unique approaches to sequencing DNA,” said NHGRI Ge-

nome Technology Program Director Jeffery Schloss, PhD. Dr. Schloss is also Director of the Division of Genome Sciences. “Despite discussion about approaching the goal of sequencing a genome for only $1,000, many challenges remain in terms of containing costs and achieving a high

Jeffery Schloss, PhD

quality of DNA sequencing data.”

This group of awards is the last for the Advanced DNA Sequencing Technology program, which began in 2004.

“There haven’t been many programs like this anywhere else over the years,” Dr. Schloss said. “NHGRI has had a hand in supporting some very novel research, and has helped chart exciting new directions for DNA sequencing technology.”

Grant Recipients The new grants are awarded (pending available funds) to: • University of California Santa Cruz $2.29 million over 3 years Principal Investigator: Mark ­Akeson, PhD Investigators plan to sequence single DNA molecules by using a nanopore device comprised of a sensor that touches, examines and identifies each nucleotide, or DNA building block, in a DNA strand as an enzyme motor moves it through the pore. The scientists will focus on DNA “resequencing,” examining the DNA nucleotides over and over because of the difficulty in accurately reading each strand initially.

• Illumina, Inc, San Diego $592,000 over 2 years Principal Investigator: Boyan ­Boyanov, PhD Dr. Boyanov and his team aim to create a hybrid protein solid-state nanopore array system that can enable sci-

entists to sequence DNA on a large scale. Their goal is to improve the robustness of nanopore platforms by combining computer chip fabrication methods with biological nanopores to enable high-throughput sequencing. The latter refers to a very high rate of sequencing DNA by sequencing large numbers of DNA samples in parallel.

• University of Pennsylvania $880,000 over 2 years Principal Investigator: Marija ­Drndic, PhD Investigators plan to develop a synthetic nanopore from grapheme, an extremely conductive material consisting of a lattice of atoms, one atom thick, that will enable the detection of individual DNA bases without the need to slow down the DNA molecule as it passes through a pore.

Researchers hope to directly identify DNA bases by measuring unique differences in current flowing through the graphene.

• Caerus Molecular Diagnostics, Inc, Mountain View, California $701,000 over 3 years Principal Investigator: Javier ­Farinas, PhD Researchers commonly use a system to identify DNA bases that entails making many copies of DNA and detecting a light signal from the DNA. Dr. Farinas and his co-workers plan to test a technology that uses an engineered enzyme switch to convert the product of a single molecule DNA sequencing reaction into many copies of a reporter molecule that are easily detected. The method promises to more accurately identify DNA bases.

• The Scripps Research Institute, La Jolla, California $4.4 million over 4 years Principal Investigator: M. Reza Ghadiri, PhD Investigators plan to produce protein nanopore arrays in order to sequence tens of thousands of DNA molecules in parallel, with the eventual goal of sequencing a human genome in as little as 10 minutes. They will explore three separate approaches, including arrays of lipid bilayers containing

nanopores, protein pores individually embedded in synthetic films, and nanopores made of DNA that are distributed on DNA scaffolds.

• Eve Biomedical, Inc, Mountain View, California $500,000 over 2 years Principal Investigator: Theofilos Kotseroglou, PhD Researchers will study a system to sequence DNA using an enzyme (polymerase) on a carbon nanotube, in an array format. Carbon nanotubes are long, thin cylindrical tubes that are highly conductive. When an enzyme is anchored on a tube, the enzyme’s motion, while interacting with a DNA sample, changes the conductivity on the nanotube, and enables bases of the sample DNA to be identified.

• University of Washington, Seattle $1.7 million over 3 years Principal Investigator: Jay Shendure, MD, PhD Dr. Shendure and his colleagues plan to develop new molecular biology techniques to efficiently and costeffectively stitch together genomes across long distances. They hope this will help improve the quality of genomes that are generated by new DNA sequencing technologies.

• University of California, San Diego $3.7 million over 4 years Principal Investigators: Kun Zhang, PhD and Xiaohua Huang, PhD This team plans to develop a system using microfluidics that will enable accurate genome sequencing of a single mammalian cell. Investigators will separate and sequence single chromosomal DNA strands, and then with the help of novel technology to make many copies of genomes, they will create DNA sequence libraries for DNA sequencing of single cells. n The grant numbers of the awards are the following: R01 HG007827, R21 HG007833, R21 HG007856, R43 HG007843, R01 HG003709, R43 HG007871, R01 HG006283, and R01 HG007836. Additional information about the National Human Genome Research Institute can be found at www.genome.gov.

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PAGE 79

Journal Spotlight Genitourinary Oncology

Minority of Older Patients With Low-Risk Prostate Cancer Managed by Observation, Rates Vary Widely Among Urologists and Radiation Oncologists

By Matthew Stenger

M

ost older men with low-risk prostate cancer receive upfront treatment, despite the absence of a clear survival benefit and potential for morbidity. In a retrospective cohort study reported in JAMA Internal Medicine, Karen E. Hoffman, MD, MHSc, MPH, of The University of Texas MD Ander-

diagnosis volume, and treatment of prostate cancer were considered in the analysis using backward selection with a P value cutoff of .10.

Patients had a median age of 72 years, and most were white (79.7%), had cT1 disease (73.4%), and were seen by a radiation oncologist (67.8%). Di-

Patients whose diagnosis was made by urologists who treated prostate cancer were more likely to receive upfront treatment and, when treated, more likely to receive a treatment that their urologist performed.

—Karen E. Hoffman, MD, MHSc, MPH, and colleagues

son Cancer Center, Houston, and colleagues found that use of observation as management in this setting varied widely among urologists and radiation oncologists.1 Patients diagnosed by urologists who treat prostate cancer were more likely to receive upfront treatment, which was also likely to be a treatment that the urologist performed.

Study Details The study involved 12,608 patients with low-risk prostate adenocarcinoma diagnosed between 2006 and 2009.

Patient and tumor data were obtained from Surveillance, Epidemiology, and End Results (SEER) cancer registries.

Data on diagnosing urologist, consulting radiation oncologist, cancer-directed therapy, and comorbid medical conditions were obtained from linked Medicare claims. Physician characteristics were obtained from the American Medical Association Physician Masterfile. Observation was defined as no cancer-directed therapy within 12 months of diagnosis.

Multivariate analysis of use of observation included age, race/ethnicity, comorbidity, clinical tumor category, and prostate-specific antigen (PSA) level. Medicaid coverage and SEER registry and urologist characteristics of decade of graduation, training location, degree, board certification,

agnoses were made by 2,145 urologists, of whom 88.2% treated non–low-risk prostate cancer.

Overall, 80.1% of patients received upfront treatment and 19.9% received observation. Upfront treatments included prostatectomy in 15.4%, brachytherapy in 23.0%, external-beam radiation therapy in 29.1%, externalbeam radiotherapy and brachytherapy in 6.2%, cryotherapy in 2.8%, and androgen-deprivation therapy in 3.6%.

Urologist and Patient Factors The case-adjusted rate of observation among urologists ranged from 4.5% to 64.2% of patients. In multi-

OR = 0.66, P = .01), and for those who treated low-risk prostate cancer (18.8% vs 25.0%, OR = 0.71, P = .01).

Management with observation was not associated with urologist diagnosis volume.

Use of observation increased with patient age, from 13.8% in those aged 66 to 70 years to 45.1% in those aged > 80 years (P < .001 for all age groups vs 66–70 years), was more likely in those with cT2 vs cT1 disease (24.4% vs 18.4%, OR = 1.23, P < .001), and was more likely in those diagnosed in 2008 (OR = 1.36, P < .001) or 2009 (OR = 1.76, P < .001) vs 2006.

Patients seen only by urologists were more likely to undergo observation than those seen by a radiation oncologist and a urologist (43.8% vs 8.6%, P < .001).

Overall, 70.8% of men who underwent observation saw only a urologist.

Multilevel analysis estimating the relative contributions of the diagnosing urologist and patient-level fixed effects to variance in the rate of observation indicated that the diagnosing urologist accounted for 16.1% of the variation in upfront treatment vs observation and that patient and tumor characteristics accounted for 7.9% of the variation.

Effect of Urologists Offering Treatment Patients who received upfront treatment were more likely to undergo prostatectomy (23.8% vs 12.4%, P < .001), cryotherapy (22.0% vs 1.0%, P < .001),

Management of Low-Risk Prostate Cancer ■■ A minority of patients had low-risk prostate cancer managed by observation.

■■ Numerous factors affected the likelihood of upfront treatment, including whether diagnosing urologists performed the specific treatment.

variable analysis adjusted for patientlevel and urologist-level characteristics, use of observation was less likely for urologists graduating before 1980 (odds ratio [OR] = 1.17, P = .04, for those graduating 1980–1989; OR = 1.26, P = .004, for those graduating after 1989), for urologists with DO vs MD degrees (13.4% vs 20.1%,

and brachytherapy (47.5% vs 21.0%, P < .001) if their urologist performed that treatment for non–low-risk disease. Patients with cancer diagnosed by urologists who billed for external-beam radiotherapy were more likely to receive that procedure (52.7% vs 42.9%, P = .005). Of 1,855 patients undergoing prostatectomy, 1,449 (78.1%) had the

procedure performed by the diagnosing urologist.

Radiation Oncologist Factors Overall, 7,554 patients met with 870 radiation oncologists. Of patients meeting with a radiation oncologist, 91.5% received upfront treatment and 8.5% underwent observation. For radiation oncologists treating ≥ 10 patients, caseadjusted rates of observation varied from 2.2% to 46.8%.

In multivariate analysis, radiation oncologists with MD vs DO degrees were more likely to use observation (P = .02). There was no association between observation and radiation oncologist treatment volume or decade of graduation. In multilevel analysis, 19.0% of the variance in upfront treatment vs observation choice was attributable to the radiation oncologist and 3.2% to patient characteristics.

The investigators concluded: Rates of management of low-risk prostate cancer with observation varied widely across urologists and radiation oncologists. Patients whose diagnosis was made by urologists who treated prostate cancer were more likely to receive upfront treatment and, when treated, more likely to receive a treatment that their urologist performed. Public reporting of physicians’ cancer management profiles would enable informed selection of physicians to diagnose and manage prostate cancer. n Disclosure: The study was supported by grants from the Cancer Prevention and Research Institute of Texas, National Cancer Institute, American Cancer Society, Duncan Family Institute, and The University of Texas MD Anderson Cancer Center. Dr Hoffman receives research support from the American Society for Radiation Oncology. For full disclosures of the study authors, visit archinte.jamanetwork.com.

Reference 1. Hoffman KE, Niu J, Shen Y, et al: Physician variation in management of low-risk prostate cancer: A population-based cohort study. JAMA Intern Med. July 14, 2014 (early release online).

See commentaries by Anthony L. Zietman, MD, and John A. Fracchia, MD, FACS, on pages 83 and 84.

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PAGE 83

Perspective Genitourinary Oncology

Active Surveillance in Low-Risk Prostate Cancer: When Will We Pay It More Than Just Lip Service?

By Anthony L. Zietman, MD

A

ctive surveillance is well established as an appropriate management option for men with lowrisk prostate cancer and particularly for those over 65 years of age. Its legitimacy is now enshrined within National Comprehensive Cancer Network guidelines, in the American Society for Radiation Oncology Choosing Wisely campaign proclamations, and, indirectly, though the new American Urological Association guidelines on early detection of prostate cancer.1-3 A recent report by Hoffman et al, reviewed in this issue of The ASCO Post, uses the Surveillance, Epidemiology, and End Results database to look at a large number of contemporary men aged 66 years and older and concludes that for those with low-risk disease, active surveillance is far “more honored in the breach than in the observance.” This is not the first report to reach such a disheartening conclusion, but it does come from a robust and representative dataset and offers additional insights into the reasons behind the reluctance to embrace it.4

Long-Available Data Why, despite accumulating evidence, might this state of affairs exist? The Hoffman et al report details a contemporary period of 2006–2009 for which Medicare data are available. The landmark PIVOT study, however, was not published until 2012, and it is possible that more recent data, if it had been available, might have shown different trends.5 Clinicians, it could be argued, may have been awaiting stronger evidence. It must be pointed out, however, that the early results of the Swedish randomized trial comparing simple observation with prostatectomy were available during this interval and, at that stage, showed no survival gains for aggressive treatment even for those with more advanced disease.6 Many large prospective active surveillance cohorts had also been published in high-profile journals. It seems, therefore, that a lack of data was not the issue.

Dr. Zietman is Shipley Professor of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston.

Goals Other Than Cure The first decade of this millennium was a time of extraordinarily exciting technologic advances in both radiation oncology and surgery, with unprecedentedly enthusiastic and rapid adoption of the new techniques into the clinic ahead of evidence. It may be that clinicians truly believed that the morbidity of their treatments was now so reduced that the scales tilted in favor of treatment.

After all, we treat everyone with mild hypertension or hyperlipidemia even though only a small proportion of the population with these conditions is destined to suffer serious consequences. We do this because the morbidity of the medications offered appears to be low and,

tion is a worthy goal, since it is likely that the adverse quality-of-life consequences of this particular form of therapy are far greater than initial treatment with surgery or radiation.

It is unclear how often a man who is diagnosed with prostate cancer and left alone without curative treatment ultimately comes to androgen deprivation, but the Swedish trial suggests it may be a significant minority by 14 years—although it must be emphasized that these were not screened men.8 That proportion is likely to be much lower in a U.S. population.

Detractors of active surveillance point to the inaccuracy of needle biopsies in staging and grading prostate cancer when compared with prostatectomy specimens. That

This is not the first report to reach such a disheartening conclusion, but it does come from a robust and representative dataset and offers additional insights into the reasons behind the reluctance to embrace [active surveillance in low-risk prostate cancer].

—Anthony L. Zietman, MD

when one considers the population rather than the individual advantages, the question is not “why?” but “why not?” Technology has not, unfortunately, rendered the consequences of a robotic prostatectomy or of intensity-modulated radiation therapy to be as innocent as a thiazide diuretic or a statin.

Some have argued that there are goals other than cure that are worth striving for in men with low-risk disease, such as freedom from anxiety and freedom from androgen deprivation. Freedom from anxiety is, I believe, the responsibility of the physician and not the treatment, and several quality-of-life studies show that a well-informed, wellcounseled, and well-supported patient is perfectly happy with active surveillance.7 Freedom from androgen depriva-

is indeed true, but is also true for all the active surveillance series in which very high rates of disease-specific survival at 10 years are routinely found despite this undergrading and understaging. Fear of missing higher-risk disease may lead to very aggressive surveillance with annual biopsies or magnetic resonance imaging, the prospect of which may also make treatment seem relatively appealing.

Cultural and Economic Obstacles The biggest obstacles to the greater use of active surveillance in the United States are, regrettably, cultural and economic in nature, and the latter was hinted at in the Hoffman et al article. When a physician enjoys a financial gain if he treats and perceives the risk of a liti-

gation loss if he does not, then the consequences are hardly difficult to predict. In our fee-for-service system, certain services are more generously reimbursed than others, and the face-time spent counseling a patient reimburses lowest of all.

If one factors in curious perverse incentives (such as dubious self-referral practices) that exist within our system, then the problem is amplified.9 Prostate cancer does not have a good record in this regard—and the massive use of androgen deprivation prevalent in the 1990s was terminated suddenly in 2003 by federal fines, a change in reimbursement, and the closing of a legal loophole.10

Reasons for Optimism I remain optimistic, however, that things will change for the better. New, high-quality evidence will emerge in the next 2 years from the ProtecT randomized trial taking place in the United Kingdom.11 This beautifully organized trial has studied screening in an enormous cohort of men, and there is a further randomization to surgery, radiation, or active surveillance for those in whom cancer is detected. It completed accrual ahead of schedule and, while we must not anticipate its findings, its wealth of data will drive future practice.

In another recent development, several groups have clearly documented that multidisciplinary clinics increase the uptake of active surveillance.12 This is likely because two or three physicians from different specialties seeing a patient together and singing harmoniously the same active surveillance song provide great reassurance for patients. It is also probable that effective, synchronous multidisciplinary clinics keep all the physicians honest and prevent exaggerated claims about any one therapy.

Also critical to patterns of practice will be health-care payment reform, which now seems inevitable.

We don’t know when it will come or what exact form it will take, but it is likely that attempts will be made to align financial incentives with best practices. continued on page 84

The ASCO Post | AUGUST 15, 2014

PAGE 84

Perspective Genitourinary Oncology

Low-Risk Prostate Cancer and Principles of Active Surveillance

By John A. Fracchia, MD, FACS

F

or specific diseases, many physicians tend to recommend interventions and therapies with which they are most comfortable and familiar. It is not surprising that urologists and radiation oncologists did so in the study reported by Hoffman and colleagues in JAMA Internal Medicine and reviewed in this issue of The ASCO Post.1 It is also not surprising that “older” urologists in this study more often implemented definitive therapies compared to their younger colleagues, since active surveillance is a relatively recent approach being taught now in training programs as an option for some men with prostate cancer.

with the principles of life expectancy estimation, to adjust this upward by 50% (6.36 years) for those in the best quartile of health.3 In addition, more than 69% of the men with low-risk prostate cancer in

The opening statement in the Hoffman et al report—‘Low-risk prostate cancer … is unlikely to cause symptoms or affect survival if left untreated.’—is probably true, but I would add ‘as long as the disease remains low-risk.’

—John A. Fracchia, MD, FACS

Baseline Assumptions The National Comprehensive Cancer Network (NCCN) guidelines recommend active surveillance, radical prostatectomy, brachytherapy, and external-beam radiation therapy as options for men with low-risk prostate cancer with at least a 10-year life expectancy. These guidelines have not changed since 2009, the last year of the data analyzed in the study by Hoffman et al.

This report’s median age of 72 represents an average anticipated life expectancy of 12.72 years for 2009.2 It may be reasonable, in accordance

agnosing urologist plays an important role in treatment selection. This is undoubtedly true for a variety of reasons, and the individualization of recommendations for particular active treatment options or no treatment is

this study had a Charlson comorbidity score of 0, and < 10% of those diagnosed had a comorbidity score ≥ 2.

Accordingly, it is reasonable to assume that the majority of men with low-risk prostate cancer in this study had life expectancy of 12.72 or more years. If the Charlson comorbidity score is relatively constant across all age groups in this report (it may not be), then the anticipated life expectancy would average about 10 years for patients aged > 80 years and marginally higher for those aged 76 to 80 years.

Dr. Fracchia is Clinical Professor of Urology, Weill Cornell Medical College, New York.

Reasons Underlying Recommendations The authors postulate that the di-

based on multiple factors.

As would be expected, the percentage of men who did not receive definitive therapy appropriately increased in each age cohort in the study. However, patients, physicians, and reports often inadvertently use the terms “observation,” “watchful waiting,” and “active surveillance” interchangeably, which often generates misunderstanding.

NCCN’s description of observation (watchful waiting) involves monitoring the course of the disease with the expectation to deliver palliative therapy if symptoms develop or there is a change in exam or prostate-specific antigen (PSA) findings suggesting that symptoms are imminent. This is

Anthony L. Zietman, MD

References 1. Mohler JL, Kantoff PW, Armstrong AJ, et al: Prostate cancer version 2.2014. J Natl Compr Canc Netw 12:686-718, 2014.

2. American Society for Radiation Oncology/Choosing Wisely Initiative: Five things physicians and patients should question. September 23, 2013. Available at www.choosingwisely.org/doctor-patientlists/american-society-for-radiation-oncology/ 3. Carter HB, Albertsen PC, Barry MJ, et al: Early detection of prostate cancer: AUA guideline. J Urol 190:419-426, 2013.

4. Hoffman KE, Niu J, Shen Y, et al: Physician variation in management of lowrisk prostate cancer: A population-based cohort study. JAMA Intern Med. July 14,

2014 (early release online).

5. Wilt TJ, Brawer MK, Jones KM, et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367:203-213, 2012.

6. Bill-Axelson A, Holmberg L, Ruutu M, et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 352:1977-1984, 2005.

7. Burnett KL, Parker C, Dearnaely D, et al: Does active surveillance for men with prostate cancer carry psychological morbidity. BJU Int 100:540-543, 2007.

8. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 370:932-942, 2014.

9. Mitchell J: Urologists’ use of inten-

continued from page 83

Hoffman et al point out the extraordinary physician variation in the management of prostate cancer and, after illustrating that it has a strong economic basis, recommend public reporting of a physicians’ cancer management profiles. This would represent a “name and shame” approach that might provide a solution while we await payment reform. If physicians cannot do the right thing for the right reasons, then the second-best resolution would be that they at least do the right thing for the wrong reasons. n

Disclosure: Dr. Zietman reported no potential conflicts of interest.

not the same as active surveillance, an approach in which there is proactive monitoring of the stability/progression of the disease and intervention if and when the disease poses an imminent threat to the patient’s survival or quality of life.

I do offer active surveillance to appropriate patients, but I often find it to be a hard sell (I am age 67 and therefore an “older” urologist). Once disease is pathologically confirmed, many men, their spouses, and their families find the suggestion of monitoring not yet definitively established benchmarks (Gleason grade change, PSA, etc) to be counterintuitive, despite the legitimate concerns about definitive treatment in older men.

The anxiety inherent in the process also influences a relatively high number of men to initially seek out or convert to conventional treatments. An easier conversation in my experience is to dissuade “older” patients and/or those with significant comorbidities from having a biopsy even though the patients are usually referred for evaluation for prostate cancer.

In Conclusion There is little doubt that not all men with low-grade prostate cancer have to be treated. The opening statement in the Hoffman et al report—“Lowrisk prostate cancer … is unlikely to cause symptoms or affect survival if continued on page 85

sity-modulated radiation therapy for prostate cancer. N Engl J Med 369:1629-1635, 2013.

10. McKoy JM, Lyons EA, Obadina E, et al: Caveat medicus: Consequences of federal investigations of marketing activities of pharmaceutical suppliers of prostate cancer drugs. J Clin Oncol 23: 8894-8905, 2005.

11. Lane JA, Hamdy FC, Martin RM, et al: Latest results from the UK trials evaluating prostate cancer treatment and screening: The CaP and ProtecT studies.

Eur J Cancer 46:3095-3101, 2010.

12. Aizer AA, Paley JJ, Zietman AL, et al: Multidisciplinary care and the pursuit of active surveillance in low-risk prostate cancer. J Clin Oncol 30: 3071-3076, 2012.

ASCOPost.com | AUGUST 15, 2014

PAGE 85

Perspective

John A. Fracchia, MD, FACS continued from page 84

left untreated.”—is probably true, but I would add “as long as the disease remains low-risk.”

The NCCN guidelines for men with low-risk prostate cancer detail the role of expectant management.

Observation (watchful waiting) is recommended for men with low-risk prostate cancer with < 10-year life expectancy. Active surveillance is an established op-

tion for men with low-risk prostate cancer and ≥ 10-year life expectancy.

Active surveillance may well stand the test of time as we learn more about the natural history of this disease. n Disclosure: Dr. Fracchia reported no potential conflicts of interest.

References 1. Hoffman KE, Niu J, Shen Y, et al: Physician variation in management of low-risk prostate cancer: A populationbased cohort study. JAMA Intern Med. July 14, 2014 (early release online).

2. Official Social Security Website:

Actuarial life table. Available at www.ssa. gov/OACT/STATS/table4c6.html. Accessed July 28, 2014.

3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, version 2.2014, PROS-A. Available at nccn.org.

Accessed July 28, 2014.

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PAGE 86

ASCO Annual Meeting Multidisciplinary Collaboration

Getting Results: How Oncologists and Pathologists Can Work Together to Facilitate Molecular Testing

By Charlotte Bath

A

dvances in molecular testing mean that highly specific information can be detailed about the molecular characteristics of a patient’s tumor, as well as indications of potential responsiveness to targeted therapy. But getting those detailed results from the pathologists can be a challenge to many oncologists. The wealth of information that next-generation sequencing can provide and how pathologists and oncologists can work together to best access and use that information were elucidated at a lung cancer education session at the 2014 ASCO Annual Meeting in Chicago.

sequencing technologies, including whole-genome, whole-exome, and targeted sequencing, each with its own advantages, disadvantages, and cost issues.

For example, targeted sequencing is highly sensitive and the lowest-cost sequencing method, but it is “not a discovery tool,” Dr. Jänne said. “You are looking for things that you already know about.” Whole-exome sequencing looks at all genes and is a discovery and research tool, but is not as sensitive. Combining the two methods can give the advantages of both, but increase costs.

“Optimal management of lung can-

Optimal management of lung cancer patients requires tumor genotyping, but understanding the characteristics of the test and potential results are important in choosing the right test.

—Pasi A. Jänne, MD, PhD

Genetic mutations can be detected by allelotyping, an assay to detect a specific predefined mutation, or sequencing, an assay to analyze DNA changes, including mutations in specific regions of a gene, explained Pasi A. Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston.1 Allelotyping is fast and sensitive, but not comprehensive, whereas sequencing is comprehensive, but slower and less sensitive.

Next-generation sequencing offers a “souped-up” version of sequencing, “able to do this in a massively enhanced way,” Dr. Jänne said. While traditional sequencing is analog, mixing together all DNA from a sample and analyzing one section of the genome at a time, next-generation sequencing is digital, sequencing all DNA strands in parallel and “can analyze multiple types of mutations at the same time,” Dr. Jänne added. Because next-generation sequencing relies on one test rather than multiple separate assays, it “is ultimately likely to be a cost-effective method,” Dr. Jänne said, adding that most biopsy samples from lung cancer patients “are not amenable” to multiple assays.

He pointed out that there are several different types of next-generation

cer patients requires tumor genotyping, Dr. Jänne concluded, but “understanding the characteristics of the test and potential results are important in choosing the right test.”

‘Tissue Is the Issue’ Because “molecular testing is relatively new in the world of ‘routine’ medical care,” noted Dara L. Aisner, MD, PhD, Assistant Professor and Co-Director of the Colorado Molecular Correlates Laboratory at the University of Colorado in Denver, logistical processes for molecular testing have not yet been established at many institutions.2 In her

Dara L. Aisner, MD, PhD

talk at the education session, Dr. Aisner maintained that creating processes geared toward accelerating or prioritizing molecular testing is more effective than “one-at-a-time management.” Set-

ting up these processes requires multidisciplinary conversations to implement these approaches and multiple technical steps to preserve material for molecular studies, she added.

There are multiple points where things can go wrong, Dr. Aisner noted.

“When you have received a specimen in pathology, it goes through a diagnostic process, and then somewhere along the way it is diverted for this molecular process,” she said. “This can become very complicated because that request for molecular testing can come at any point along the process, including after the slides have been filed and shipped away.”

There may be insufficient tissue left for genotyping because the request was received late in the process, or because a pathologist who is unaware that a diagnosis had already been made performed another complete diagnostic workup.

“In my opinion, [lack of] communication is the number 1 obstacle, because the overall process typically involves so many different people along the line.

You have the person ordering the biopsy, the person who is procuring the biopsy, and the person who is transporting the biopsy.… As you move along the line, it’s very easy for the message to get lost,” Dr. Aisner said.

“How do you establish specific needs for a specific specimen?” she continued. “Having systems-based approaches is much more effective than culling individual specimens and … saying this one particular specimen needs this [type of testing].”

Specialized Instructions and Handling The University of Colorado has over 3 years’ experience with a systemsbased process to identify cases that are prioritized for molecular analysis, Dr. Aisner reported. Integral to that process are specialized ordering instructions and handling of biopsy material, and increasing awareness among pathologists.

“We have specialized language that goes into our electronic orders,” she explained. “We also have specialized tissue handling. In a typical pathology process, all pieces of a small sample might be put into one block. In order to get a complete cross-section adequate for diagnosis, sometimes you have to dig into that block quite a ways.” For molecular testing–prioritized specimens, “we separate

tissue into individual blocks. We do very shallow facing and, by doing that, we are able to preserve a substantial amount of material for molecular testing.”

Other special instructions involve molecular testing for bone metastases.

“In a pathology gross lab setting where we are operating on volume and mass movement of tissue, if a sample comes in and the requisition says ‘bone,’ it can be a knee-jerk reflex to put that sample into decalcification solution,” Dr. Aisner said. “However, tumor metastatic to bone often does not require decalcification. That lytic lesion may have consumed the very hard portion of the bone that would normally render decalcification a requirement. Again, this comes down to communication—letting the laboratory know in advance that this is a sample for molecular testing, that it’s a bone sample, and that you would like them to see if it’s possible to do this without decalcification,” she continued.

Suitable Specimens “Resection specimens are nearly always acceptable for molecular analyses, but you need to recognize that some specialized tests require that fresh tissue be submitted and not formalin tissue.

That’s something that requires specialized procurement approaches be employed,” Dr. Aisner advised.

“One rapid-growth area is the posttreatment biopsy,” she noted. “Biopsy at the time of progression is certainly becoming more common, but it is important to recognize that treatment-related changes often impact the ability to use that specimen.”

There are also “substantial challenges” to getting a post-treatment biopsy, she added. “As we increase our use of posttreatment biopsies to explore molecular mechanisms of resistance and new therapeutic options, we may have to be more aggressive about tissue acquisition.”

How to Talk to Your Pathologist “The focus I’d like to take on this is the more nebulous issue of not what it is you’re talking to your pathologists about, but how you talk to them,” noted Jan A. Nowak, MD, PhD, Director of the Molecular Diagnostics Laboratory at North Shore University Health System, Evanston, Illinois.3 “We are a relatively small four-hospital health-care system. In all of our hos-

ASCOPost.com | AUGUST 15, 2014

PAGE 87

ASCO Annual Meeting pitals, we probably see 50,000 to 60,000 surgical specimens per year. We have 13 or 14 full-time surgical pathologists, and we have a molecular diagnostic laboratory,” he said.

during the week, by noon the following Tuesday, when we have our chest conference where treatment planning is made, we have those results available,” Dr. Nowak said. “It is rare that we say that there’s insufficient material.

Pathologist-Oncologist Interaction

Jan A. Nowak, MD, PhD

“Our volume has grown from fewer than 200 molecular tests in 2008 to more than 1,000 in 2013. Most of this increase has come from non–small cell lung cancer. We added ALK FISH [fluorescence in situ hybridization] a few years ago, as well as EGFR and KRAS testing. It just continues to grow,” Dr. Nowak reported.

“Our results typically are available in under 2 days. If a patient has a procedure

One of the major reasons Dr. Nowak cited for why molecular testing is working well at the North Shore University Health System is the interaction between oncologists and pathologists.

As an example, he cited e-mails he and other pathologists received from an oncologist—the first e-mail requesting that a specimen from a patient with lung cancer not be delcalcified, so that molecular testing could be done, and the second updating the patient’s status and reiterating his requests concerning decalcification and EGFR testing.

“What’s important here? First, this oncologist was wise enough to give us a heads-up. He sent us an e-mail saying look out for this specimen; I need some-

thing important here…. Second, he knows multiple pathologists by name; he can contact us. Third, he is wise enough to know that you can’t decalcify these specimens and expect to get molecular testing done. He is telling us exactly what he needs,” Dr. Nowak reported. “I get these e-mails all the time.”

Dr. Nowak predicted that biomarker testing in a large community hospital setting, with “clinically relevant turnaround times” and even with very small specimens is “going to be the standard in the next few years. To do all of this, however, you need to have an engaged pathologist, someone who can look at the cytology and say, yes, there’s enough here for molecular testing. Whether the testing is done in house or sent outside to a reference laboratory, you still need that interface,” Dr. Nowak said.

Summing up, Dr. Nowak stated, “You need to engage your pathologist in the care of your patients. They are his patients, too. Whatever new technologies come into play, the tissue specimen will always be critical because

that’s variable. The pathologist is the key interface between the specimen and the test; between your patient and the choices you will have to treat him. Don’t call the laboratory. Call the pathologist.

That’s your colleague.” n

Disclosure: Dr. Jänne is a consultant or advisor for AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Clovis Oncology, Genentech, Pfizer, Roche, and Sanofi, owns stock in Gatekeeper Pharmaceuticals, and has received other remuneration from LabCorp. Dr. Aisner is a consultant or advisor for Boehringer Ingelheim and has received honoraria from Abbott Molecular. Dr. Nowak reported no potential conflicts of interest.

References 1. Jänne PA: What are we talking about: Next-generation sequencing, Sanger sequencing, etc. ASCO Annual Meeting. Education Session. Presented June 1, 2014.

2. Aisner D: Tissue is the issue: The pathologist’s role in facilitating molecular analysis. ASCO Annual Meeting. Education Session. Presented June 1, 2014.

3. Nowak JA: The practitioner’s guide to using molecular testing. ASCO Annual Meeting. Education Session. Presented June 1, 2014.

Science in Society

Life: Magnified Exhibit Continues to Heighten Public Awareness About Science, On Display and Online Life: Magnified is an exhibit of scientific images showing cells and other scenes of life magnified by as much as 50,000 times. The exhibit is on display at Washington Dulles International Airport’s Gateway Gallery from June through November 2014. A Web companion is available through NIH here http:// www.nigms.nih.gov/education/ life-magnified/Pages/default.aspx Earlier this year The ASCO Post published selected images from the exhibit (see The ASCO Post, July 10 issue). On occasion, we will continue to publish images from the exhibit as done here.

W

hen biologists disabled proteins critical for cell movement, the result was dramatic. The membrane, normally a smooth surface enveloping the cell, erupted in spiky projections.

This image (see Fig. 1), which is part of the Life: Magnified exhibit, resembles a supernova. Although it looks like it ex-

ploded, the cell pictured is still alive.

To create the image, Rong Li, PhD, and Praveen Suraneni, PhD, NIH-funded cell biologists at the Stowers Institute for Medical Research in Kansas City, Missouri, disrupted two proteins essential to movement in fibroblasts—connective tissue cells that are also important for healing wounds. The first, called ARPC3, is a protein in the Arp2/3 complex. Without it, the cell moves more slowly and randomly.1 Inhibiting the second protein gave this cell its spiky appearance. Called myosin IIA (green in the image), it’s like the cell’s muscle, and it’s critical for movement. The blue color is DNA; the red represents a protein called F-actin.

Drs. Li and Suraneni are studying cell movement because it is vital throughout development. In embryos, cells wriggle to their correct location. In the developing brain, neurons migrate to settle in their designated brain structure. Immune cells move toward bacterial and viral invaders—and skin fibroblasts squirm toward injuries to patch wounds.

Disrupting the proteins crucial for movement can wreak havoc: immune diseases, birth deformities, and even death.

On the other hand, blocking cell movement could actually be beneficial in certain circumstances. For example, when a cancer cell breaks away from its primary tumor and migrates, resettling in another part of the body—called metastasis—the results can be deadly. Finding a target on these cancer cells to hinder movement could slow, or even block, metastasis.

The next challenge for Dr. Li’s team is to explore the role of Arp2/3 in other cell types, such as stem cells, to determine whether this complex of proteins also holds the key to their ability to move. n Life: Magnified is a joint project among the National Institute of General Medical Sciences, the American Society for Cell Biology and the Metropolitan Washington Airports Authority’s Arts Program, which utilizes the arts to enhance travel experiences at Dulles International and Reagan National Airports. ZEISS provided additional support of the exhibit.

Reference 1. Suraneni P, Rubinstein B, et al: The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration. J Cell Biol 16:197:239-251, 2012.

Fig. 1: Cells missing a key molecule appear spiky and cannot move normally This is a fibroblast, a connective tissue cell that plays an important role in wound healing. Normal fibroblasts have smooth edges. In contrast, this spiky cell is missing a protein that is necessary for proper construction of the cell’s skeleton.

Its jagged shape makes it impossible for the cell to move normally. In addition to compromising wound healing, abnormal cell movement can lead to birth defects, faulty immune function and other health problems. Courtesy Praveen Suraneni and Rong Li, Stowers Institute for Medical Research, Kansas City, Mo.

The ASCO Post | AUGUST 15, 2014

PAGE 90

Announcements

ASTRO Names Angelita Habr-Gama, MD, PhD, Honorary Member

T

he American Society for Radiation Oncology (ASTRO) has named Angelita Habr-Gama, MD, PhD, as the 2014 Honorary Member, the Society’s highest honor. Dr. Habr-Gama is Professor of Surgery at the University of Sao Paulo School of Medicine and Staff

Angelita Habr-Gama, MD, PhD

Surgeon of Coloproctological Surgery at Hospital Alemao Oswaldo Cruz in Sao Paulo, Brazil.

Dr. Habr-Gama will be inducted as the 2014 ASTRO Honorary Member during the Awards Ceremony on Tuesday, September 16, at ASTRO’s 56th Annual Meeting in San Francisco.

“Dr. Habr-Gama’s extensive research in developing and promoting nonoperative treatment approaches for rectal cancer, including radiation therapy, is important to providing optimal cancer care for each patient’s unique situation,” said Colleen A.F. Lawton, MD, F ­ ASTRO, chair of ASTRO’s Board of Directors.

“Her continued study of additional treatment strategies and her emphasis on a change in the standards of care demonstrate her dedication to improving the lives of cancer patients worldwide.”

Nonoperative Approaches for Treating Rectal Cancer Dr. Habr-Gama is internationally recognized for her work in developing and supporting selective nonoperative treatment approaches for rectal cancer. She has published 177 articles in peer-reviewed medical journals. Dr. Habr-Gama founded the Division of Coloproctology at the University of Sao Paulo School of Medicine, and has been a member of the Board of the Oncology Foundation of Sao Paulo since 1990.

In the late 1980s, Dr. Habr-Gama discovered that patients with rectal cancer who had received neoadjuvant chemoradiation therapy did not have residual cancer; however, the patients were still undergoing abdominal perineal resections.

“When we discovered this, I could not offer this operation anymore without at least a suspicion that the tumor was still there and without a thorough discussion with the patient,” Dr. Habr-Gama said. “This led us to start reassessment of response 8 weeks after completion of chemoradiation therapy instead of immediately scheduling an operation. When I started reassessing these patients, I realized that some tumors actually completely disappeared on clinical evaluation.”

Landmark Paper Shows 100% 5-Year Overall Survival This assessment led to Dr. HabrGama’s landmark paper, “Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results,” published

in the Annals of Surgery in October 2004.1 Her team’s research showed a 100% 5-year overall survival rate and complete clinical response of the primary tumor in patients with locally advanced rectal cancer treated with chemoradiation therapy and managed only with observation. Two patients experienced local failures; however, they were successfully managed without radical resection. This strategy avoids the surgery that has been the standard of care for this disease.

“This approach has been criticized for years. All of the downsides and potential harms have been pointed out, and we have worked hard to demonstrate that, in experienced hands, this is a safe and valid alternative that has to be considered individually for each patient,” continued Dr. Habr-Gama.

Strong Advocate for Radiation Therapy Dr. Habr-Gama is a strong advocate for the role of radiation therapy in rectal cancer treatment, explaining the benefit of preoperative radiation for rectal cancer and encouraging investigators to reconsider before marginalizing radiation from the standard treatment of rectal cancer.

“Many people outside of Latin America thought I was a radiation oncologist,” Dr. Habr-Gama said. “I am a big proponent of preoperative radiation because I know it works and because our fantastic group of radiation oncologists have made us comfortable with the process and have delivered treatment

with very low complication rates.”

Dr. Habr-Gama believes that her research will impact treatment approaches for rectal cancer, both in the United States and internationally. In the decade since this research was first published, her team has published several prospective and retrospective studies that further refine the protocol to help maximize the clinical response and safety of this treatment approach.

“Our research on this approach has provided a considerable amount of evidence to suggest that select patients with complete clinical response to neoadjuvant chemoradiation therapy may be safely spared from immediate radical surgery.

There is indication that there will be trials in the United States using this treatment strategy,” she said. “This represents a significant change in the surgical, medical and radiation oncology communities and will allow a more robust understanding of the role of ‘watch and wait’ for the management of select patients with rectal cancer.”

ASTRO first awarded Honorary Membership in 1989. Including Dr. Habr-Gama, 31 individuals have been selected to receive Honorary Membership in ASTRO. For more information about ASTRO’s 56th Annual Meeting, visit www.astro.org/AnnualMeeting. n Reference 1. Habr-Gama A, Perez RO, Nadalin W, et al: Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results. Ann Surg 240:711-717, 2004.

Don’t Miss These Important Reports in This Issue of The ASCO Post Lauren C. Harshman, MD, on anti–PD-1 agents in renal cell carcinoma see page 3

Melinda L. Telli, MD, on platinium therapy in triple-negative breast cancer see page 5

Stephen B. Riggs, MD, on surgery in germ cell tumors see page 40

Elena Elimova, MD, Shumei Song, MD, PhD, and Jaffer A. Ajani, MD, on EGFR as a therapeutic target for gastroesophageal cancer see page 33

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | AUGUST 15, 2014

PAGE 91

Expert’s Corner Immunotherapy

Prominent Immunotherapy Researcher Sees Success Beyond the Challenges

By Ronald Piana to the bedside. We invent, develop, and translate engineered cell-based therapies.

Current Research

Michel Sadelain, MD, PhD

A

ctivating the immune system for therapeutic benefit in cancer patients has long been a goal in the scientific community. After decades of disappointment, this intriguing approach has come to the forefront of cancer research, showing promising results in several malignancies.

To keep abreast of this rapidly advancing field, The ASCO Post recently spoke with one of the nation’s leading immunology experts, Michel Sadelain, MD, PhD, Director of the Center for Cell Engineering and the Gene Transfer and Gene Expression Laboratory at Memorial Sloan Kettering Cancer Center, New York.

Innovation and Clinical Translation Please tell the readers a bit about your background and how you arrived at the Center for Cell Engineering, Memorial Sloan Kettering Cancer Center.

After obtaining a medical degree and a PhD in Immunology, I went to MIT in 1989 to conduct research on genetransfer biology, which was then very rudimentary. My goal was to unravel whether T lymphocytes could be genetically engineered and, if so, whether one could “instruct the immune system” to perform any task we deemed useful.

In 1994, I started a stem cell and Tcell engineering program at Memorial Sloan Kettering, where I later (in 2008) founded the Center for Cell Engineering with the support of then-President Harold E. Varmus, MD. The Center for Cell Engineering primarily focuses on cancer immunotherapy, as well as stem-cell therapies for blood and neurologic disorders. The two hallmarks of the program are innovation, as best seen in the chimeric antigen receptor (CAR) field, and clinical translation, with major strengths in patient cell manufacturing and clinical trial implementation. These enable us to bring the novel concepts and methods we devise

Please describe your current line of inquiry in immunotherapy and chimeric antigen receptor therapy.

It has taken over 2 decades to establish the technologic platform for human T-cell engineering (based on the use of retroviral vectors) and to design and test synthetic receptors that effectively direct potent, targeted immune responses.

These receptors for antigen, which we eventually called chimeric antigen receptors, went through a series of evolutionary steps. The most critical of these, perhaps, was the incorporation of costimulatory domains into the receptors, which we termed second-generation CARs. This design extends the function

Dendritic Cell Therapy Dendritic cell therapy is garnering significant attention in a wide range of malignancies. What is your opinion on the research being done in this area of immunotherapy?

Dendritic cells are the most effective cells in the body to initiate the immune responses that are carried out by T cells, which the dendritic cells specifically activate. The potency of dendritic cells in preventive interventions, such as vaccines against infectious diseases, is well established. The question has long been whether their ability to elicit and amplify T-cell responses is sufficient after the disease is diagnosed, ie, as a therapeutic intervention rather than a prevention step, and especially against cancer, where most of the antigens are typically less immunogenic than those found in infectious organisms.

So while the tolerability of dendritic

Immunotherapy is not monolithic. It is a rich field encompassing multiple approaches.

—Michel Sadelain, MD, PhD

and lifespan of the engineered T cells.

This functionality is, in turn, the key to creating “living drugs” that persist long enough in the body to induce complete remissions, as we see today in patients with B-cell malignancies, especially in acute lymphoblastic leukemia (ALL).

We proposed CD19 as a CAR target over 10 years ago1 because of its relevance to several cancers—ALL, other leukemias, several lymphomas, Waldenstrom’s macroglobulinemia, etc—and its very restricted expression in other tissues. CD19 is now the paradigm for CAR therapy, and ALL, the CD19-linked disease where current CARs work the best.

The results achieved in adults with chemorefractory, relapsed ALL patients have exceeded any forecast. Most important, our early results in 5 patients, reported in 2013,2 are holding up in larger cohorts of patients (16 reported earlier this year).3 We are developing furtherenhanced CD19 CARs for those B-cell malignancies that require them.

We are also making rapid progress in understanding the occasional toxicities that we see in patients treated with CAR T cells. The unknown frontier is whether CARs will work in solid tumors, which I firmly believe will be the case.

To attain this goal, we need to identify the right targets and tackle the microenvironmental resistance mechanisms that are found in different tumor types.

cell therapy is high, questions remain as to its suitability for treating patients with advanced cancer, immune dysfunction, and/or rapidly progressing disease. This is why we chose to bypass this natural immune-stimulatory pathway and focused on the rapid generation of large cohorts of ready-to-fight targeted T cells using CARs. Fortunately, cancer immunotherapy offers many approaches to tackling cancer, which will ultimately give us the flexibility to select or combine the better approaches to meet each patient’s needs.

Stem Cell Engineering Stem cell engineering is a relatively new field. Please shed light on how this intriguing science could translate into clinical therapeutic approaches in cancer.

Stem cell engineering is the foundation for regenerative medicine, which many of us anticipate will bring another revolution in patient care in the years to come. The isolation, expansion, differentiation, genetic engineering, and large-scale manufacturing of stem cells still pose significant biologic and technical challenges, but research is advancing at a steady pace.

In some regards, the development of T-cell therapies is laying the groundwork for the advent of stem cell–based regenerative medicines. Stem cell therapies will benefit cancer patients in several ways, ranging from tissue repair (eg, bones) to organ regeneration (eg, liver) to immune

reconstitution. The latter will be especially important in aging populations.

One area that we are actively pursuing is how to use cultured stem cells (“in a dish”) to generate T cells that are ready and ideally suited to fight cancer. We were the first to succeed in making T cells— CAR T cells, of course—from human pluripotent stem cells and to cure tumorbearing mice with such “artificial” T cells.4

Closing Thoughts Immunotherapy has had a long and, at times, difficult road in oncology. Please share a few last thoughts about this field’s future in the fight against cancer?

Immunotherapy is not monolithic. It is a rich field encompassing multiple approaches. The immunotherapies that have taken oncology by storm in the very recent years are different from those that had been tried earlier. Both checkpoint blockade and T-cell engineering approaches act on the patient’s T cells, not the tumor.

Our work on CAR T-cell engineering targeting CD19, complemented by studies from the National Cancer Institute and University of Pennsylvania, where other researchers were eventually attracted to pursue this intriguing approach, demonstrates the feasibility and efficacy of CD19 CAR therapy. The fact that three centers independently reported promising results has given enormous credibility to the potential of CAR therapy.

The second-generation CAR design opened the door to T-cell potency and impressive therapeutic responses. We now need to better harness this powerful tool and tailor the design of CAR T cells to take on the challenge of solid tumors. n

Disclosure: Dr. Sadelain reported no potential conflicts of interest.

References 1. Brentjens RJ, Latouche JB, Santos E, et al: Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes costimulated by CD80 and interleukin-15. Nat Med 9:279-286, 2003.

2. Brentjens RJ, Davila ML, Riviere I, et al: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapyrefractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra38, 2103.

3. Davila ML, Riviere I, Wang X, et al: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25, 2014.

4. Themeli M1, Kloss CC, Ciriello G, et al: Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol 31:928933, 2013.

The ASCO Post | AUGUST 15, 2014

PAGE 92

Announcements

Michael Bookman, MD, Joins US Oncology Research as Medical Director of Gynecology Research Program

M

ichael Bookman, MD, of the University of Arizona Cancer Center will join Arizona Oncology, a practice in The US Oncology Network, and serve

centers. His extensive experience includes the multidisciplinary management of gynecologic oncology care, medical informatics, outcomes database development, budget and contract development for clini-

cal research, and regulatory compliance.

He continues to serve as Chair of the Ovarian Committee for GOG, which has been integrated with NRG Oncology under the NCI National Clinical Trials Network. He

also serves as Director of Educational Resources for the International Gynecologic Cancer Society (IGCS), with a commitment to support meaningful outreach within the developing world. n

Michael Bookman, MD

as Medical Director of the US Oncology Research Gynecology Research Program.

In his new role, effective October 6, 2014, Dr. Bookman will use his extensive medical experience to bring more high-priority gynecologic clinical trials to US Oncology Research while managing the gynecologic oncology research portfolio and patient accrual at a national level.

Cutting-Edge Clinical Trials “Dr. Bookman’s recruitment is an important next step as we strive to prevail over [ovarian and other gynecologic cancers],” said Michael Seiden, MD, Chief Medical Officer, The US Oncology Network. “Offering patients access to cuttingedge clinical trials in a community setting is a critical part of advancing the quality and science of cancer care. I’m confident Dr. Bookman will succeed in helping us to build a world-class gynecologic research program that achieves these goals.”

“Our clinical research environment is evolving rapidly, with an emphasis on industry-sponsored trials of molecular targeted agents, often in selected patient populations with predictive biomarkers, using smaller randomized pilots to select and validate promising regimens for definitive phase III trials,” said Dr. Bookman. “US Oncology Research is uniquely positioned to stay ahead of this trend and offer important trials to patients with a variety of gynecologic cancers, including rare diseases and uncommon molecular subtypes. I look forward to collaborating with our local teams.”

Extensive Experience Dr. Bookman has more than 25 years of clinical trial experience, encompassing the intramural National Cancer Institute (NCI) program, Gynecologic Oncology Group (GOG), National Comprehensive Cancer Network, and positions at two NCI-designated comprehensive cancer

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PAGE 93

Announcements

Holy Name Medical Center of New Jersey Welcomes Sharyn N. Lewin, MD, FACS, and Phyllis Tarallo, DNP, DCC

H

oly Name Medical Center (HNMC) welcomes gynecologic oncologist, hereditary cancer risk, and women’s health specialists Sharyn N. Lewin, MD, FACS, and Phyllis

A. Tarallo, DNP, DCC, both of whom will be members of the Holy Name Physician Network. Holy Name Medical Center is a fully accredited, not-for-profit healthcare facility in Teaneck, New Jersey.

Sharyn N. Lewin, MD, FACS Dr. Lewin is a board-certified gynecologic oncologist specializing in the diagnosis, treatment and management of ovarian, endometrial, uterine,

cervical, vulvar, and vaginal cancers.

At Holy Name, Dr. Lewin will serve as Medical Director of the Regional Cancer Center’s Gynecologic Oncol-

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continued on page 94

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Announcements Holy Name Medical Center continued from page 93

ogy Division, and will spearhead the development of a Women’s Comprehensive Health Center, a femalefocused initiative providing care and support for women of all generations.

Dr. Lewin’s expertise includes complex surgical procedures for gyneco-

Sharyn N. Lewin, MD, FACS

logical cancers, and she has extensive training in robotics and other minimally invasive techniques. She uses intraperitoneal chemotherapy and has research interests in novel chemotherapeutic agents for recurrent ovarian cancer. She is a national educator on hereditary breast and ovarian cancer syndrome, the author of more than 100 publications,

and an advocate for quality improvement in female-focused health care.

Dr. Lewin completed her fellowship in gynecologic oncology at Memorial Sloan-Kettering Cancer Center, and her residency in obstetrics and gynecology at Washington University School of Medicine/Barnes Jewish Hospital in St. Louis, MO.

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PAGE 95

Announcements

She earned her medical degree from the University of Kansas School of Medicine.

Phyllis A. Tarallo, DNP, DCC, Nurse Practitioner Joining Dr. Lewin is Phyllis A. Tarallo, DNP, DCC, a nurse practitioner and diplomate of the American Board

Phyllis A. Tarallo, DNP, DDC

of Comprehensive Care. Dr. Tarallo assists in performing radical surgeries for gynecologic malignancies and performs related procedures, including colposcopy; uterine, vaginal and vulva biopsies; and chemotherapy management.

Dr. Tarallo also comes to Holy Name from Columbia University Medical Center, Presbyterian Hospital, where

she was a member of both the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology, and the Department of Surgery, as well as Director of Women’s Health in the Center for Liver Disease and Transplantation. She is widely published, lectures, and provides inservices on female cancers. n

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The ASCO Post | AUGUST 15, 2014

PAGE 96

Announcements

Lynda Chin, MD, Named a Recipient of the Chancellor’s Health Fellowship by The University of Texas Systems

T

he University of Texas System named MD Anderson scientist Lynda Chin, MD, as a recipient of the System’s Chancellor’s Health Fellowship.

Dr. Chin, Chair of the Department of

Genomic Medicine, was recognized for development of a patient-centric oncology care delivery system initiated in late 2012.

As a Fellow, she will coordinate the planning and development of a similar effort

in the use of technologies and big data to improve health-care delivery, focusing on management of diabetes in South Texas.

The UT System Office of Health Affairs created the Chancellor’s Health Fel-

lowship in 2004 to recognize high impact innovative work at individual health institutions that are aligned with the overarching mission of the UT System and have potential for broad societal impact on health care, education, and research.

“Dr. Chin’s medical and scientific leadership and expertise can augment the

Lynda Chin, MD

clinical strengths being assembled by the new medical school at the University of Texas Rio Grande Valley and its affiliated hospitals and partners,” said University of Texas System Chancellor Francisco G. Cigarroa, MD.

Patient-Centric Model of Care

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Dr. Chin, a member of the Institute of Medicine (IOM) of the National Academies since 2012, believes that this patientcentric model has the potential to dramatically reduce disparity in access to expert care, enhance the effectiveness of care, and improve overall patient outcomes while reducing the cost. She will collaborate with the founding Dean of the medical school at The University of Texas Rio Grande Valley, Francisco ­Fernandez, MD, as well as the university’s faculty and administrative leadership.

During her one-year appointment as a Chancellor’s Health Fellow for the UT System, Dr. Chin will continue her roles as Professor and Chair of the Department of Genomic Medicine and Scientific Director of the Institute for Applied Cancer Science at MD Anderson. She will also continue to lead the project to develop a new cancer care delivery prototype at the Cancer Center.

“Being selected as a Chancellor’s Health Fellow is a great honor,” Dr. Chin said. “At UT MD Anderson, we are making progress in collaboration with our colleagues in academia and in industry to build a different model of cancer care delivery. I firmly believe that our experiences, lessons learned and foundational capabilities in the cancer program can be leveraged to leapfrog an innovative program for diabetes management in South Texas and beyond.” n

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PAGE 97

In the Clinic Hematology

Idelalisib for Relapsed CLL in Combination With Rituximab and for Relapsed Follicular Lymphoma or Small Lymphocytic Lymphoma

By Matthew Stenger

n July 23, 2014, idelalisib (Zydelig) was approved for use in combination with rituximab (Rituxan) for treatment of patients with relapsed chronic lymphocytic leukemia (CLL) in whom rituximab alone would be considered appropriate therapy due to other comorbidities. Idelalisib also received accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma who have received at least two prior systemic therapies.1,2

that median progression-free survival as assessed by an independent review committee was not reached in the idelalisib/rituximab group vs 5.5 months in the rituximab/placebo group (hazard ratio [HR] = 0.18, P < .0001).

Accelerated approval in relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma was based on results of a single-arm openlabel trial in 123 patients with relapsed indolent non-Hodgkin lymphomas who were started on idelalisib 150 mg twice daily.2,4 The overall response rate as assessed by an independent review committee was 54% (95% confidence interval [CI] = 42%–66%) in patients with follicular lymphoma, with median response duration not evaluable, and 58% (95% CI = 37%–77%) in patients with small lymphocytic lymphoma, with median response duration of 11.9 months.

Supporting Trials

How It Works

The approval in CLL was based on results of a phase III trial in which 218 patients were randomly assigned to receive idelalisib 150 mg twice daily plus

Idelalisib is an inhibitor of the PI3Kdelta kinase, which is expressed in both normal and malignant B cells. Idelalisib inhibits a number of cell signaling pathways, including B-cell receptor signaling and CXCR4 and CXCR5 signaling, which are involved in transit of B cells to lymph nodes and bone marrow. In preclinical studies, idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B cells and in primary tumor cells; treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion and reduced cell viability.

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

OF NOTE Idelalisib carries boxed warnings for serious or fatal hepatotoxicity, diarrhea, colitis, pneumonitis, and intestinal perforation.

rituximab (n = 110) or rituximab plus placebo (n = 108).2,3 Rituximab was administered in eight doses (first dose at 375 mg/m2, subsequent doses at 500 mg/m2) every 2 weeks for four infusions and then every 4 weeks for four infusions. The trial was stopped early based on an interim analysis showing

How It Is Given The recommended maximum starting dose of idelalisib is 150 mg twice daily in CLL and in follicular lymphoma/small lymphocytic lymphoma, with treatment

Idelalisib in Chronic Lymphocytic Leukemia, Follicular Lymphoma, and Small Lymphocytic Lymphoma ■■ Idelalisib (Zydelig) was approved for use in combination with rituximab for treatment of patients with relapsed chronic lymphocytic leukemia (CLL) in whom rituximab alone would be considered appropriate therapy due to other comorbidities.

■■ Idelalisib received accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma who have received at least two prior systemic therapies.

■■ The recommended maximum starting dose of idelalisib is 150 mg twice daily in CLL and in follicular lymphoma/small lymphocytic lymphoma, with treatment continued until disease progression or unacceptable toxicity.

OF NOTE Idelalisib is an inhibitor of the PI3Kdelta kinase, which is expressed in both normal and malignant B cells. It inhibits a number of cell signaling pathways, including B-cell receptor signaling and CXCR4 and CXCR5 signaling, which are involved in transit of B cells to lymph nodes and bone marrow.

continued until disease progression or unacceptable toxicity. Optimal and safe dosing regimens for patients receiving treatment for longer than several months have not yet been characterized.

The full prescribing information provides details of idelalisib dose modifications for pneumonitis, ALT/AST elevation, bilirubin elevation, diarrhea, neutropenia, and thrombocytopenia.

Idelalisib should be discontinued in patients developing intestinal perforation.

Idelalisib is a strong CYP3A inhibitor and increases exposure to sensitive CYP3A substrates (eg, aprepitant, budesonide, lovastatin, midazolam). Idelalisib exposure is reduced by concomitant treatment with strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) and increased with strong CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole).

Coadministration of idelalisib with strong CYP3A inducers and sensitive CYP3A substrates should be avoided.

Safety Profile In the CLL trial, the most common grade ≥ 3 clinical adverse events in patients receiving idelalisib/rituximab were pneumonia (16% vs 13% in patients receiving rituximab/placebo), sepsis (7% vs 4%), and diarrhea (5% vs 0%). The most common grade ≥ 3 laboratory abnormalities were neutropenia (37% vs 27%), increased lymphocyte count (18% vs 5%), lymphopenia (9% vs 4%), and increased AST (8% vs 1%). Serious adverse events occurred in 49% of idelalisib/rituximab patients, with the most common being pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%).

Adverse events led to dose interruption in 35% of patients, dose reduction in 15%, and discontinuation in 10%, with the most common reasons for discontinuation being hepatotoxicity and diarrhea/colitis.

In the follicular lymphoma/small lym-

phocytic lymphoma trial, the most common grade ≥ 3 clinical adverse events were pneumonia (16%) and diarrhea (14%), and the most common grade ≥ 3 laboratory abnormalities were neutropenia (25%), increased ALT (19%), and increased AST (12%). Serious adverse events occurred in 50% of patients with the most common being pneumonia (15%), diarrhea (11%), and pyrexia (9%). Adverse events led to interruption or discontinuation of treatment in 53%, with the most common reasons being diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

Idelalisib carries boxed warnings for serious or fatal hepatotoxicity (observed in 14% of patients), diarrhea (14%), colitis, pneumonitis, and intestinal perforation. Hepatic function must be monitored prior to and during treatment. Patients should be monitored for pulmonary symptoms and bilateral interstitial infiltrates. Idelalisib also carries warnings/precautions for severe cutaneous reactions, anaphylaxis, neutropenia, and embryo-fetal toxicity. Blood counts should be routinely monitored. n References 1. U.S. Food and Drug Administration: Idelalisib. Available at www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm406410.htm.

2. ZYDELIG® (idelalisib) tablets prescribing information, Gilead Sciences, Inc, July 2014. Available at www.accessdata.fda.gov/ drugsatfda_docs/label/2014/206545lbl.pdf.

3. Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997-1007, 2014.

4. Gopal AK, Kahl BS, de Vos S, et al: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370:1008-1018, 2014.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/ report.htm, by faxing (800-FDA0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

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In the Clinic Hematology

Ibrutinib in Previously Treated CLL and CLL With 17p Deletion

By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n July 28, 2014, the approved use of ibrutinib (Imbruvica) in previously treated chronic lymphocytic leukemia (CLL) was expanded to patients with CLL involving the chromosome 17p deletion.1,2 Ibrutinib received a Breakthrough Therapy designation for this use. Ibrutinib has new labeling reflecting demonstration of improved progression-free survival in patients with CLL and in those with CLL with the 17p deletion.

The drug received accelerated approval for treatment of CLL in February 2014 based on response rate in a small single-arm study. Ibrutinib also previously received accelerated approval for treatment of patients with Mantle cell lymphoma who have received at least one prior treatment.

Supporting Trial The new approval and labeling were based on the results of a phase III trial in which 391 patients with previously treated CLL (n = 273) or small lymphocytic lymphoma (n = 18), including 127 with the 17p deletion, were randomly assigned to receive ibrutinib at 420 mg daily (n = 195, 63 with 17p deletion) or ofatumumab (Arzerra) at an initial dose of 300 mg followed 1 week later by a dose of 2,000 mg weekly for seven doses and then every 4 weeks for four additional doses (n = 196, 64 with 17p deletion).2,3 Patients had a median age of 67 years, 68% were male, 90% were Caucasian, and all had Eastern Cooperative Oncology Group performance status of 0 or 1. Median time since diagnosis was 91 months and median number of prior treatments was 2 (range, 1 to 13). At baseline, 58% of patients had at least one tumor ≥ 5 cm.

A total of 29% of patients in the ofatu-

OF NOTE Ibrutinib carries warnings/precautions for hemorrhage, infection, cytopenias, atrial fibrillation, second primary malignancies, and embryofetal toxicity.

mumab group crossed over to ibrutinib following disease progression.

The trial was stopped early, after an interim analysis showed that median progression-free survival assessed by an independent review committee was significantly longer in the ibrutinib group (not reached vs 8.1 months, hazard ratio [HR] = 0.22, 95% confidence interval [CI] = 0.15–0.32). Median overall survival was significantly prolonged (HR = 0.43, 95% CI = 0.24–0.79) and overall response rate was higher (42.6% vs 4.1%, all partial responses) in the ibrutinib group. Among the 127 patients with the 17p deletion, median progression-free survival was significantly prolonged with ibrutinib (not reached vs 5.8 months, HR = 0.25, 95% CI = 0.14–0.45). The objective response rate was 47.6% vs 4.7%.

Lymphocytosis consisting of a ≥ 50% increase in absolute lymphocyte count from baseline and to > 5,000/µL occurred in 77% of patients. The isolat-

for grade 3 or higher nonhematologic toxicities, grade 3 or higher neutropenia with fever, and grade 4 hematologic toxicities. With resolution of toxicity to grade 1 or baseline status, treatment can be reinitiated at the starting dose. The dose may be reduced to 280 mg and

OF NOTE Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase that inhibits malignant B-cell proliferation and survival in vivo and cell migration and substrate adhesion in vitro.

then to 140 mg for recurrent toxicity.

Coadministration of ibrutinib with strong or moderate CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole) should be avoided. If a strong inhibitor is to be used for ≤ 7 days, interruption of ibrutinib during this period should be considered. If a moderate inhibitor must be used, the

Ibrutinib in Previously Treated CLL With 17p Deletion ■■ The approved use of ibrutinib (Imbruvica) in previously treated chronic lymphocytic leukemia (CLL) was expanded to patients with CLL involving the chromosome 17p deletion.

■■ The recommended dose of ibrutinib in CLL is 420 mg once daily.

ed lymphocytosis occurred during the first month of treatment and resolved by a median of 23 weeks (range, 1 to > 104 weeks).

How It Works Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.

Bruton’s tyrosine kinase activity via signaling through the B-cell surface receptor results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Ibrutinib forms a covalent bond with a cysteine residue in the Bruton’s tyrosine kinase active site, leading to inhibition of Bruton’s tyrosine kinase enzymatic activity. Preclinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival in vivo and cell migration and substrate adhesion in vitro.

How It Is Given The recommended dose of ibrutinib in CLL is 420 mg once daily. Ibrutinib treatment should be interrupted

ibrutinib dose should be reduced to 140 mg. Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity.

Since ibrutinib is metabolized in the liver, significant increases in exposure are expected in patients with hepatic impairment, and patients with aspartate transaminase or alanine transaminase at least 3.0 times the upper limit of normal were excluded from clinical trials.

Use of ibrutinib should be avoided in patients with hepatic impairment; there are insufficient data to recommend a dose in such patients.

Ibrutinib exposure is not altered in patients with creatinine clearance > 25 mL/ min. There are no data in patients with severe renal impairment or on dialysis.

Safety Profile In the phase III trial, the most common clinical adverse events of any grade in ibrutinib patients were diarrhea (48% vs 18% in ofatumumab patients), fatigue (28% vs 30%), musculoskeletal pain (28% vs 18%), and nausea (26%

vs 18%), and the only grade 3 or 4 event occurring in > 2% of patients was pneumonia (10% vs 9%). Neutropenia, thrombocytopenia, and anemia of any grade occurred in 51% vs 57%, 52% vs 45%, and 36% vs 21% of patients, respectively, and grade 3 or 4 events occurred in 23% vs 26%, 5% vs 10%, and 0% vs 0%, respectively.

In the phase III study and the singlearm trial (n = 48) that supported the earlier accelerated approval of ibrutinib, adverse events led to ibrutinib dose reduction in 6% of patients and to discontinuation in 5%, with reasons for discontinuation including infection, subdural hematoma, and diarrhea.

Ibrutinib carries warnings/precautions for hemorrhage, infection, cytopenias, atrial fibrillation, second primary malignancies (including skin cancers and other carcinomas), and embryo-fetal toxicity. Patients must be monitored for bleeding, fever, infection, and atrial fibrillation. Complete blood counts should be monitored monthly. Women must be advised of potential fetal risk and counseled to avoid pregnancy while taking ibrutinib. n References 1. U.S. Food and Drug Administration: FDA expands approved use of Imbruvica for chronic lymphocytic leukemia. Available at www.fda.gov/newsevents/newsroom/pressannouncements/ucm406916. htm.

2. IMBRUVICA® (ibrutinib) capsules prescribing information, Pharmacyclics, Inc, and Janssen Biotech, Inc, July 2014.

Available at www.imbruvica.com/downloads/Prescribing_Information.pdf.

3. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 2014.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

ASCOPost.com | AUGUST 15, 2014

PAGE 99

Pioneering Medical Oncologist Remembers a Time Before the Subspecialty Was Created A Conversation With Pierre R. Band, MD

By Ronald Piana

Pierre R. Band, MD

W

hile the first written record of cancer dates back to ancient Egypt, the history of modern oncology is fairly short, dating back only slightly more than half a century. Clinical trials in the early days of the National Cancer Institute (NCI) and the emerging cooperative groups were led by a relatively small group of researchers who left an indelible footprint on the treatment of cancer. The ASCO Post recently spoke with one member of that select group of trailblazers, Pierre R. Band, MD, the author of the recently published Therapeutic Revolution: The History of Medical Oncology From Early Days to the Creation of the Subspecialty (Bentham Science Publishers).

Early Life Please tell the readers a bit about your early life, where you were raised, and your education prior to entering college.

My parents were Hungarian and moved to France, where I was born.

Our family was rather poor. We lived in Versailles, not too far from the famous palace, where my grandmother took me several times a week. While following and listening to the tour guides, I acquired a fair knowledge of the palace and of its beautiful park.

I liked school and was fond of the teachers I had, until the morning I entered the Lycée [state-run secondary school], where the main teacher, a stiff and military man, ordered that we learn

the Latin first declension by heart for the next day. I began to hate school— particularly Latin—which turned out to have unexpected repercussions a few years later.

When I was about to turn 16, we moved to Montreal. Being separated from my friends and my neighborhood overnight was a major shock for me. I refused to go back to school and worked in a restaurant. After a year, I decided to go back to school but to avoid Latin at all costs. Instead of focusing on “classical studies” as they were called in Montreal at the time, which included Latin, I opted for the high school that did not teach this subject.

Path to Medical School In the introduction to your book, you talked about the difficulty you had being accepted to the university. Please elaborate

the first year of medicine, I would then take the premedical courses. The interviewer allowed me to enter medical school directly, and during my first year of medicine, I was first in my class in all subjects, including … histology!

Oncology Career Your interest in cancer medicine developed at a time when oncology was not a specified clinical discipline. Please tell the readers a bit about your pursuit of the subject, and how it led to the NCI. When the time came to choose a specialty, I wanted to remain close to internal medicine but not follow the beaten path. I opted for cancer medicine. It was an easy choice, although it did not exist as a specialty. My grandmother, who had died of cancer, may have subconsciously influenced me.

I started my oncology career at the

I consider my book on the history of medical oncology to be one of my greatest achievements: it is my legacy to the future generations of young medical oncologists.

—Pierre R. Band, MD

on that and your eventual path to medical school.

After high school, I decided to enter medical school. However, to enter the Faculty of Medicine at the University of Montreal, classical studies were mandatory! To make a long story short, I took private courses in Latin and compressed the 7 years required at the French Lycée into 2 years.

With that out of the way, before being accepted to medical school, I had to pass an interview. The person who interviewed me was the histology teacher. He noted that my curriculum had been far from orthodox and suggested that I take a year of premedical courses called PCB, for physics, chemistry, and biology. I pleaded that he allow me to enter medical school and gave my word of honor that if I failed

Institut Gustave-Roussy in France in the Department of Georges Mathé, MD, who was well known worldwide for his work in bone marrow transplantation. My main clinical activities focused on the treatment of childhood acute leukemia, and I also got involved in the collaborative activities of a group that later became the European Organisation for the Research and Treatment of Cancer (EORTC), which Dr. Mathé founded.

I subsequently joined the Department of Medicine headed by James F. Holland, MD, at Roswell Park Memorial Institute in Buffalo, New York. I consider Dr. Holland the mentor who taught me cancer medicine and who introduced me to two of the main cooperative oncology groups, the Acute Leukemia Group B (subsequently Cancer

and Leukemia Group B) and the Eastern Cooperative Oncology Group (ECOG).

During those years, I benefited from Dr. Holland’s pioneering work at what was the forefront of cancer medicine.

Professional Highlights Please share what you might consider some of the highlights of your long, illustrious career.

When I returned to Canada at the University of Alberta in Edmonton, I joined the ECOG as an active member, which turned out to be the first time someone from a Canadian institution joined that group. I wrote the protocol that became the first long-term surgical adjuvant study in breast cancer, the L-PAM study, carried out jointly by the ECOG and the National Surgical Adjuvant Breast and Bowel Project (NSABP).

I also wrote the protocol for the study of tamoxifen in metastatic breast cancer, and was the first physician in North America to treat a patient with breast cancer with this compound. That study played a major role in the U.S. Food and Drug Administration’s approval of tamoxifen for the treatment of advanced breast cancer. I consider my book on the history of medical oncology to be one of my greatest achievements: it is my legacy to the future generations of young medical oncologists.

Life in Retirement What activities are you involved in now?

I have now retired from my clinical activities without any regrets. I enjoy my family and my friends, I inherited a dog (that my son was supposed to care for), and I take great pleasure in going to the market. However, an important task is awaiting me: in 2010, I recorded a 2-hour video of three of the great pioneers of medical oncology—Drs. Emil Frei III, Emil J. Freireich, and James F. Holland. I am thinking of making a short documentary with the unique material I obtained. n

The ASCO Post | AUGUST 15, 2014

PAGE 100

African Medical Education Is Being Transformed by U.S. Program

M

edical education in sub-Saharan Africa is being revitalized and expanded through a U.S.-funded effort that is dramatically increasing enrollment, broadening curricula, upgrading Internet access, and providing cuttingedge skills labs and other technologies.

In the first substantial publication by participants of the $130 million Medical Education Partnership Initiative (MEPI), more than 225 authors detailed progress being made at the African institutions. Their reports were published this month in a supplement to the journal Academic Medicine.1

International Education Innovation Begun in 2010, MEPI is funded by the President’s Emergency Plan for AIDS Relief (PEPFAR) and the National Institutes of Health, and is co­ administered by NIH’s Fogarty International Center and the Health Resources and Services Administration.

“MEPI is a major venture in international educational innovation that has generated new thinking, energy and optimism in the field of medical education in Africa,” the program partners write in a foreword article to the supplement.

The 32 articles include case studies of national strategies to increase numbers of doctors and health professionals trained; educational innovations such as e-learning and regional training sites; research capacity development, and partnerships that leverage advances across the MEPI network.

MEPI participants provided details of accomplishments made through the program, including: • In Zimbabwe, medical student and postgraduate enrollment have both nearly doubled, from 260 in 2010 to 513 in 2013, and the Ministry of Higher Education has committed additional financial support to sustain the progress.

• A decentralized training network of

•

•

•

•

14 regional hospitals has been established in Kenya, and has provided instruction for more than 300 medical, nursing, dental and pharmacy students.

Internal medicine (IM) physicians were in short supply in Mozambique, so salary supplements, Internet access, and notebook computers were offered to encourage recruitment, resulting in an increase in IM residents from 10 before MEPI to 75 in 2012.

Fourteen new master’s level programs were begun in Zambia, including physiological sciences, pharmacology, anatomy, pathology, microbiology and nursing.

A virtual microscopy system was introduced in Zambia, containing 4,000 electronic images, which increased student access and is more cost-effective than optical microscopy using glass slides.

A research administration office was created in Ethiopia to assist faculty in grant writing and management, and 18 faculty members were supported to present their research at international conferences.

Global Health Experts Comment The supplement on MEPI progress also includes commentaries from global health experts such as former U.S. Global AIDS Coordinator Eric Goosby, MD, MEPI Coordinating Center principal investigator Francis G. Omaswa, MD, and Fogarty International Center Director Roger I. Glass, MD. The critical shortage of physicians, researchers and health-care workers across sub-Saharan Africa spurred ­MEPI’s creation. While the region suffers 25% of the global burden of disease, it has only 3% of the world’s health-care workers, according to the World Health Organization. The impact of HIV/ AIDS created an urgent need to increase capacity, wrote Dr. Goosby and his co-

MEPI Principal Investigator, Nelson Sewankambo, MD, leads a discussion with a group of medical students at Makerere University. Photo by Richard Lord for Fogarty/NIH.

author Deborah von Zinkernagel, former PEPFAR Deputy. “Although concerns arose that resources were being diverted from “services,” it was evident to PEPFAR leadership that the ongoing and expanding needs of the HIV-infected community could not be successfully sustained without increasing the number of trained health professionals,” they added.

By awarding the grants directly to African institutions, MEPI is cultivating sustainable local leadership, Omaswa maintained. “For Africa to accelerate the speed of the ongoing transformation, it is necessary for Africans to step up and take ownership and responsibility for what happens in their own backyards,” he said.

Research is embedded in curricula developed through MEPI, to expand local capacity that will drive innovation. African scientists have already contributed to many “game-changing” HIV-related advances such as development of rapid diagnostics for detecting and monitoring HIV infections, noted Dr. Glass and his Fogarty coauthors.

“The research perspective provided to students and faculty, the ability to raise and answer questions, and the idea that medical knowledge and practice are

continually changing are being supported by MEPI sites and will hopefully endure long after the program ends,” they continued.

Second Phase of Investment in Planning Stage Initially conceived as a 5-year program, MEPI funders and participants are now developing plans for a second phase of investment in Africa’s medical education.

Fogarty, the international component of the NIH, addresses global health challenges through innovative and collaborative research and training programs and supports and advances the NIH mission through international partnerships. For more information, visit: http://www.fic.nih.gov. n

Disclosure: Funding and support for this work came from the Office of the U.S. Global AIDS Coordinator in the State Department and the National Institutes of Health (NIH) and are administered by both the NIH Fogarty International Center and the HIV/AIDS Bureau of the Health Resources and Services Administration in the Department of Health and Human Services.

Reference 1. Academic Medicine: Journal of the Association of American Medical Colleges 89(suppl 8):s1-s116, August 2014.

In postmenopausal women with advanced HR+, HER2-negative breast cancer,

After letrozole or anastrozole fails,

Discover a treatment worth a DOUBLE take Abbreviation: HR+, hormone receptor-positive.

DOUBLE INHIBITION In advanced disease, targeting one pathway may not be enough AFINITOR® (everolimus) Tablets plus exemestane is the only regimen to deliver dual inhibition of the ER and PI3K/Akt/mTOR signaling pathways, providing synergistic inhibition of tumor survival signaling.1-3 Aromatase inhibition

Typical ER Pathway Blockade

Estrogen

In HR+ breast cancer, NSAI treatments (eg, letrozole or anastrozole) inhibit the production of estrogen, thereby reducing ER signaling, a key driver of tumor growth and survival in breast cancer.4,5

ER

Nucleus Cell Proliferation and Survival Aromatase inhibition

Key Mechanism of Progression

Estrogen

P ER

In the advanced setting, multiple signaling pathways and hyperactivation of the PI3K/Akt/mTOR pathway can give tumor cells alternate pathways for progression.4,6-8

mTOR

P ER

Nucleus Cell Proliferation and Survival

Cell Proliferation and Survival

AFINITOR + exemestane

Double Inhibition

Estrogen

AFINITOR

ER

mTOR

Cell Proliferation and Survival

Cell Proliferation and Survival

Nucleus

In patients who have progressed on an NSAI, AFINITOR, in combination with exemestane, offers a unique treatment strategy to address disease progression through dual inhibition of the ER and PI3K/Akt/mTOR signaling pathways.4,5

Only AFINITOR plus exemestane offers dual inhibition of the ER and mTOR pathways1 AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated

• For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances.

If toxicity recurs at grade 3, consider discontinuation of AFINITOR • For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • The development of pneumonitis has been reported even at a reduced dose Abbreviations: BOLERO-2, Breast Cancer Trials of Oral Everolimus-2; ER, estrogen receptor; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; NSAI, nonsteroidal aromatase inhibitor; P, phosphorylation; PFS, progression-free survival.

DOUBLE MEDIAN PFS AFINITOR plus exemestane more than doubled median PFS over exemestane alone1

55%

Combination Therapy Gives You More: Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

reduction in risk of progression or death1

HR=0.45 [95% CI, 0.38-0.54] Log-rank P value: <0.0001

PFS curves began to diverge at

6 weeks

(the first tumor assessment)1,3

PFS Probability (%)

80

Median PFS

7.8 months

60

40

[95% CI, 6.9-8.5] Median PFS

3.2 months

[95% CI, 2.8-4.1]

20

0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

Time (months) AFINITOR plus exemestane (n/N=310/485)

Exemestane plus placebo (n/N=200/239)

Exemestane plus placebo (n/N=200/239)

62% reduction in risk of progression or death1

Independent central assessment confirmed benefit1 Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6] (HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

Overall survival (OS) results were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted (HR=0.77 [95% CI, 0.57-1.04]).1 Important Safety Information (cont) Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR

• Be vigilant for signs and symptoms of infection and institute appropriate

treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

Important Safety Information .

AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Impaired Wound Healing: • Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma • These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the perisurgical period Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared with 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age • Careful monitoring and appropriate dose adjustments for adverse reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function • Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR • Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported.

Monitoring of complete blood count is recommended prior to treatment and periodically thereafter Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less

© 2014 Novartis

Hepatic Impairment: • Exposure to everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST, 69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT, 51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%) Please see Brief Summary of Prescribing Information on adjacent pages.

To learn more, please visit www.AFINITOR.com.

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2014. 2. Fedele P, Calvani N, Marino A, et al. Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going?

Crit Rev Oncol Hematol. 2012;84:243-251. 3. Data on file. AFINITOR CRAD001Y2301 Clinical Study Report. Novartis Pharmaceuticals Corp; March 2012. 4. Johnston SRD. Enhancing the efficacy of hormonal agents with selected targeted agents. Clin Breast Cancer. 2009;9(suppl 1):S28-S36. 5. Miller TW, Hennessy BI, González-Angulo AM, et al.

Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406-2413. 6. Di Cosimo S, Baselga J. Management of breast cancer with targeted agents: importance of heterogeneity. Nat Rev Clin Oncol. 2010;7(3):139-147. 7. Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96(12):926-935. 8. De Laurentiis M, Arpino G, Massarelli G, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res. 2005;11(13):4741-4748.

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AFB-1086973

AFINITOR® (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information.

1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis.

If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information] .

For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. The development of pneumonitis has been reported even at a reduced dose.

Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

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Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions].

Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Impaired Wound Healing Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period.

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations].

Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions] .

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions] .

Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information].

For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Embryo-fetal Toxicity Based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia.

The most common Grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).

Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) + exemestanea N=482 All grades Grade 3 Grade 4 % % % Any adverse reaction 100 41 Gastrointestinal disorders 67 8 Stomatitisb Diarrhea 33 2 Nausea 29 0.2 Vomiting 17 0.8 Constipation 14 0.4 Dry mouth 11 0 General disorders and administration site conditions Fatigue 36 4 Edema peripheral 19 1 Pyrexia 15 0.2 Asthenia 13 2 Infections and infestations 50 4 Infectionsc Investigations Weight decreased 25 1 Metabolism and nutrition disorders Decreased appetite 30 1 Hyperglycemia 14 5 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 Back pain 14 0.2 Pain in extremity 9 0.4 Nervous system disorders Dysgeusia 22 0.2 Headache 21 0.4 Psychiatric disorders Insomnia 13 0.2 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 Dyspnea 21 4 Epistaxis 17 0 Pneumonitisd 19 4 Skin and subcutaneous tissue disorders Rash 39 1 Pruritus 13 0.2 Alopecia 10 0 Vascular disorders Hot flush 6 0 Median duration of treatmente

Placebo + exemestanea N=238 All grades Grade 3 Grade 4 % % %

9

90

22

5

0 0.2 0.2 0.2 0 0

11 18 28 12 13 7

0.8 0.8 1 0.8 0.4 0

0 0 0 0 0 0

0.4 0 0 0.2

27 6 7 4

1 0.4 0.4 0

0 0 0 0

1

25

2

0

0

6

0

0

0 0.4

12 2

0.4 0.4

0 0

0 0 0

17 10 11

0 0.8 2

0 0 0

0 0

6 14

0 0

0 0

0

8

0

0

0 0.2 0 0.2

12 11 1 0.4

0 0.8 0 0

0 0.4 0 0

0 0 0

6 5 5

0 0 0

0 0 0

0

14

0

0

23.9 weeks

13.4 weeks

Grading according to CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo Key observed laboratory abnormalities are presented in Table 3.

Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory parameter

Hematologyb Hemoglobin decreased WBC decreased Platelets decreased Lymphocytes decreased Neutrophils decreased Clinical chemistry Glucose increased Cholesterol increased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Triglycerides increased Albumin decreased Potassium decreased Creatinine increased

AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % 68 58 54 54 31

6 1 3 11 2

0.6 0 0.2 0.6 0

40 28 5 37 11

0.8 5 0 5 0.8

0.4 0.8 0.4 0.8 0.8

69 70 69 51 50 33 29 24

9 0.6 4 4 0.8 0.8 4 2

0.4 0.2 0.2 0.2 0 0 0.2 0.2

44 38 45 29 26 16 7 13

0.8 0.8 3 5 0 0.8 1 0

0.4 0.8 0.4 0 0 0 0 0

Grading according to CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively.

• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

Concomitant strong inhibitors of CYP3A4/PgP should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions].

Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions].

Agents That May Decrease Everolimus Blood Concentrations CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone.

Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information].

Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a nonCYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf).

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Risk Summary Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman.

Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus [see Warnings and Precautions].

Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development.

These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA.

The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in disease-related symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown.

Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information].

Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information]. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information].

Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITORtreated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age.

Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions].

In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information].

No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information].

Females and Males of Reproductive Potential Contraception Females AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

Infertility Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR [see Adverse Reactions (6.2, 6.4, 6.5) and Nonclinical Toxicology in the full prescribing information].

Males AFINITOR treatment may impair fertility in male patients based on animal findings [see Nonclinical Toxicology in the full prescribing information].

Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (ChildPugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Revised Feb 2014 © Novartis T2014-16/T2014-17 February 2014/February 2014

ASCOPost.com | AUGUST 15, 2014

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Expert’s Corner Survivorship

Discussing Sexual Health Issues With Female Cancer Survivors A Conversation With Don S. Dizon, MD, FACP

By Ronald Piana

Don S. Dizon, MD, FACP

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dvances in cancer treatment have led to increasing numbers of long-term survivors, bringing greater attention to the needs of this growing population. Female cancer patients often experience difficult adjustments related to sexual health and intimacy. To better understand the complexity of this important issue, The ASCO Post recently spoke with Don S. Dizon, MD, FACP, Assistant in Medicine at Harvard Medical School and the founder and Director of the Oncology Sexual Health Clinic, Massachusetts General Hospital, Boston.

Difficult Areas How well are providers communicating with their female cancer patients about issues surrounding sexual health and intimacy?

Despite all our gains in cancer communications, sexual health and intimacy issues are still difficult areas for many clinicians to broach. Most of us are very comfortable talking with our patients about fertility issues, but for some reason putting a discussion about vaginal health in the context of sexual health continues to be problematic.

I think we’ve fallen into the trap of assuming that if there’s an issue important to the patient, then the patient will bring it up. Unfortunately, that’s not always the case, and most of our data suggest that unless a provider opens that door, it will not be discussed.

Women treated for cancer often experience difficult issues related to sexual health and intimacy, and they frequently cite this as a major area of concern, even among longterm survivors. So it’s an unmet need in the quality-of-life continuum in oncology.

Approaching the Issue Sexual health is a subjective term. Is there a way to give physicians a better understanding of this issue so that we can bridge this communication gap?

One method that might make physicians more comfortable is letting them know that when they initiate a discussion on sexual health, they don’t need to open with penetrative intercourse. Not talking specifically about sex can remove one of the barriers in this discussion. Moreover, providers might not be prepared or knowledgeable enough about sexual issues to counsel their patients.

There is a lot more involved in sexual health and intimacy than sex itself. There’s a term in the literature that really hits home— the “coital imperative,” which is the idea that for sex to be real, there must be penetrative intercourse. But not every woman you are treating wants to have penetrative intercourse, or, for that matter, wants to discuss her treatment-related issues that make intercourse painful or unwanted.

So one way to approach this issue is by using terms you are comfortable with. For instance, for a surgeon who’s removing a woman’s breast, a body-image discussion might lead to a deeper discussion about sexual health. Or if a medical oncologist is

First, it’s important that sexual health issues be viewed in the overall context of women’s health issues, because issues related to cancer often overlap with normal changes related to the female aging process. Obviously, the effects of surgical procedures such as hysterectomy and oophorectomy can impact sexual health because of direct anatomic changes or hormonal imbalances. And, of course, women who undergo breast surgery have varying degrees of body image challenges.

However, among side effects–related sexual health issues, chemotherapy stands out as the biggest risk for future sexual dysfunction. The reasons are quite varied.

Most cytotoxic agents result in fatigue and nausea, which can severely limit a woman’s interest in sex or intimacy beyond a certain level. The constitutional symptoms associated with chemotherapy include the body-image problem of hair loss, not only on the head but also in private regions of the body.

In a way, grappling with chemotherapy-induced fatigue and nausea would be

I think we’ve fallen into the trap of assuming that if there’s an issue important to the patient, then the patient will bring it up. Unfortunately, that’s not always the case, and most of our data suggest that unless a provider opens that door, it will not be discussed.

—Don S. Dizon, MD, FACP

talking about chemotherapy-induced premature amenorrhea, talking about vaginal health could open the door for a larger sexual health discussion. While talking about other more comfortable issues, we can say, “in addition, the vaginal atrophy you’re experiencing could lead to painful sensations that might interfere with intimacy.”

More important, people should not assume, either subconsciously or consciously that oncology sexual health is just about getting patients to a better place where intercourse is comfortable, because that’s not what we do. Sexual health is an important survivorship issue in women who have cancer and must be looked at in the context of the numerous physical and psychological challenges that cancer patients face.

Problematic Side Effects What are some of the treatment-­induced side effects that affect a woman’s sexual health?

akin to trying for intimacy while having a bad flu. Beyond that are the physiologic changes such as atrophy and toxicities to the vagina and pelvis. All of these issues dampen a woman’s libido.

An issue that comes up quite often for women is the psychological feeling that they’ve been de-feminized. Women who lose a breast, ovaries, or uterus to cancer often feel that parts of their bodies that make them a woman have been removed.

Data also suggest that women who have had colorectal surgery requiring placement of an ostomy were at significant risk for sexual health issues and psychological distress, again due to body image.

Useful Resources Are there guides to help physicians tackle the challenging discussions about mechanical difficulties that arise after cancer treatments?

There is a lot of sexual health information available that providers and patients should know about. Physicians can also

incorporate sexual health questionnaires in their routine review of patients both during and after active treatment, to guide management and discussion.

Several models can help initiate these discussions, such as the PLISSIT, which stands for Permission, Limited Information, Specific Suggestions, and Intensive Therapy. Not surprisingly, there are also websites for providers that address the issue of sexual health. One that I’ve contributed to is the Living Beyond Breast Cancer website (www.lbbc.com), which offers an online brochure on sex and intimacy.

This is a multifaceted issue, so it’s important to break it down to its core components. First, we need to make sure that our patients know that this is an important issue not only to them, but also for us as their providers. It’s also important for providers not to expect to have all the answers about sexual health. And if pressed for answers, they should be comfortable in telling their patients that there are other resources outside the oncology office that can help them through this difficult period.

At the cancer center at Massachusetts General, I collaborate with great nurse practitioners who take these discussions as far as they can, discussing issues like vaginal estrogen, dilators, and lubricants. But once they reach a point where they don’t feel their suggestions are helpful, they send them to me. Approaching this issue with a clear understanding of your personal comfort level is essential.

Role of Community Oncologists Are busy community oncologists equipped to handle these issues?

That’s a difficult question. Community oncologists are being tasked to do quite a lot, especially with the new Commission on Cancer guidelines that ask us to address distress, which is a broad area that includes sexual dysfunction. Sexual dysfunction was rated by a LIVESTRONG survey as one of the top three complaints among people treated for cancer. So I would hope that before initiating treatment, community oncologists would explain that certain common side effects such as nausea and fatigue might affect sexual health. Patients who are informed about the risks are more likely to seek out help proactively. It’s a complicated issue, but it is part of the continuum of quality care, and we need more awareness about it. n

Disclosure: Dr. Dizon reported no potential conflicts of interest.

The ASCO Post | AUGUST 15, 2014

PAGE 108

Book Review

A Book of Solid Advice and ‘Silver Linings’ for Patients With Breast Cancer

By Ronald Piana

O

ver the past several decades the oncology community has made notable advances in cancer treatment.

But there’s also been a hard-fought culture change in the approach to the continuum of care. The phrase “treat the whole patient, not just the tumor,” is often heard in the oncology vernacular.

But that wasn’t always so. Like many advances in oncology, the emerging supportive care disciplines of psychosocial care and integrative oncology were the results of decades of work and struggle by many dedicated pioneers such as Jimmie Holland, MD, and Barrie Cassileth, MS, PhD, of Memorial Sloan Kettering Cancer Center.

Supportive care disciplines in oncology have also attracted people interested in writing about this important issue, such as palliative care nurse, Hollye Jacobs, RN, MS, MSW. In her new book, The Silver Lining: A Supportive & Insightful Guide to Breast Cancer, Ms.

California. She also depicts the shock of her cancer diagnosis, since she was a “healthy, happy, vegan-eating, marathon-running thirty-nine-year-old, with no family history of breast cancer.”

All books need to be about something, and Ms. Jacobs describes her book as “my journey of self-discovery through illness, finding silver linings in life, and celebrating grace and positive thinking from the time of my breast cancer diagnosis through treatment, recovery, and ultimately the celebration of life after breast cancer.”

The book is that, but fortunately it is a lot more. One of the most appealing parts of Ms. Jacobs’ book is its architecture. Each of the nine chapters in the table of contents has its own descriptive photograph, offering artistic windows into the forthcoming content. Moreover, each chapter is subdivided into three sections: Memoir, The Silver Lining, and Practical Matters.

Pain interrupts sleep. Pain decreases mobility. Pain decreases endurance and energy…pain can also impair the immune response and your subsequent ability to get better… virtually nothing positive can resume until physical pain is managed.

—Hollye Jacobs, RN, MS, MSW

Jacobs not only brings her insight as a palliative care nurse to her narrative, but also as a breast cancer survivor. As often mentioned, the shelves are overflowing with books on cancer, from dense scientific tomes, histories, memoirs, and survivorship books. Thus, writing a book that doesn’t get lost among other similar titles is a daunting task. Ms. Jacobs solves the problem of being noticed by having written a glossy, coffee-tablestyle book replete with splendid photographs by award-winning photographer, Elizabeth Messina. At first, pairing beautiful and at times provocative fullcolor photographs with a guide to surviving breast cancer might seem incongruous, but, for the most part, it works.

Self-Discovery Through Illness In the introduction, the author describes herself as a happily married wife, mother, palliative care nurse, and social worker living in Santa Barbara,

The first section Memoir is the chronicle of the author’s experiences, offering her highs and lows from the terrifying diagnosis on through treatment and survivorship. The second section, Silver ­Linings, gives the reader practical sources of hope and inspiration, both of which are essential components of the healing process. The Practical Matters section of each chapter pertains to all things necessary to know during every phase of therapy. In this section, Ms. Jacobs’ experience, as a palliative care nurse is evident.

This section is also formatted in easy-toread and well-written bulleted lists. This type of “practical advice” for patients is certainly not new, but here you’ll find advice that is more complete and thoughtful than in most books on the market, making this part a special gem for breast cancer patients and their loved ones.

Still another value-added part of the book’s interesting format is found within the Memoir section of each chap-

ter called “Lifelines.” These are call-outs of sorts that are personal suggestions from the author herself, both personal as well as professional, to, as she writes, “Prevent some of the calamities (oh yes, calamities) that I faced.” For example: Lifeline—Cleaning all foods will help prevent infection, especially in an immune-system-compromised body.

Focus on Need for Improved Pain Management In chapter 3, one of the book’s strongest, the author discusses recovery issues following breast surgery. In a compelling section of this chapter, Ms. Jacobs describes her experience in the recovery room following a double mastectomy.

“I remember nothing about recovery or room transfer. Instead, I woke up in a pitch-black room, nearly glued to the ceiling with pain. Pain the like of which I had never experienced before.” As it turned out, the nurses in the recovery room had neglected to turn on the pump, after loading it with a cartridge of hydromorphone.

But there’s more here, valuable information for every cancer patient and their caregivers. The nurses in the recovery room were not adequately trained in pain management. Moreover, the oncology community still faces a serious problem in the undertreatment of cancer pain.

Being a palliative care nurse, Ms. Jacobs correctly points out in vivid, unvarnished language why pain management must be a priority with everyone in the cancer care continuum. She writes, “Are you wondering why I’m so obsessed with pain management? Well, because pain is bad.

Pain interrupts sleep. Pain decreases mobility. Pain decreases endurance and energy…pain can also impair the immune response and your subsequent ability to get better…virtually nothing positive can resume until physical pain is managed.”

There’s more about pain, and every word is needed. This is an area the oncology community needs to work harder on, and the author is spot on with her criticism and solid advice. It’s also a clarion call to all cancer patients to be well educated about their disease, treatment, and survivorship issues. Ms. Jacobs stresses a vital message throughout the book about the need for a true doctor-patient partnership.

Stunning Photography The photographs by Elizabeth Messina are nothing short of beautiful, in a tasteful and understated way.

Bookmark Title: The Silver Lining: A Supportive & Insightful Guide to Breast Cancer Editors: Hollye Jacobs, RN, MS, MSW Publishing Platform: CreateSpace Publication information: Simon & Schuster, published March 2014.

Available at Amazon, Barnes and Noble, Indiebound, and other local bookstores.

But still, arty photographs? The author addresses that, too.

“You may be wondering: What’s up with these photographs? We believe that these beautiful images will bring peace and comfort on days that you don’t have the energy to read… our intention is not to make the breast cancer experience beautiful, but rather to add some beauty to the experience.”

One of the most telling images is a black-and-white shot of the author bare from the waist up, after breast reconstruction. Looking at that photo, it’s well worth noting that there was a time in our not-so-distant past when women with breast cancer were discouraged from mentioning it in public. This is an interesting, informative, and elegantly constructed book for patients and their doctors. n For more information, visit www. thesilverpen.com.

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Announcements

New TV Ads, New Stories for CDC’s Tips From Former Smokers Campaign

T

he Centers for Disease Control and Prevention (CDC) continues its national tobacco education campaign—Tips From Former Smokers— with hard-hitting, new ads that show the harms caused by smoking. Beginning last month, ads will appear for a total of 9 weeks across television, radio, billboards, and online media as well as in theaters, magazines, and newspapers.

Ads will run on English and Spanish television.

to quit are expected to stay quit.

• An estimated 6 million nonsmokers talked with friends and family about the dangers of smoking.

• An estimated 4.7 million additional nonsmokers recommended quit services to their friends and family.

Smoking remains the leading cause of preventable death and disease in the United States, killing more than 480,000 Americans each year. For every smokingrelated death, at least 30 people live with B:7.875 in a smoking-related illness. The only provin en strategy to protect T:7.625 yourself from harm

is to never smoke, and if you do smoke or use tobacco products, to quit. n Reference 1. Xiao D, Chen Z, Wang C: Effects of a short-term mass-media campaign against smoking. Lancet 382:1964-1966, 2013.

S:6.625 in

CLINICAL EVIDENCE INDICATES...

July 2014 Tips Participants The new ads feature seven real people whose lives have been permanently affected by smoking. All of the people featured in the Tips ad campaign hope their stories will help other smokers quit.

Three of those stories are as follows: Rose: Rose grew up in a small Texas town, and at age 13, she started smoking. Over time, she developed a twopack-a-day cigarette addiction and nearly lost a foot because of clogged blood vessels. Before Rose could have surgery on her leg, a chest x-ray showed that she had lung cancer, which later spread to her brain. Two surgeries later, Rose stays in close contact with her cancer doctors. “I regret picking up smoking in the first place,” said Rose.

Shawn: Shawn lives in Washington and started smoking at age 14 to fit in at a new school. In his mid-40s, a chronic cough and laryngitis turned out to be throat cancer. He endured 38 radiation treatments and finally quit smoking— but doctors were unable to save his larynx. He now has a stoma (opening) that allows him to breathe and a laryngeal implant that allows him to speak.

Terrie: Terrie lived in North Carolina and began smoking in high school.

At age 40, she was diagnosed with oral and throat cancers and had her larynx removed. Terrie courageously fought cancer until her death at age 53 in the fall of 2013. She shares a powerful message in a new ad, filmed days before she passed away. More than anything, Terrie wanted to help motivate smokers to quit so they could avoid the pain and suffering that she went through.

THERE ARE DISTINCT WAYS TO HELP MANAGE ADVANCED PROSTATE CANCER * INHIBIT ANDROGEN PRODUCTION

BLOCK THE ANDROGEN RECEPTOR

EACH PLAYS AN IMPORTANT ROLE 1-3 Learn more at inhibitandrogen.com/distinct

Tips Campaign Results

*Other treatment options may also be considered.

CDC launched the first Tips From Former Smokers campaign in 2012 to lower smoking rates and save lives. A CDC study published in The Lancet1 indicates that because of the campaign in 2012: • An estimated 1.64 million Americans tried to quit smoking.

• At least 100,000 smokers who tried

References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990;144(4):934-941. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgensensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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The ASCO Post | AUGUST 15, 2014

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Perspective

Facing Cancer Together

By Dan Shapiro, PhD

D

avid sits at his desk, tapping angrily. He’s tired of his abusive, ignorant boss, the VP for regional sales.

The man’s sales targets are absurdly high, he’s impossible to reach on the phone, his “motivational” speeches evoke the stress of Glengarry Glen Ross, and even his fake all-light-brown hair color is irritating. No one’s hair is that consistent a color! As the senior salesperson, David knows it’s his job to protect the team.

Now he considers bolting past Thomas, his boss’s secretary, and rushing the door. He rehearses how the conversation will go. David will clap his fist into his hand and announce that things have to change. No, things are going to change. No more bullying.

He stands. The office door is only 20 yards away. He’s taking his first steps when his cell phone buzzes. Huh? It’s his wife. Should he answer? It will only delay him a few moments. He taps the glass, answering. After he whispers his plan into the phone, there’s a long pause. “Are you still there?” he asks her, more aggressively than he intends.

“Uh, Davy, are you sure that’s a good idea? What happens if he lets you go?” his wife asks.

He swallows. Uh, no, he suddenly realizes. Maybe I haven’t thought this through….

His wife knew that only a few days before, he’d had a biopsy for possible prostate cancer and they were still awaiting results. Since then, he’d gotten angry at the trash collectors who routinely service their complex at 5:30 AM, he’d Dr. Shapiro is a clinical psychologist and Chair of the Humanities Department at the Penn State College of Medicine, Hershey, Pennsylvania. He is a cancer survivor and the spouse of a survivor. His tips are adapted from his book, And in Health: A Guide for Couples Facing Cancer Together (Trumpeter, 2013), which won a national book award in May 2014.

sworn at two drivers who moved too slowly after a light change or forgot to signal a turn, and, of course, he’d blown up at her for mailing a donation to the Red Cross that was $50 larger than he’d had in mind, after ravaging tornadoes erased a town a few states over. Yet she knew he was typically a cheerful, generous, soft-spoken man.

And, in fact, David was violating a simple marital rule that applies to all patients visiting the “cancer world” (see Tip 1 below).

Seven Tips Tip 1. Couples should never—not ever—make major life decisions while awaiting results of biopsies, tests, scans, or other medical oracles. Do not pur-

I was not. When our patients visit cancer world, they probably aren’t, either.

Two years ago, with my wife’s breast cancer adventure still fresh in my mind, I interviewed 40 couples from around the country and worked to distill what I learned into a number of key lessons.

Here are a few more.

Tip 2. Cancer is a new experience.

Couples may need to learn to tolerate not being great at it at first. It’s normal to lose one’s keys, park in the wrong place, and forget to bring one’s insurance card to chemotherapy. But like any new skill, we get better at it. Successful couples have patience with one another and quickly forgive rookie mistakes.

Tip 3. It’s happening to both mem-

Couples should never—not ever— make major life decisions while awaiting results of biopsies, tests, scans, or other medical oracles.

—Dan Shapiro, PhD

chase or sell property, do not change jobs, and especially do not adopt a ferret with a tricky thyroid. Do not discuss one’s relationship or any other important issues with a spouse.

Unfortunately, David’s results were not what he’d hoped. But after the kneebuckling bad news, a decision on a treatment plan, and a brief conversation with a clinic social worker, he recognized the dark alchemy that turned his fear into anger, and he stopped taking it out on his wife, his coworkers, and even the sanitation workers.

This is the first of a number of tips I’ve accumulated after personally being a cancer patient and then the spouse of a patient. As a psychologist, I thought I’d be inoculated from needing this advice, but

bers of the couple. When I had cancer, it felt like I was driving into an intersection too quickly. But I had my foot on the brake and my hands on the wheel.

I had some semblance of control, even if it was illusory. But when my wife was diagnosed, it felt like I was 200 yards away, watching her drive too quickly into an intersection, her windows rolled up, too far away to hear me.

When I was a patient I was selfcentered and had little appreciation for how my illness impacted my loved ones.

It took being the spouse to understand how difficult life is on both sides of the bed. Oncology professionals do couples a service when they alert them that it is painful on both sides of the bed.

Tip 4. Couples who are willing to

be flexible with household jobs and roles do better than those who rigidly try to cling to the way things have always been. Sometimes cancer prevents us from doing our typical tasks. This means our partner or someone else has to do those jobs.

Yet we are often kinder to our pets than we are to our loved ones when trying to teach them new things. Flexibility means being willing to calmly encourage our spouse, even when they are backing up a boat trailer for the first time or laundering our delicates.

Tip 5. Spouses may need to learn to advocate for their partners. Some physicians are brilliant, organized, and kind. Some are overworked, tired, or even sloppy. And some clinics and medical systems are still designed more for the convenience of health professionals (or billers) than patients.

It often falls to spouses to ask questions and assertively speak up.

Medical systems do not award popularity prizes. While I’m not suggesting we antagonize well-intentioned health professionals unnecessarily, I am urging that spouses must sometimes learn to speak up and insist that the patient’s needs are met.

Tip 6. Couples need to stop fighting over how a spouse is thinking about cancer. The popular culture is rife with notions of thinking one’s way to better health. It is painful to accept that horrible things happen to good people, and there is no one magic way to cope with the experience. That said, if a member of a couple is depressed, get treatment!

Tip 7. Be generous with one’s spouse. It’s hard for both of you. Even if you can do little else to combat the illness beyond what you are already doing, you can be kind to one another.

A soft word, the gentle touch, an offcolor joke—these can be a soothing balm when you feel that your lives are ablaze. n

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | AUGUST 15, 2014

PAGE 111

Announcements Psychosocial Oncology

IPOS Celebrates 30th Anniversary at World Congress in Lisbon

T

he International Psycho-Oncology Society (IPOS) will be celebrating its 30th anniversary at the 16th World Congress of PsychoOncology and Psychosocial Academy being held in Lisbon, Portugal from October 20-24, 2014. The Congress will feature a plenary session with nine past presidents, whose terms spanned many significant milestones in the development of psycho-oncology around the world.

“The mission of IPOS is to promote global excellence in psychosocial care of people affected by cancer,” said Luzia Travado, IPOS Vice-President and Chair of the 16th World Congress. “This year, IPOS will be celebrating its 30th anniversary and admission into official relations with the World Health Organization (WHO).

In honor of these important milestones, and many others achieved over the last 30 years, we invite participants to join the conversation and make our 2014 Annual Congress very much action oriented.”

• Fostering psychosocial oncology care in Europe and development of training programs in Eastern Europe in collaboration with the European Partnership for Action Against Cancer (EPAAC) • Collaboration on policy around

lifestyle and behavioral factors in cancer control with the NCD Alliance, whose mission is to combat the noncommunicable disease epidemic.

B:7.875 in “The presidents of IPOS would like T:7.625 in to commend cancerS:6.625 programs around in

the world for their efforts to provide whole patient care, including mandatory screening and treatment of emotional distress,” said Barry D. Bultz, MD, President of IPOS. For more information on the World Congress, visit www.ipos2014.com. n

IN ADVANCED PROSTATE CANCER…

DO YOUR PATIENTS HAVE

MORE ANDROGEN THAN YOU CAN CATCH WITH ANDROGEN RECEPTOR BLOCKADE?

Major Milestones In addition to counting 7,000 federated members in 25 national societies around the world and recent developments with the World Health Organization (WHO), IPOS also saw its recommendations accepted in 2013, when the International Union for Cancer Control (UICC) called for universally available distress management services in Target 8 of the World Cancer Declaration. Other significant milestones include: • Establishment of Distress as the 6th Vital Sign, after temperature, pulse, blood pressure, respiratory rate and pain, which is now endorsed by 75 organizations around the world • Creation of the distress thermometer, a cost-effective distress screening tool with universal applicability • Establishment of Psychosocial Cancer Care as a Human Right, which will culminate in a declaration and motion at the World Congress in Lisbon • Creation of the journal, Psycho-Oncology, published by Wiley-Blackwell • Application of psycho-oncological research to define cancer-related distress and enable the codification of distress screening and management in advanced clinical care models • Development and implementation of psychosocial academies for professionals in low- and middleincome countries

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies.

Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed.

Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2013 9/13 002097-130903

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PAGE 112

Palliative Care in Oncology Using Patient-Reported Outcome Measures in Palliative Care Clinical Practice A Conversation With Ethan Basch, MD

By Jo Cavallo

I

ncorporating patient-reported outcomes into the palliative care clinical setting can improve patients’ symptom management, quality of life, and overall communication with their oncologists, according to Ethan Basch, MD. Dr. Basch is Director of the Cancer Outcomes Research Program and Associate Professor of Medicine at the University of North Carolina’s Lineberger Comprehensive Cancer Center in Chapel Hill, and has conducted research in patient-reported outcomes, drug regulatory policy, and comparative effectiveness research.

Two years ago, Dr. Basch and his colleagues developed guidance for integrating patient-reported outcome performance measures into the design of

into palliative care services remains to be seen. The overriding point is that there should be some approach in place to make use of patient-reported information to get patients the most appropriate support services at every stage of their care.

Among patients who have advanced or metastatic cancers, drug side effects and functional status impairments are common. Patients often have these experiences while they are away from the clinic, and unfortunately these experiences frequently go undetected by providers. Quite a bit of evidence shows that introducing patient-reported outcomes into clinical practice improves patients’ symptoms, quality of life, and their functional abilities. As a result,

Patient self-reports of symptoms and quality-of-life issues are valuable at every point in the continuum of cancer care.

—Ethan Basch, MD

clinical trials1 to ensure that data collection include patients’ directly reported experiences to improve the quality of clinical research in health-care decision-making. In addition to being used in clinical trials, responses from patient-reported outcome questionnaires measuring patients’ symptoms (such as nausea and pain), physical functioning (such as difficulty climbing stairs or walking), and mental health (such as anxiety and depression) are also used to evaluate hospital performance.

The ASCO Post talked with Dr. Basch about how patient-reported outcome measures can be utilized in palliative care clinical practice to assess symptoms caused by cancer and/or its treatment.

Valuable Information Please talk about how patient-reported outcome performance measures are used in the palliative care setting.

Patient self-reports of symptoms and quality-of-life issues are valuable at every point in the continuum of cancer care. Exactly how patient-reported measures to assess drug toxicity and symptom severity will be incorporated

patient satisfaction improves and, overall, there is more efficient and accurate communication between patients and their providers.

It is also important to continue collecting this information throughout survivorship. For example, we are only beginning to understand how many patients with localized prostate cancer suffer long-term sexual side effects or urinary problems after prostatectomy or radiation therapy. So even when patients are purportedly cured of their cancer, they may live lifelong symptoms related to their disease or treatment.

It might be helpful to integrate patient-reported outcome measures into survivorship care plans as well. There are many reasons to continue to monitor survivors, including the detection of disease recurrence. Beyond that, we have to manage how people feel over the long term.

How widely used are patient-reported outcome measures in clinical care?

There is increasing interest, but generally it is limited to individual providers or practices rather than at the institutional level. That said, there is a

burgeoning interest in patient-reported outcomes to enhance clinical care and to measure quality of care delivery.

GUEST EDITOR

Different Strategies How are assessments made about a patient’s symptoms or functional status? Are the questionnaires completed during the office visit?

There are different strategies being developed. Increasingly, there is interest in collecting this information electronically. Some of the major electronic health record vendors have designed patient portals that include the ability to send electronic questionnaires to patients and capture their responses in the medical record. For example, before the office visit, either while at home or in the waiting room, patients could answer questions about their symptoms or problems they may be having, which could then be addressed during the visit.

Another strategy being explored is monitoring patients between visits. Out of sight, out of mind has been the rule in health care, but evolving technologies promise to give us non–real-time ability to interact with our patients and respond to their concerns between office visits.

An example of that would be an automated system that makes phone calls or sends e-mails to patients every week or two, reminding them to report any problems they may be having. If anything in their [patient-reported outcomes] report includes a significant change in symptom severity or functional or mental health status, a message would be sent to a nurse on the medical team and the patient would get a phone call to be triaged.

There are a couple of types of symptom scales to determine patients’ physical and mental health, including numeric scales of 0 to 10 that ask patients to describe their levels of pain, fatigue, nausea, etc, and verbal descriptor scales.

Verbal descriptor scales might ask patients to describe how intense—from mild, moderate, and severe, to very severe—their symptoms are.

While symptom monitoring and managing is something we already do, [patient-reported outcomes] increase the fidelity and efficiency of the information collected and allow us to be more patient-centered in the way that we monitor and manage symptoms.

Jamie H. Von Roenn, MD

A

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited

by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

Mental Health How effective are patient-reported outcomes in assessing mental health issues?

Providing sufficient mental health services in cancer care is a substantial problem. Oncologists and oncology nurses often are not specifically trained to detect or manage anxiety and depression in patients. Sometimes it is challenging to understand the extent to which a patient’s mood is an appropriate response to his or her diagnosis, as opposed to a problem beyond this level that may be interfering with the patient’s ability to function.

We know from monitoring levels of depression and anxiety that questionnaires like the Patient Health Questionnaire (PHQ)-9 are better at precisely identifying the magnitude of some mental health problems compared to non–mental health clinicians. These questionnaires can enhance existing care approaches.

Often, we don’t have adequate time at medical oncology visits to conduct a thorough assessment of these issues. By integrating a questionnaire as a screening tool, for example, if a patient scores high on the PHQ-9 questionnaire for depression and anxiety, the physician or nurse can recommend further clinical assessment and perhaps a referral to psychiatric services.

As mental health care becomes increasingly folded into oncology praccontinued on page 113

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PAGE 113

Announcements

Lung Cancer Alliance Commends National Cancer Institute for Its New Scientific Framework for Small Cell Lung Cancer

T

he National Cancer Institute (NCI) recently presented to Congress a scientific framework that lays out important steps needed to make advances in small cell lung cancer.

The report, entitled “Scientific Framework for Small Cell Lung Cancer (SCLC)” was mandated by the Recalcitrant Cancer Research Act of 2013, which requires the NCI to develop new research plans to provide strategic direction and guidance to accelerate progress against cancers with 5-year relative survival rates below 50% and an incidence of death of at least 30,000 people a year. The statute required NCI to give priority to pancreatic and lung cancers. “[The report] marks an important day for the lung cancer community,” said Lung Cancer Alliance President and CEO Laurie Fenton-Ambrose. “Our longsought effort to devise a national strategy to improve lung cancer’s survival rate has taken a concrete step forward.”

While the report focuses on small cell lung cancer, the scientific framework also brings research momentum to the reshaping of strategies for all lung cancers. The report considered questions related to basic, translational, and clinical research and offered recommendations to improve prevention, detection, diagnosis, and treatment of the disease.

Five initiatives were recommended: • Develop better research tools for the study of small cell lung cancer that optimize the collection of tumor tissue specimens representing distinct phases of SCLC and developing new tumor models that reflect the phase of SCLC found in the clinic.

Patient-Reported Outcomes

• Develop focused, comprehensive genomic profiling to improve the basic understanding of the frequency, distribution, and range of molecular abnormalities that exist both at diagnosis

and following therapeutic relapse.

• Develop new diagnostic approaches for populations at high risk of developB:7.875 in ing SCLC. T:7.625 in • Facilitate novel therapeutic developS:6.625 in

ments that focus on specific molecular vulnerabilities of SCLC. • Define the mechanisms that allow for rapid response to initial treatment as well as the resistance to treatments. n

In mCRPC, is it appropriate to

INHIBIT ANDROGEN PRODUCTION BEFORE BLOCKING THE ANDROGEN RECEPTOR?*

continued from page 112

tice and palliative care services, we can develop pathways within an institution where mental health assessment is fairly systematic. We know that anxiety and depression are common among our patients, and when we think about providing comprehensive palliative care, psychosocial support and mental health services are an important piece of that. n Disclosure: Dr. Basch reported no potential conflicts of interest.

Reference 1. Basch E, Abernethy AP, Mullins CD, et al: Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology. J Clin Oncol 30:4249-4255, 2012.

THIS APPROACH IS AN OPTION FOR TREATMENT IN ADVANCED PROSTATE CANCER.1,2 Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, prospective clinical study data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer.

References: 1. Sartor AO, Tangen CM, Hussain MHA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008; 112(11):2393-2400. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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PAGE 114

Integrative Oncology

By Jyothirmai Gubili, MS Editor, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center

Red Clover Scientific name: Trifolium pratense Common names: Cow clover, wild clover, purple clover, beebread, cow grass, meadow clover

T

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness.

Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information.

The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. We chose red clover for this issue because of its popularity among breast cancer patients.

Compiled by Barrie R. Cassileth, MS, PhD, and Jyothi Gubili, MS, Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, Memorial Sloan Kettering Cancer Center.

Overview

Red clover is a perennial herb that commonly grows in meadows in Asia and Europe, and is now prevalent in North America as well. It produces dark

pink flowers in thick inflorescences that are used in herbal medicine.

Red clover has been used in traditional medicine to treat skin disorders such as psoriasis and eczema, cough, and mastitis. It was also valued as a blood purifier and used as a folk treatment for cancer. It is an ingredient in some “alternative” (nonviable) cancer treatments such as Hoxsey therapy.

It was the identification of phytoestrogenic isoflavones that made red clover popular as an alternative to hormon-

GUEST EDITOR

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.

In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. late proliferation of estrogen receptor (ER)-positive breast cancer cells.

The Science al therapy for the relief of menopausal symptoms. However, clinical data on red clover’s ability to alleviate menopausal symptoms are inconclusive.

Red clover is available in the form of teas, tinctures, tablets, and capsules, as an ointment for topical application, and as extracts standardized to specific isoflavones. Two heavily promoted extracts include Promensil, for the treatment of menopausal symptoms, and Trinovin, for prostate health.

Patients with breast cancer should avoid red clover because it may stimu-

Red clover extract acts as an estrogen agonist and stimulates proliferation of ER-positive breast cancer cells in vitro.1 However, biochinin A, a red clover isoflavone, inhibits aromatase activity and expression,2 and may confer a protective effect.

Isoflavone-enriched red clover extracts also demonstrated neuroprotective effects in human cortical neurons,3,4 and by increasing collagen content, red clover reduced skin aging in mice.5 Clinical data indicate that red clover isoflavone supplementation improves menopausal symptoms.6-8

But analyses of systematic reviews conflict: One suggests a small benefit; the second found no evidence of effectiveness.9,10 In a study of postmenopausal women, red clover supplements alleviated vasomotor and menopausal symptoms.11 Red clover isoflavones may reduce bone loss12 and improve arterial compliance, an index of the elasticity of large arteries, an important risk factor for cardiovascular disease.13 However, red clover was shown to increase resistance of prostate cancer cells to high dose radiation, and prevent the growth of normal prostate cells.14 In summary, red clover appears useful in alleviating menopausal symptoms, but there are no data to support its anticancer effects.

Learn More About

Herbs, Botanicals, & Other Products For additional information, visit the free About Herbs website at

www.mskcc.org/cancer-care/ herb/red-clover

ASCOPost.com | AUGUST 15, 2014

PAGE 115

Integrative Oncology Adverse Effects

Case report: A 53-year-old woman suffered subarachnoid hemorrhage after taking an herbal supplement (containing red clover, dong quai, and Siberian ginseng) for hot flashes associated with perimenopause. Her symptoms resolved following discontinuation of supplement use.15

OF NOTE Physicians should be aware of the estrogenic effects of red clover and its potential for interactions with certain prescription drugs.

Herb-Drug Interactions

Anticoagulants/antiplatelets: Red clover may enhance their effects.16 Cytochrome P450 enzymes: Red clover inhibits CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4, and may interact with substances metabolized by these enzymes.17 Methotrexate: Concurrent use of red clover with methotrexate injections resulted in severe vomiting and epigastric pain.18 n

Disclosure: Ms. Gubili reported no potential conflicts of interest.

References 1. Le Bail JC, Champavier Y, Chulia AJ, et al: Effects of phytoestrogens on aromatase, 3beta and 17beta-hydroxy­ steroid dehydrogenase activities and human breast cancer cells. Life Sci 66:12811291, 2000.

2. Wang Y, Man Gho W, Chan FL, et al: The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. Br J Nutr 99:303-310, 2008.

3. Chen HQ, Jin ZY, Li GH: Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage through inhibition of microglia activation and proinflammatory factors generation. Neurosci Lett 417:112-117, 2007.

4. Occhiuto F, Zangla G, Samperi S, et al: The phytoestrogenic isoflavones from Trifolium pratense L. (Red clover) protects human cortical neurons from glutamate toxicity. Phytomedicine 15:676-682, 2008.

5. Circosta C, De Pasquale R, Palumbo DR, et al: Effects of isoflavones from red clover (Trifolium pratense) on skin changes induced by ovariectomy in rats. Phytother Res 20:1096-1099, 2006.

6. Lukaczer D, Darland G, Tripp M, et al: Clinical effects of a proprietary combination isoflavone nutritional supplement

Don’t Miss Dr. Cassileth’s New Book:

Survivorship: Living Well During and After Cancer Featuring up-to-date, evidence-based guidance about integrative medicine along with important information for your patients and their families For more information, visit http://bit.ly/1dvI0q3

Author: Barrie Cassileth, PhD Format: Paperback ISBN: 978-1-938170-35-5 Pages: 216 Publication Date: April 1, 2014 Dimensions: 5.5 × 8.5 Also Available: eBook

in menopausal women: A pilot trial. Altern Ther Health Med 11:60-65, 2005.

7. Hidalgo LA, Chedraui PA, Morocho N, et al: The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: A randomized, double-blind, placebo-controlled study.

Gynecol Endocrinol 21:257-264, 2005.

8. van de Weijer PH, Barentsen R: Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 42:187-193, 2002.

9. Coon JT, Pittler MH, Ernst E: Trifolium pratense isoflavones in the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine 14:153-159, 2007.

10. Lethaby AE, Brown J, Marjoribanks J, et al: Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev (4):CD001395, 2007.

11. Lipovac M, Chedraui P, Gruenhut C, et al: The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women. Gynecol Endocrinol 28:203-207, 2012.

12. Atkinson C, Compston JE, Day NE, et al: The effects of phytoestrogen isoflavones on bone density in women: A double-blind, randomized, placebo-controlled

trial. Am J Clin Nutr 79:326-333, 2004.

13. Nestel PJ, Pomeroy S, Kay S, et al: Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab 84:895-898, 1999.

14. Hasan Y, Schoenherr D, Martinez AA, et al: Prostate-specific natural health products (dietary supplements) radiosensitize normal prostate cells. Int J Radiat Oncol Biol Phys 76:896-904, 2010.

15. Friedman JA, Taylor SA, McDermott W, et al: Multifocal and recurrent subarachnoid hemorrhage due to an herbal supplement containing natural coumarins.

Neurocrit Care 7:76-80, 2007.

16. Heck AM, DeWitt BA, Lukes AL: Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 57:1221-1227, 2000.

17. Unger M, Frank A: Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom 18:2273-2281, 2004.

18. Orr A, Parker R: Red clover causing symptoms suggestive of methotrexate toxicity in a patient on high-dose methotrexate. Menopause Int 19:133-134, 2013.

Save the Date 11th International Conference of the Society for Integrative Oncology October 26–October 28, 2014, Houston The 11th International Conference of the Society for Integrative Oncology will be held in Houston, Texas, at the Omni Houston Galleria Hotel October 26–28, 2014. The conference theme is “Personalized Integrative Oncology: Targeted Approaches for Optimal Outcomes.”

2014 Conference Co-Chairs Richard Lee, MD Peiying Yang, MS, PhD The University of Texas MD Anderson Cancer Center For more information, visit integrativeonc.org

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines.

The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40138 January 2014.

The ASCO Post | AUGUST 15, 2014

PAGE 118

Announcements

Patrick Soon-Shiong, MD, to Lead Providence Health Cancer Services and Bioinformatics

P

rovidence Health & Services has announced that Patrick SoonShiong, MD, will serve as the healthcare system’s new Global Director for Cancer Services and Bioinformatics.

In this role, Dr. Soon-Shiong will work closely with oncology clinicians and researchers across the five-state Providence system—Alaska, California, Montana, Oregon, and Washington.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Dr. Soon-Shiong is based in Los Angeles and is also a Professor of Microbiology, Immunology, Molecular Genetics, and Bioengineering at the University of California Los Angeles.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

Clinical Genomic Network for Whole-Genomic Sequencing Dr. Soon-Shiong, through his Chan Soon-Shiong Institute of Molecular Medicine, and Providence also announced their partnership to create the country’s first clinical genomic network for whole-genomic sequencing. They have installed an Illumina HiSeq X Ten sequencing system,

Patrick Soon-Shiong, MD

to establish the first CLIA-approved clinical facility to drive molecular decisions for cancer patients.

Providence will be the first health-care system that will use the sequencing system, giving a comprehensive view of each patient’s disease. Rod Hochman, MD, President and CEO of Providence, said “With the leadership of Dr. Soon-Shiong and the many leading oncology clinicians and researchers across our five-state organization, we will have a vast amount of genetic information, technology, and science to pinpoint the best care and possible outcomes for patients.”

Currently, Providence and its affiliates care for more than 25,000 new cancer patients annually with nearly 100,000 patients under active care.

Physician, Surgeon, Scientist Dr. Soon-Shiong is a physician, surgeon, and scientist who has pioneered treatments for both diabetes and cancer, published more than 100 scientific papers, and has over 95 issued patents on groundbreaking advancements across a myriad of fields. He invented and developed nab-paclitaxel (Abraxane), the FDA-approved protein nanoparticle albumin-bound delivery technology approved for treating breast, lung, and pancreatic cancers. He serves as Chairman of the Chan Soon-Shiong Family Foundation, and Chairman and CEO of the Chan Soon-Shiong Institute for Advanced Health (the CSS Institute), the Healthcare Transformation Institute, and NantWorks, LLC, a company whose mission is to converge semiconductor technology, supercomputing, advanced networks, and proven innovation. n

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Books

Oncologists Tell Inspiring Stories of What It’s Like to Treat Cancer in The Big Casino A Conversation With Stan Winokur, MD

By Jo Cavallo

I

n May, Stan Winokur, MD, and coeditor Vincent Coppola, published The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, a compilation of forty-two essays

cacy groups to distribute The Big Casino for free to patients with cancer through oncologists’ offices.

Dr. Winokur was a medical oncologist with a community practice in Atlanta

All the essays show the human side of oncology. My goal was to show that oncologists are human beings with the same feelings, fears, and happiness as their patients.

—Stan Winokur, MD

written by some of the leading oncologists in the country about their experiences treating cancer. The inspiration for the book, said Dr. Winokur, came from his desire to give oncologists a venue to express their personal stories of courage and compassion they have witnessed in their patients and to give patients with cancer an inside look into how treating the disease affects not only patients, caregivers, and friends, but their physicians and other members of their medical teams as well.

The book is available on Amazon. com and at thebigcasino.org. Dr. Winokur is also working with patient advo-

from 1973 to 1995. He is currently Medical Director of Axess Oncology, an oncology and medical industry consulting firm.

The ASCO Post talked with Dr. Winokur about his inspiration for doing the book and why it was important for him to publish The Big Casino. Below is an excerpt from The Big Casino called “Family,” written by Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and Medical Director of the Kraft Family Blood Center, Dana-Farber Cancer Institute in Boston. In the essay, Dr. Anderson writes about advances in the treatment of multiple myeloma that he has witnessed dur-

ing his 40 years in practice as well as life lessons he has learned from his patients, mentors, and family.

Odds of Survival Where did the title for your book, The Big Casino, come from?

When I started practicing oncology in the 1970s, it was common for doctors to avoid the word “cancer” when talking with their patients and instead refer to the disease as The Big C or The Big Casino because it was less frightening. Back then, you rolled the dice and the odds were not in the patient’s favor.

Now, with the advancements being made in cancer treatment, the odds of survival for many patients are changing dramatically.

Invaluable Gifts What do you hope to accomplish with the book?

I wanted to create a book that demonstrates the invaluable gifts that America’s top cancer doctors—both in private practice and in academia—have received from their patients, including the gift of courage, the gift of strength, the gift of love, and the gifts of compassion, endurance, and equanimity.

When I was in community practice,

Bookmark Title: The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories Editors: Stan Winokur, MD, and Vincent Coppola Publishing Platform: CreateSpace Publication date: May 2014 Price: $9.99; Paperback, 160 pages

continued on page 120

Family

By Kenneth C. Anderson, MD

I

’ve witnessed incredible courage and zest for life among so many patients from so many walks of life—individuals committed to helping others in spite of their own adversity.

Forty years ago, when survival for patients with multiple myeloma was Dr. Anderson is the Kraft Family Professor of Medicine at Harvard Medical School and Medical Director of the Kraft Family Blood Center at Dana-Farber Cancer Institute in Boston. “Family” is excerpted from The Big Casino (May, 2014) with permission from the book’s publishers, Stan Winokur, MD, and Vincent Coppola.

Additional essays from The Big Casino will be published in future issues of The ASCO Post.

a matter of months, I knew that every person I sat down with was going to die, and probably die quickly, despite whatever I could try to do to help. As a young man who’d gone into medicine to make the world a better place, this was not an easy thing [to accept].

Looking back, it was my mentor at Johns Hopkins University School of Medicine, Dr. Richard Humphrey, who kept me from despairing. “Make science count for patients,” he insisted. “Treat patients as family. Make new discoveries that translate from the bench to the bedside to improve diagnosis, prognosis, and treatment of patients.” His words have been the center of my academic and clinical life ever since.

At Harvard Medical School’s Da-

Kenneth C. Anderson, MD

na-Farber Cancer Institute, I’ve had the privilege of seeing the grim natural history of multiple myeloma brighten dramatically. We’ve moved from conventional chemotherapy when I began [practicing], to high-dose therapy and stem cell transplantation, to novel therapies that target the tumor in its

microenvironment. Over the last decade, my team has made fundamental scientific discoveries that helped translate to clinical trials and FDA approval for eight new treatments. Our trainees have become the academic and clinical leaders in myeloma nationally and internationally. The ultimate benefit is that patients have now doubled or tripled their survival, and what was an incurable illness is, in many patients, chronic.

Potential for Cure on the Horizon Targeting the cancer cell in its microenvironment has made the difference. When cancer cells are studied continued on page 120

The ASCO Post | AUGUST 15, 2014

PAGE 120

Books Stan Winokur, MD continued from page 119

at the end of all office visits I thanked my patients for coming in. And the reason I thanked them was because they were giving me hope, courage, and strength.

Every one of the authors in this book tells the story of how their patients have affected their lives.

All the essays show the human side of oncology. My goal was to show that oncologists are human beings with the same feelings, fears, and happiness as their patients.

I also hope the book will be therapeutic for readers. For example, in the essay by Kishore K. Dass, MD [Medical Director of South Florida Radiation Oncology in Wellington, Florida] called “Courage Under Fire,” he is paying homage to an oncology nurse who had breast cancer. It’s his way of thanking her for the inspiration she gave him to become a better physician every day.

All of the stories in the book express the feeling of gratitude and inspiration these oncologists have received from

Kenneth C. Anderson, MD

their patients. The authors also convey how their patients’ courage keeps them motivated to continue working toward a time when all patients can live long, high-quality lives after cancer.

Role of Fear There is still so much fear surrounding a cancer diagnosis. How can

The Big Casino help patients feel less afraid?

Fear is an emotion that is present not just in the patient with cancer, but in the oncologist as well. The stories relayed in the book describe the fear oncologists have of letting their patients down and the fear of not curing their patients.

I’m hoping this book helps patients understand that it is okay to express their fear to their oncologist, because then the oncologist can validate it and say, “I know you are afraid, but here is the reality. Now we have these drugs, and treatment is more effective. I will be here for you and we will face this together.” n

Activated T Cell Inactivated T Cell

PD-L1

PD-1 Receptor PD-L2

PD-1 Receptor PD-L1

continued from page 119

in a test tube, in vitro, you can determine whether certain drugs or treatments work. But tumor cells grow in vivo, in various organs (that is, a microenvironment or neighborhood). The microenvironment confers growth, survival, and drug resistance. In myeloma it’s the bone marrow.

The challenge is validating newtargeted treatments that can kill the tumor cell in spite of all the advantages the microenvironment confers.

Making the World a Better Place Today, there are classes of drugs that actually revolutionize the way we treat the tumor.

Cancer research is only half my story. I grew up in Auburn, a small town in central Massachusetts, and was the first in my family to graduate from college. My mother was a nurse; my father attended a trade school.

My ambition was to be a general practitioner (GP) in my hometown. To my parents, the values and the rewards of helping others were always paramount and never a one-way street. At continued on page 121 Artist’s interpretation based on scanning electron microscopy.

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Books

Kenneth C. Anderson, MD continued from page 120

the end of the day, their question was always, “What have you done to make the world a better place?”

Yes, research breakthroughs have obviously been critical in altering the

terrible course of myeloma, but Dr. Richard Humphrey’s counsel to treat patients as family rings true all these years later.

I’ve learned my most important life lessons from my patients. Family and friends are the most important things.

We, who are caregivers, must treasure health above all else. The clinic is where the research lab and real life run together. I’ve witnessed incredible courage and zest for life among so many patients from so many walks of life—individuals committed to help-

Discover PD-1: An immune checkpoint pathway1 Some tumor cells can evade the body’s immune response, which may result in disease progression2,3 • One function of the body’s immune response is to detect and destroy tumor cells through activated T cells and other mechanisms; tumor cells express multiple antigens that are not expressed in normal tissue.1—3 • However, some tumor cells may evade the body’s immune response by exploiting the PD-1 checkpoint pathway through expression of the dual PD-1 ligands PD-L1 and PD-L2.1,2,4—7 • PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumor cells to evade the immune response.1,2,8 Merck is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway.

TO DISCOVER MORE ABOUT THE PD-1 CHECKPOINT PATHWAY IN CANCER AND TO REGISTER FOR UPDATES, VISIT WWW.DISCOVERPD1PATHWAY.COM.

PD-1=programmed cell death protein 1; PD-L1=programmed cell death ligand 1; PD-L2=programmed cell death ligand 2.

References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264.

2. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 4. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013;108(8):1560–1565.

5. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477.

6. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862. 7. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157. 8. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–268.

Copyright © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1105870-0000 02/14 merck.com

ing others in spite of their own adversity who turn their own hardships into hope and opportunities for others and who serve as a personal inspiration to all of us in all that we do. There isn’t a day that goes by that I am not inspired.

I’ve been privileged to meet all kinds of patients, not only locally, but nationally and internationally as well—some of whom have been political, business, and sports leaders on the world stage.

Cancer is a great equalizer. One common bond is that when cancer occurs, it happens not only to an individual but also to a family. Often, if the family is very close, it actually brings people closer together. The love and the warmth that is a bond for them grow even stronger. Sometimes, tragically, it becomes such a stress that the opposite happens: bonds break apart. Our challenge as practitioners is to help our patients adjust and deal with their illness personally, and also from a family point of view.

Forty years ago, I could not find words to comfort my patients or offer treatments that held any promise. Today, I’ll often say, “I’m sorry we have to talk about myeloma, but if you are going to have the cancer, this is the best time ever to have it. We have effective treatments now.

New and even more promising therapies are coming.” I try to help them deal with the shock of such a life-altering illness, but I can realistically offer the promise of long life, quality of life, and the ability to have a family, see children and grandchildren grow up, and attend college graduations, weddings, and everything else.

To see patients enjoy the milestones of life with their families is the most wonderful reward I could have ever hoped for. The answer to my parents’ long-ago challenge is crystal clear. My patients make the world a better place. n

The ASCO Post Wants to Hear From You Write to The ASCO Post at editor@ASCOPost.com.

The ASCO Post | AUGUST 15, 2014

PAGE 122

FDA Update

FDA Takes Steps to Help Ensure the Reliability of Certain Diagnostic Tests

T

he U.S. Food and Drug Administration (FDA) recently took important steps to ensure that certain tests used by health-care professionals to help diagnose and treat patients provide accurate, consistent, and reliable results.

First, the FDA is issuing a final guidance on the development, review, and approval or clearance of companion diagnostics, tests used to identify patients who will benefit from or be harmed by treatment with a certain drug.

Second, consistent with the requirements of the FDA Safety and Innovation Act of 2012 (FDASIA), the agency is notifying Congress of its intention to publish a proposed risk-based oversight framework for laboratory developed tests, which are designed, manufactured, and used within a single laboratory.

“Ensuring that doctors and patients have access to safe, accurate, and reliable diagnostic tests to help guide treatment decisions is a priority for the FDA,” said FDA Commissioner Margaret A. Hamburg, MD. “Inaccurate test results could cause patients to seek unnecessary treatment or delay and sometimes forgo treatment altogether. [The recent] action demonstrates the agency’s commitment to personalized medicine, which depends on accurate and reliable tests to get the right treatment to the right patient.”

Companion Diagnostics Guidance Companion diagnostic tests are intended to aid physicians in selecting appropriate therapies for individual patients. These tests are commonly used to detect certain types of gene-based

cancers. The companion diagnostics guidance is intended to help companies identify the need for these tests during the earliest stages of drug development and to plan for the development of a drug and a companion test at the same

include some genetic tests and tests that are used by health-care professionals to guide medical treatment for their patients. The FDA already oversees direct-to-consumer tests regardless of whether they are lab-developed tests

[The recent] action demonstrates the agency’s commitment to personalized medicine, which depends on accurate and reliable tests to get the right treatment to the right patient.

—Margaret A. Hamburg, MD

The agency’s oversight would be based on a test’s level of risk to patients, not on whether it is made by a conventional manufacturer or in a single laboratory, while still providing flexibility to encourage innovation that addresses unmet medical needs.

—Jeffrey Shuren, MD

time. The ultimate goal of the final guidance is to stimulate early collaborations that will result in faster access to promising new treatments for patients living with serious and life-threatening diseases. This guidance finalizes and takes into consideration public comment on the draft guidance issued in 2011.

Laboratory Developed Tests Laboratory developed tests (LDTs)

or traditional diagnostics. While the FDA has historically exercised enforcement discretion over lab-developed tests(generally not enforced applicable regulatory requirements), today these tests may compete with FDA-approved tests without clinical studies to support their use. The LDT notification to Congress provides the anticipated details of the draft guidance through which the agency would propose to establish

an LDT oversight framework, including premarket review for higher-risk Lab-developed tests, such as those that have the same intended use as FDA-approved or cleared companion diagnostics currently on the market. The draft guidance would also propose to phase in enforcement of premarket review for other high risk and moderate risk labdeveloped tests over time.

The agency intends to propose continuing to exercise enforcement discretion for low-risk lab-developed tests, lab-developed tests for rare diseases and, under certain circumstances, labdeveloped tests for which there is no FDA-approved or cleared test.

Balanced Approach for All Diagnostics “With [the recent] notification of the agency’s intent to issue the lab-developed test draft guidance, the FDA is seeking a better balanced approach for all diagnostics. The agency’s oversight would be based on a test’s level of risk to patients, not on whether it is made by a conventional manufacturer or in a single laboratory, while still providing flexibility to encourage innovation that addresses unmet medical needs,” said Jeffrey Shuren, MD, Director of the FDA’s Center for Devices and Radiological Health.

The FDA also intends to publish a draft guidance outlining how laboratories can notify the FDA that they are currently manufacturing and using labdeveloped tests, how to provide information about their lab-developed tests, and how they can comply with the medical device reporting requirements. n

AACR Issues Statement to Applaud FDA’s Actions

I

n a statement released earlier this month, the American Association for Cancer Research (AACR) applauded

the U.S. Food and Drug Administration (FDA) for issuing its final guidance on “In Vitro Companion Diagnostic Devices” and proposing its “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs).” Both are key steps to protecting our nation’s health and advancing personalized medicine. (See above story.)

Catalyst for Incentivizing Innovation Carlos L. Arteaga, MD

“The recent announcements by the FDA are aimed at providing patients

and their physicians with an important level of confidence and certainty with regard to the highly complex molecular and genetic information that these diagnostic tests are determining,” said Carlos L. Arteaga, MD, AACR President, and Professor of Medicine and Cancer Biology and Associate Director for Clinical Research at the VanderbiltIngram Cancer Center of Vanderbilt University in Nashville. “In addition, these actions by the FDA will serve as a catalyst for incentivizing innova-

tion, which is vital during this time of unprecedented scientific opportunity.”

Dr. Arteaga added, “As an organization that represents the entire continuum of research, from the laboratory to the clinic, including the clinical researchers and physician-scientists engaged in cancer patient care, the AACR looks forward to continuing to engage with the FDA to ensure that the molecular and genetic diagnostic tests that are being utilized by physicians (and patients) are based on solidly supported scientific evidence.” n

ASCOPost.com | AUGUST 15, 2014

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World Congress on Head and Neck Cancer Perspective

Michael Douglas Shares His Experience With Stage IV Oropharyngeal Cancer

By Jo Cavallo

A

cademy Award winning actor and producer Michael Douglas was the guest of honor at the opening day of the International Federation of Head and Neck Oncologic Societies (IFHNOS) 5th World Congress on July 27 in New York (see page 22 for more on the World Congress). He came not to plug the release of his latest film And So It Goes, but to talk about the devastating diagnosis of stage IV oropharyngeal cancer he received in 2010, which jeopardized not only his career but his life as well.

Mr. Douglas spoke after a video presentation by former President Bill Clinton and was introduced by his oncologist, Jatin P. Shah, MD, FACS, Chief, Head and Neck Service at Memorial Sloan Kettering Cancer Center in New York, Congress Chairman of IFHNOS, and Past President of the American Head and Neck Society.

His remarks before the more than 3,100 specialists in head and neck cancer in attendance at the conference appear below. Mr. Douglas’ speech has been edited for space and clarity.

I

t is a pleasure to be here and a privilege. I’ve always thought that speaking after a former President would mean that I’ve done something pretty extraordinary in life, but it turns out all I had to do was have cancer. Generally, when I’m on a stage at a prestigious event like this I’m accepting some kind of an award, so obviously today is a little bit different for me. Standing in front of 3,000 doctors, I’ll just be grateful to walk out of here without another prognosis of some sort.

In all seriousness and in every sense

David Pfister, MD

oncology. And particularly to Dr. Shah, David Pfister, MD [Chief, Head and Neck Oncology Service at Memorial Sloan Kettering Cancer Center], Nancy Lee, MD [Radiation Oncologist at Memorial Sloan Kettering Cancer Center], and the main teams that helped and supported me at Memorial Sloan Kettering.

Some of you might have heard of my case. I had stage IV oropharynx cancer.

Even though I have played a doctor in my movies a couple of times, I’m ready to concede that you all certainly know much more than me just how many cases of oropharyngeal occurrences happen every year in the population and what the prognosis and treatments generally are. I think that’s what you all call medicine.

One of the ways my case was very similar to that of thousands of other cancer patients is that I was initially misdiagnosed. Not once, not twice, but three times. To you all, that is probably a familiar story. It all started out pretty innocently with a soreness of my gum behind my last molar. And being pretty diligent about my health, I went to see my general practitioner, who thought I had an infection and so was prescribing antibiotics, which, being a good patient, I took. And then I saw an ear, nose, and throat specialist, and then I saw a periodontist. But after a number of months when this supposed infection hadn’t gone away despite multiple rounds of treatment, I was pretty certain that this wasn’t simply just a sore gum.

Getting the Diagnosis I was up in Canada with a friend who put me in touch with Saul ­Frenkiel, MDCM, FRCS(c), [Chair of the Department of Otolaryngology—Head and

Nancy Lee, MD

of the word, I’m very fortunate to be here today and I’m comfortable in saying that I owe most of that good fortune to the venerable field of head and neck

Saul Frenkiel, MDCM, FRCS(c)

Neck Surgery] at McGill University and he examined me. We had one of those “uh, oh,” moments, which is never a good thing to hear from your plumber or me-

I’m living proof of the progress this field is making and for that I can offer my wholehearted gratitude for your collective dedication and for your expertise.

—Michael Douglas

chanic, but is a really bad thing to hear from your doctor. And after confirming the diagnosis with a CT scan, Dr. Frenkiel and I started talking about what I was going to do next. I told him I would like to be treated in New York where I live so I could go back to my home every night.

Dr. Frenkiel looked into who would be the right doctor for me to see and given my specific case and after checking with a few of his colleagues, he came back with one name, which had been unanimously recommended and that was none other than Dr. Shah.

Now, when I learned that I had stage IV cancer, I’m pretty sure that my eyes rolled into the back of my head and from what little I knew, this wasn’t good, and I think that was probably the scariest moment I faced. But it was then that Dr. Shah’s ability, not just as a surgeon, since fortunately I cannot attest to his expertise in that regard, but as what you would better think of a physician became very apparent to me. He said something, which I found so intelligent even in that very difficult moment or maybe because it was at a difficult moment that it mattered so much to me, which is, “We are going to think of this first as a cancer of the throat and not of the tongue, because as you know the throat we can treat one way and the tongue another.” And it was best to start with what we could hope for before turning to the darker question of surgery and what that would mean for me and my career.

But that was one of the things that I found over the course of my treatment at Sloan Kettering, there was always a positive note, never a false note and I knew that I was in the best possible hands, even if those hands were reaching down my throat more often that I would have liked. But there was a confidence knowing that not just Dr. Shah, but Dr. Pfister and Dr. Lee, who provided my chemotherapy and radiation

treatments, as well as every layer of staff at the hospital, were in sync working to help me get better. And that allowed me to put [myself] in their hands and to do what I needed to do as a patient.

Going Through Treatment Looking back on the experience I realized that you learn a few valuable things as a patient. One is that cancer is one of those things in life for which you will always want to hear the bad news first. Having stage IV cancer is pretty bad. Learning from Dr. Shah what stage IV cancer meant in the context of the head and neck was a little bad. And over the course of my treatment and my series of regular follow-up exams, things moved to the side of better and gradually even became good.

I went through 7 weeks of radiation and chemotherapy, which somehow seemed very accurately mapped to the seven cycles of hell, and each week I sank a little lower and I felt a lot worse.

I had been given a choice of having a feeding tube put in my stomach, which would have had consequences for swallowing and taste later on or refusing that and dealing with that as best I could, which is what I did. And I did lose 40 pounds as a result. But I had been prepared for all that. The doctors and nurses at Sloan Kettering had warned me not to expect to feel great the moment those 7 weeks were over and that there would be another 5 weeks of feeling pretty awful until I could even hope to improve.

In the meantime, I was referred to a nutritionist who worked with me on a regular basis to help me maintain as much of my weight as possible. And [that was] something that made a great difference, not just with my physical health, but in giving me a sense of control and an involvement in what was happening and all of that was enorcontinued on page 124

The ASCO Post | AUGUST 15, 2014

PAGE 124

World Congress on Head and Neck Cancer Michael Douglas continued from page 123

mously important. Like a soldier, I prepared for battle, and from the outset I knew it was their job to treat me and they were among the best-trained and most capable medical teams on the face of this planet. And it was my job to toughen up and get ready for the treatment and later on for my recovery and that is what I was able to do.

Now, one of the other things I’ve learned as a patient is that how to distinguish a doctor is by seeing how many fellows and residents there are following behind him. So by this standard, it was quite clear that Dr. Shah was highly regarded. But as I thought more about this I realized that there is a lot of meanings in that correlation: doctors come to this department from all over the world to learn from one of the best in the field. Why? Because like any great science, medicine depends on the transfer and dissemination of knowledge to drive progress. Doctors have to know what works and what doesn’t. And they have to know who

has tried this or that treatment so they don’t unnecessarily replicate it rather than trying something new.

Lessons Learned To you, this is probably not a new point, but to me it’s an important one nonetheless. And maybe one of the most important things I learned through having and overcoming this disease is that cancer cannot be fought as a series of individual battles, but [rather] as a wellplanned war in which all of us, both medical professionals like yourselves and patients like me, are allies.

Now, looking at things from this perspective, I realized that being misdiagnosed had nothing to do with whether or not I had good doctors. I had great doctors. What was missing in the equation was a simple bit of information that could have led my doctor to consider this one option, which to you as specialists is the area that might be pretty clear, but to doctors working in other specialties, it’s not. There is an obvious incumbency to share knowledge to learn from one another, doctors learning from doctors, pa-

tients from patients, and institution from institution. The role technology plays is especially important, not just in healing the body but in connecting medical communities to each other to make sure the latest advances reach every corner of the field. The International Federation of Head and Neck Oncologic Societies and the American Head and Neck Society and Memorial Sloan Kettering [Cancer Center] are powerful allies who every day push the field a little bit further, changing the way we understand head and neck cancer and not just saving the lives of countless patients, but improving the quality and effectiveness of their treatment [as well].

Advancing Knowledge About Head and Neck Cancer And through your tireless efforts that spans nations, continents, cultures, and languages, and the courage you display in confronting something seemingly so implacable as cancer, you embody the essential values of cooperation, education, and the sharing of knowledge. The proposal made by the

International Federation of Head and Neck Oncologic Societies to proclaim today, July 27, as the world head and neck cancer day is a right move to share and advance knowledge to the world by organizing educational activities each year on this day. I wholeheartedly support this proclamation. This is the road on which I believe progress lies and this, of course, is why you all are here today.

For a century, Memorial Sloan Kettering Cancer Center has helped lead the way in head and neck oncology, that century I can say, saved my life. With this room full of men and women like yourselves devoted to this field, pushing it forward with every case you take and each patient that you treat we can only imagine what the next century will bring. And short of that we can look around and we can say that something is working. I’m living proof of the progress this field is making and for that I can offer my wholehearted gratitude for your collective dedication and for your expertise and I want to thank you all very much for having me here today. n

Peer-to-Peer Viewpoints on Issues in Oncology Visit ASCOPost.com to view the series Recorded Live at ASCO’s 50th Annual Meeting, Chicago The ASCO Post is pleased to present a special video series of interviews by and with leaders in oncology as recorded live at ASCO’s 50th Annual Meeting in Chicago. Visit ASCOPost.com/video or use the QR code to access the program and view these one-on-one interviews: James O. Armitage, MD, speaks with:

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Brian I. Rini, MD: Advances in Renal Cell Carcinoma

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Franco Cavalli, MD: Important Data in Lymphoma Presented at ASCO 2014

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Richard I. Fisher, MD: Standard of Care in Mantle Cell Lymphoma

Siu-Long Yao, MD: Prostate Cancer: A Statistician’s Perspective

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Clifford A. Hudis, MD, FACP: ASCO Today: Science and Society

James L. Mulshine, MD, speaks with:

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Michael Pfreundschuh, MD: Diffuse Large B-Cell Lymphoma

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Carolyn Aldige: Issues in Lung Cancer Screening: An Advocate’s Perspective

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Fred R. Hirsch, MD, PhD: Issues in the Early Detection of Lung Cancer

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Natasha Leighl, MD: Issues in Lung Cancer Screening

Nancy E. Davidson, MD, speaks with: ■■

Lisa Carey, MD: Anti-HER2 Therapy for Breast Cancer

Derek Raghavan, MD, PhD, speaks with: ■■

Karim Fazizi, MD: French Genitourinary Tumor Group Studies

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Maha Hussein, MD: Prostate Cancer, Bladder Cancer

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Daniel Petrylak, MD: Bladder Cancer: Neoadjuvant and Adjuvant Therapy

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David I. Quinn, MD: Prostate Cancer, Bladder Cancer, Adrenocortical Carcinoma

Plus, the following presentations: ■■

Halle C.F. Moore, MD, on Fertility Preservation in Young Women With Breast Cancer

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John F. Smyth, MD, on Improving the Efficacy of Developing New Medicines—and Finding Solutions to Making Them More Affordable

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Alok A. Khorana, MD, on Colorectal Cancer: Results From CALGB/SWOG 80405

indications

ignited we stand with

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

Important Safety Information WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

(cont’d)

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively.

Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Please see next page for adverse events in the NSCLC study.

Pancreatic Adenocarcinoma Study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%) • Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/ gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 06/14 US-ABR140034

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment.

Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN • For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014.

All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

significantly superior ORR in first-line ITT population with advanced NSCLC Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

CATEGORY 1 ABRAXANE + carboplatin %

33

n=521

(170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin %

25

n=531

0

A National Comprehensive Cancer Network ® (NCCN ®) Category 1 recommendation1,2,b,c

5

10

15

20

25

(132/531) 95% CI: 21.2%-28.5% 30

35

40

45

First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

c

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

50

ORR (%)

ITT=intent-to-treat; ORR=overall response rate. a P value based on chi-square test.

b

P=0.005a

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

There was no statistically significant difference in overall survival between the 2 study arms.

41% ORR in squamous patients ORR by histology in the phase 3 NSCLC trial 50 45 40

ABRAXANE + carboplatin

41%

ORR (%)

35 30

24%

25

26% 27

%

Paclitaxel injection + carboplatin

33% 24% 15%

15%

20 15 10 5 0

94/229

54/221

Squamous cell carcinoma

66/254

71/264

3/9

Carcinoma/adenocarcinoma

2/13

Large cell carcinoma

7/29

5/33

STUDY DESIGN • Multicenter 1:1 randomized, phase 3 study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

Other

Adverse events in the NSCLC study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information.

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)].

2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].

2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.

For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.

For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated.

Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc MBC NSCLCc Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.25 x ULN Moderate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not 2 x ULN recommended 50 mg/m2 not Severe < 10 x ULN AND 2.01 to 130 mg/m2 b 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].

Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more than 7 days Platelet count less than 50,000/mm3 Severe sensory Neuropathy – Grade 3 or 4

Second

Third First Second First Second Third

50

3

Discontinue Treatment 75 4.5 Discontinue Treatment 75 4.5 50 3 Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count.

Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at Febrile Neutropenia: Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.

Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)].

In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].

5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].

5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine.

5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.

5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution.

The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)].

5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)].

The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).

In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).

The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).

6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175 mg/m2 over 3 hb 260 mg/m2 over 30 min (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 30 Patients with Normal Baseline 35 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 10 2 Severe Symptomsd Myalgia / Arthralgia Any Symptoms 44 49 8 4 Severe Symptomsd Asthenia Any Symptoms 47 39 8 3 Severe Symptomsd Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials.

Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention.

ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.

Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible.

Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.

Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.

6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion.

The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.

The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group).

Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 2 25 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).

For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral 227 (54%) 70 (17%) 51 (13%) 3 (1%) neuropathya Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract 47 (11%) 10 (2%) 20 (5%) 1 (<1%) infectionsb Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.

Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.

Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.

6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.

Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.

Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.

Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.

6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].

There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.

Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.

Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.

No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.

8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.

8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light.

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].

• Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved.

Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_ALL_HCP_BSv007 10_2013

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Expert’s Corner Teleoncology

How Technology Is Helping Bring Health Care to Patients A Conversation With Richard J. Boxer, MD, FACS

By Jo Cavallo

Richard J. Boxer, MD, FACS

T

he term “telemedicine,” which is sometimes used interchangeably with “telehealth” and “m-health” (for mobile health) and is now collectively called “connected health,” involves the use of information and communications technology to connect patients with their providers through a variety of electronic devices, including interactive videoconferencing, e-mail, smart phones, handheld wireless tools such as tablets, and other types of telecommunications technology. Another term gaining traction is “teleoncology”—the application of telemedicine in the advancement of cancer care, including diagnostics, treatment, and supportive care.

Telemedicine can offer oncologists a way to consult remotely with specialists in other disciplines in other parts of the country or the world to help in their assessments and diagnoses. For patients with cancer, telemedicine can expand access to care, facilitate their reporting of treatment side effects and outcomes, and even improve their quality-of-life.

Results from the Indiana Cancer Pain and Depression study,1 which evaluated the use of telephone-based care management and automated symptom monitoring to reduce depression and pain in patients with cancer, show that these symptoms were significantly improved.

“The technology that is available today is helping bring about a fundamental change in U.S. health care,” said Richard J. Boxer, MD, FACS, Visiting Professor of Urology, David Geffen School of Medicine at University of California, Los Angeles, and Visiting Scholar, the Business of Science Center, UCLA. “The current system of bringing patients to health

care is changing because of technology. With innovations such as videoconferencing, telephone-based care management, and automated symptom monitoring, high-quality health care is becoming much more convenient and much more affordable, and providing greater access to care. Now, it is possible to bring health care to the patient instead of bringing the patient to health care. I cannot envision the future of health care without connected health.”

The ASCO Post talked with Dr. ­Boxer, who was Chief Medical Officer at T ­eladoc, a telemedicine company, from 2006 to 2013, and is currently a consultant for several technology-enabled healthcare services companies, including Pager (www.getpager.com) and 2nd.MD (www.2nd.md.com), about how telemedicine may impact cancer care in the future.

Better Access to Care How can telemedicine provide better quality health care to patients?

Interactive videoconferencing and Internet-based technologies are allowing physicians from a variety of specialties, including oncology, cardiology, dermatology, and neurology, to provide access to medical care to larger segments of the population, regardless of where patients are located.

Currently, while a large number of people in the U.S. receive outstanding health care, it is often very expensive and inconvenient to access. And there

nologies, such as patient Web portals, will enable patients to learn more about their cancer and treatment and how to manage their care, connect with providers, and receive social support through online support groups.

Remote Services Please explain how cancers might be diagnosed or monitored remotely.

If a person is worried about a possible skin cancer, for example, and can’t get to her dermatologist for a diagnosis, she can upload a photo of the skin lesion to her doctor’s office, and the physician and consulting dermatologist may make a decision about whether the patient needs to come to the office for an in-person skin check.

For patients with cancer who need to be monitored by their oncology team, but either live long distances from their medical center or don’t need or cannot be physically in the oncologist’s office for a checkup, the oncology team would be able to virtually visit the patient in the patient’s home.

Alleviating the Workforce Shortage In March, ASCO published its report The State of Cancer Care in America: 2014,2 which detailed a potential workforce shortage of oncologists over the next decade just as the demand for oncology services will be surging. Can telemedicine or teleoncology help mitigate the problem of a physician workforce shortage?

Yes. This will be especially true

Now, it is possible to bring health care to the patient instead of bringing the patient to health care.

I cannot envision the future of health care without connected health.

—Richard J. Boxer, MD, FACS

are still tens of millions more Americans who don’t have access to the best oncologists. Telemedicine will provide patients with cancer greater access to better care.

For example, there is substantial evidence that cancer outcomes are worse in rural or remote areas of the country. Telemedicine or teleoncology can decrease the travel burden on these patients.

In addition, Internet-based tech-

for primary care physicians, where the workforce shortage is even greater than it is in oncology. Currently, there is a disconnect between where the physician is and where the patient is. That disconnect can be reversed through telemedicine, or teleoncology, through videoconferencing or telephone-based care management.

The technology of connected health increases the number of avail-

able time slots a doctor may use to care for patients. One of the great inefficiencies in medicine is that the doctor and the patient are disconnected through time or physical distance.

Each appointment slot in a doctor’s office calendar that is not filled due to cancellations or incomplete scheduling results in another patient not receiving medical care. If these empty appointment slots can be filled with a virtual office visit, the doctor’s time is efficiently used and the patient receives care.

In addition, the technology allows other populations of physicians, such as retired, disabled, or stay-at-home moms and dads, to continue to use their medical expertise by practicing medicine as virtual consultants as long as they maintain their board certification and keep current through CME courses.

Growth Potential How prevalent is telemedicine in the practice of oncology?

The application is just beginning in oncology. In primary care practice, there are about 50,000 telemedicine consultations a month in the U.S. vs 80 million in-person medical consultations each month, so the sky is the limit in terms of telemedicine growth potential.

In oncology, the use of communications technology can facilitate second opinions for patients seeking confirmation of their diagnosis or proposed treatment plan. There are companies specializing in obtaining remote second opinions. Patients upload their medical data to the company’s server, the company contacts and pays a world-class consulting oncologist, and then the patients have a videoconferencing or telephonic interaction within a couple of days of their request.

The opportunities for any oncologist to offer first or second opinions are nearly endless. I predict that every medical office, especially medical specialists’ offices, will have a dedicated room for virtual consults.

Supplementary Care Are patients likely to use virtual technology to supplement the physical interaction they receive from their oncologist and continued on page 133

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Appointments

V. Craig Jordan, PhD, to Join MD Anderson Cancer Center

T

he University of Texas MD Anderson Cancer Center has announced that V. Craig Jordan, PhD, will join the institution in October 2014 as a Professor in Breast Medical Oncology and Molecular and Cellular Oncology. Dr. Jordan will focus on the new biology of estrogen-induced cell death with the goal of developing translational approaches for treating and preventing cancer.

“This is an exciting moment and I’m delighted that Dr. Jordan will be contributing to significant translational research activities in breast cancer here at MD Anderson,” said Ron DePinho, MD, President of MD Anderson. “His international reputation as a trailblazer in translational research and his many achievements and honors are well deserved. As we progress in our mission of ending cancer in Texas, the nation and the world, it is outstanding scientists like Dr. Jordan who will play key roles in delivering on that promise.”

Long and Distinguished Career Dr. Jordan’s career has included leadership positions at several prestigious biomedical institutions. Currently, he is Scientific Director of the Lombardi Comprehensive Cancer Center

Richard J. Boxer, MD, FACS continued from page 132

other members of their medical team?

Teleoncology or telemedicine is not meant to replace the physical interaction between the patient and doctor. The first interaction between a patient and the doctor is always in-person. The use of telecommunications technologies is reserved for follow-up, second opinion, and supportive care.

at Georgetown University in Washington D.C., and the Vincent T. Lombardi Chair of Translational Cancer Research. He also serves as Vice Chairman of the Department of Oncology and Professor of Oncology and Pharmacology at Georgetown University’s Medi-

In addition to his National Academy membership, Dr. Jordan’s list of achievements, awards, and accomplishments is long and features more than four-dozen international awards, including The St. Gallen Prize for Breast Cancer (2011) and The David A. Karnofsky Award from the American Society of Clinical Oncology (2008), among others.

Prolific Author

V. Craig Jordan, PhD

cal School. In addition, he is a Visiting Professor of Molecular Medicine at the University of Leeds in England, and an Adjunct Professor of Molecular Pharmacology and Biological Chemistry at Northwestern University in Chicago.

“Dr. Jordan’s election as a member of the National Academy of Sciences in 2009 is just one of the many honors he’s received as a result of his incredible contributions to our understanding of cancer biology,” said Ethan Dmitrovsky, MD, MD Anderson Provost and Executive Vice President.

Oncologists commonly have nurse practitioners, physician assistants, nutritionists, various therapists, social workers, and other professionals on their oncology team. Any of these professionals could perform virtual patient care.

Cost Issues Can telemedicine reduce health-care expenses?

Yes. Bringing virtual health care to the patient reduces brick-and-mortar

Dr. Jordan has contributed to more than 700 publications, 99% of which pertain to cancer research. He has edited 11 books and has more than 26,000 scientific citations. He’s author of the book “Tamoxifen, Pioneering Medicine in Breast Cancer.”

Dr. Jordan, who was born in New Braunfels, Texas and raised in England, has dual British and U.S. citizenship.

In 2002, he received the Order of the British Empire from Queen Elizabeth II for services to international breast cancer research. He earned a PhD and DSc degree from the University of Leeds and in 2001 received an honorary MD degree from his alma mater.

“I am proud to join MD Anderson Cancer Center,” said Dr. Jordan. “It is indeed an honor to continue my work at this world renowned cancer center overhead and increases efficiencies for improved access to care. Everyone wins in the connected health scenario. Patients receive rapid access to appropriate care, more doctors are immediately introduced into the system, potentially reversing the dire predictions of workforce shortages, and physicians are better compensated for improved efficiencies. n Disclosure: Dr. Boxer was Chief Medical Officer at Teladoc, a telemedicine company,

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where I look forward to working with my distinguished colleagues.”

‘Father of Tamoxifen’ Dr. Jordan, deemed the “Father of Tamoxifen,” is credited with reinventing a failed contraceptive (known as ICI 46,474) as a breast cancer treatment. The drug, in existence since the 1960s, was originally created to block estrogen in the hopes of preventing pregnancy. Dr. Jordan developed the strategy of long-term adjuvant tamoxifen therapy, as well as describing and deciphering the properties of a new group of medicines called selective estrogen receptor modulators (SERMs).

He was the first to discover the preventive abilities of both tamoxifen and the drug raloxifene. The medicines were approved by the Food and Drug Administration for reducing breast cancer incidence in high-risk women.

Prior to joining Georgetown University, Dr. Jordan served on the faculties at Northwestern University Medical School, the University of Wisconsin School of Medicine, Madison, the Ludwig Institute for Cancer Research at the University of Berne, Switzerland, and the University of Leeds, England. n from 2006-2013. He is currently a consultant for several technology-enabled health care services companies.

References 1. Kroenke K, Theobald D, Wu J, et al: Effect of telecare management on pain and depression in patients with cancer: A randomized trial. JAMA 304:163-171, 2010.

2. The State of Cancer Care in America, 2014: A report by the American Society of Clinical Oncology. J Oncol Pract 10:119-142, 2014.

The ASCO Post | AUGUST 15, 2014

PAGE 134

ASCO State Affiliates Focus on the Florida Society of Clinical Oncology

By Jo Cavallo

Alan R. Marks, MD

T

he Florida Society of Clinical Oncology (FLASCO) was founded in 1977, just 13 years after the founding of ASCO. Today, the Society has had such an impact on the practices of medical, radiation, surgical, gynecologic, and pediatric oncologists throughout the state, membership has risen to over 1,300—approximately 70% of all cancer specialists in the state of Florida are FLASCO members— and now includes nurse practitioners and physician assistants and other health-care professionals as well.

In addition to being among the oldest and largest of ASCO’s State Affiliates, FLASCO is among the most active legislatively and was influential in securing passage of major legislation, including Florida’s Oral Chemotherapy Parity Law, which went into effect in July. FLASCO was also instrumental in securing funding for the Bankhead-Coley Cancer Research Program, which awards grants to Florida-based universities and research institutions investigating prevention strategies and cures for cancer.

FLASCO is the recipient of three ASCO State Affiliate Grants. Two grants, one in 2005 and one in 2007, were to help in the development and continuation of its initiative, the Florida Clinical Trials Network (FCTN).

FCTN increases patient accrual in cancer clinical trials throughout the state.

And in 2006, FLASCO received an ASCO State Affiliate Grant to implement an annual statewide conference for physician assistants and nurse practitioners.

The ASCO Post talked with ­FLASCO President Alan R. Marks, MD, a hematologist/oncologist with 21st Century Oncology and Baptist Health, Jacksonville, about the Society’s biggest challenges and its goals for the future.

Mutually Beneficial Partnership

Activities in Puerto Rico

Why was it important for FLASCO to become an ASCO State Affiliate and have its own oncology society?

FLASCO was formed with the assistance of the Florida Division of the American Cancer Society. At the time, ASCO was focused on increasing membership and FLASCO was determined to maintain its existence; it seemed mutually beneficial to form this partnership.

What is FLASCO’s relationship with cancer care in Puerto Rico?

Our Immediate Past President is ­Gerardo Colon-Otero, MD, and over the years he has organized FLASCO meetings in Puerto Rico to help educate oncologists on the business aspect of their practices. As a result, we have increased our relationship with oncologists there, and we are supporting them by continuing to provide an annual Business of Oncology Conference to assist them in their efforts to improve cancer care in Puerto Rico. We have also offered to help Puerto Rico become an ASCO State Affiliate.

Quick Growth In less than a year, membership in FLASCO grew from 350 to over 1,300.

How were you able to increase membership so quickly?

We went to the major cancer institutions in Florida and offered them a deal they could not refuse. We first met with the Managing Director of the Florida Cancer Specialists & Research Institute and asked that its 170 physicians join FLASCO. We came up with a plan that waived the dues to join FLASCO on the condition that the physicians attend one FLASCO educational meeting or a FLASCO cosponsored event such as an ASCO highlights meeting each year and/or make a personal contribution to our foundation to continue being an active member.

Florida Cancer Specialists agreed, and then we made the same offer to oncologists and allied health professionals at Broward Heath, Cancer Care Center of Brevard, Winter Haven Hospital Cassidy Cancer Center, Florida Hospital Gynecologic Oncology, Memorial Cancer Institute/Memorial Health Systems, Moffitt Cancer Center, Oncology Resource Networks, Space Coast Cancer Center, the University of Florida, and the Mayo Clinic in Jacksonville. They all became members.

Costly Endeavors What are your biggest challenges?

Our biggest challenges are to retain a significant membership, stay financially solvent, pursue our legislative initiatives, and increase funding. We are in the process of redesigning our website so we can provide educational webinars and make information more easily available and more appealing to members, and that is a costly process.

Through our foundation we award travel grants to fellows to attend ASCO’s Annual Meeting as well as a number of other important meetings, including the annual meetings of the American Society of Hematology and the American Society for Radiation Oncology.

We want to continue that program.

We also support ASCO’s Young Investigator Award (YIA) with the stipulation that the award goes to a Florida investigator. The Young Investigator Award provides funding to promising investigators to encourage and promote quality research in clinical oncology.

Fast Facts ■■ The Florida Society of Clinical Oncology was founded in 1977.

■■ The current President is Alan Marks, MD. ■■ The Founding President was Robert C. Seelman, MD. ■■ The Society has over 1,300 members.

■■ The Society’s mission is to ensure access to quality cancer care for Florida’s patients with cancer, to assist cancer practitioners in providing the most cost-effective care to patients, to act as an advocate for patients and their families, to coordinate the dissemination of information and provide the opportunity for oncologists and other oncology professionals to network and exchange information about cancer care, and to serve as a resource to other organizations and agencies seeking to interact with the Florida cancer care community.

■■ The Society holds two educational meetings each year—one in the spring and one in the fall—and also conducts an annual Business of Oncology Conference for members and the pharmaceutical industry.

The purpose of this research grant is to fund physicians during their transition from a fellowship program to a faculty appointment. We have provided funding for two YIAs and plan on funding one in 2015. Each of the awards is in the amount of $60,000.

We are trying to encourage young oncologists and scientists to stay and practice in Florida because of the increased need for oncology specialists as our population ages and as leadership in FLASCO ages. We want to ensure that we have a steady stable of talented oncology professionals to continue our mission. I’m happy to say that this year, about half the oncology fellows in Florida stayed in the state after their training. So that is a big accomplishment.

All of these endeavors, however, are costly, and we are studying new ways to ensure future funding. As with many other State Affiliates, much of our funding comes from the pharmaceutical industry, and we need to find new avenues to raise money. That’s going to take some innovation.

Major Goals What are your future goals for FLASCO? Two of our major goals are to implement a patient navigator initiative and to become more active in social media, because the younger generation of oncologists relies on social media to communicate. We are also trying to develop a tutor-based program to encourage interaction among our members.

Also, as I mentioned, over the past 2 years, FLASCO has been successful in securing relationships with academic cancer centers across Florida. As a result, we’ve increased our membership.

We hope to continue to expand those relationships, so we can fulfill our mission to bring the highest-quality care to our patients. n Disclosure: Dr. Marks reported no potential conflicts of interest.

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Announcements

Don Shula Foundation Donates $1.5 Million to Moffitt Cancer Center

T

he Don Shula Foundation is donating $1.5 million to Moffitt Cancer Center to establish The Don Shula Breast Cancer Research Fund (The Shula Fund). Scientists at Moffitt will use The Shula Fund to support cutting-edge research projects that will generate new treatment and prevention strategies for breast cancer patients in Florida and beyond.

Don Shula, the winningest coach of all time, and his wife, Mary Anne, joined Moffitt in announcing the fund at an event held recently in Fort Lauderdale. The Shula family was joined

by Pro Football Hall of Famer and Miami Dolphins legend Bob Griese, the Chairman of Moffitt’s national Board of Advisors.

sonally, and I know that the more we give to cancer research, the closer we are to finding a cure,” said Coach Shula, a member of Moffitt’s national Board of Advisors.

A committee comprised of Shula designees, Moffitt leadership, and a Mof-

fitt breast cancer physician-scientist will select the most promising breast cancer research projects to fund. Recent scientific advances in breast cancer research B:7.75” the best at Moffitt include outlining T:7” and testing, use of genetic counseling S:6.5” impact on assessing a gene mutation’s

Now

BLADDER

cancer risk and lifestyle, and identifying environmental risk factors contributing to the disease. The Shula Fund will continue to support similar innovative breast cancer research projects that are being translated into novel treatments to improve patient outcomes. n

Enrolling A Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (UBC) (NCT02108652, Study ID GO29293)

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

Patients with locally advanced or metastatic UBC who are treatment-naïve and ineligible for cisplatin-based chemotherapy or have failed platinum-containing therapy

Left to right: Moffitt Vice President of Diversity & Community Relations Dr. B. Lee Green, Bob Griese, Don Shula, Mary Anne Shula, and Moffitt Center Director & Executive Vice President Thomas Sellers.

N=330

MPDL3280A1 (an engineered anti-PDL1 antibody)

The New Shula Fund The Don Shula Foundation was established in Miami more than 20 years ago as a tribute to Mr. Shula’s late wife, Dorothy. According to Mr. Shula, the new Shula Fund will fuel important breast cancer research discoveries that will improve patient outcomes.

“Cancer has touched our family per-

Primary Endpoint:

Secondary Endpoints:

• Objective response rate

• Duration of response • Progression-free survival • Overall survival • Safety: incidence of adverse events • Incidence of antitherapeutic antibodies

to MPDL3280A • Maximum serum concentration (Cmax)

of MPDL3280A

Contact

The ASCO Post

Key Inclusion Criteria 2: • Documented locally advanced or metastatic • • •

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

Key Exclusion Criteria 2:

• • •

transitional cell carcinoma of the urothelium Representative tumor specimens ECOG performance status of 0-1 Life expectancy ≥12 weeks Measurable disease, as defined by RECIST v1.1 Adequate hematologic and end-organ function Refractory or ineligible for platinum-based chemotherapy

• History of autoimmune disease • Active hepatitis B or hepatitis C • HIV-positive • Administration of a live, attenuated vaccine

within 4 weeks before Cycle 1, Day 1 • Prior treatment with CD137 agonists, or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002467300 Printed in USA.

The ASCO Post | AUGUST 15, 2014

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2014-2015 Oncology Meetings August

Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org 16th Annual Scientific Meeting: AGITG Trials in Action August 20-22 • Brisbane, Australia For more information: www.agitg.asnevents.com.au 29th International Papillomavirus Conference and Clinical & Public Health Workshops August 20-25 • Seattle, Washington For more information: http://www.hpv2014.org/ 6th Latin American Conference on Lung Cancer August 21-23 • Lima, Peru For more information: www.lalca2014.org 7th International Symposium on Focal Therapy and Imaging in Prostate & Kidney Cancer August 21-23 • Pasadena, California For more information: http://www.focaltherapy.org/ ISEH Society for Hematology and Stem Cells 43rd Annual Scientific Meeting August 21-24 • Montreal, Canada For more information: www.iseh.org Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org

6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606 North Carolina Oncology Association (NCOA) Annual Membership Conference August 23 • Wilmington, North Carolina For more information: http://www.ncoa-northcarolina.com

September Association of Pediatric Hematology/Oncology Nurses 38th Annual Conference September 4-6 • Portland, Oregon For more information: www.aphon.org Breast Cancer Symposium September 4-6 • San Francisco, California For more information: breastcasym.org 16th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy September 4-7 • Philadelphia, Pennsylvania For more information: http://www.esh.org/conference/eshicmlf-16th-annual-john-goldmanconference-on-chronic-myeloidleukemia-biology-and-therapy/ 18th Annual Palliative Care Conference September 5-6 • Houston, Texas For more information: http://www.mdanderson.org/ education-and-research/educationand-training/schools-and-programs/ cme-conference-management/ conferences/index.html

2014-2015

2014 APAO Annual Conference September 10-14, 2014 • Austin, Texas Sheraton Austin at the Capitol For more information: www.apao.cc/node/9 American Society of Head & Neck Radiology (ASHNR) Annual Meeting 2014 September 10-14 • Seattle, Washington For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/ Acute and Chronic Leukemias 2014 September 13 • Rochester, Minnesota For more information: http://www.mayo.edu/cme/ hematology-and-oncology-2014s435 American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org Cancer Medicine and Hematology 2014 September 14-19 • Boston, Massachusetts For more information: www.hmscme .com/cancermedicine 18th Annual Meeting: Collaborative Group of the Americas on Inherited Colorectal Cancer September 15-16 • New Orleans, Louisiana For more information: http://www.clevelandclinicmeded. com/live/courses/cga/default.asp Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: www.aonnonline.org

NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/ meetings/hematological/ Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/ meetings--workshops/specialconferences/advances-in-melanomafrom-biology-to-therapy.aspx European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress 2nd International Conference on Hematology & Blood Disorders September 29–October 1 • Linthicum, Maryland For more information: http://omicsgroup.com/hematologyblood-disorders-conference-2014/ index.php Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29-October 2 • Cambridge, Massachusetts For more information: steelelab.mgh.harvard.edu

For Your NPs and PAs A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2nd Loews Royal Pacific Hotel at Universal Orlando, FL apsho.org/jadprolive

ASCOPost.com | AUGUST 15, 2014

PAGE 137

2014-2015 Oncology Meetings October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org

11th Annual Meeting of the International Society of Gastrointestinal Oncology (ISGIO) October 23-24 • Arlington, Virginia For more information: http://www.isgio.org

2nd Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/breastcancer/ pages/index.aspx 18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home.aspx

ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org 11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com 14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/ CourseDetail.aspx/80028747 CNS Anticancer Drug Discovery/ Development Conference November 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org

2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org Atlanta Lung Cancer Symposium October 18 • Atlanta, Georgia For more information: www.phillipsgilmore.com/alcs2014

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org 3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

International Cancer Imaging Society Meeting and 14th Annual Teaching Course October 9-11 • Heidelberg, Germany For more information: www.icimagingsociety.org.uk/index. cfm?task=meetings&meetingid=37 11th Meeting of the European Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php

2014-2015

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com 20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians

Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgicalspecialties-2014s306 19th Annual Meeting of the Society for Neuro-Oncology November 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl RSNA 2014: Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

December American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org 24th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists December 5-7 • Vienna, Austria For more information: iasgo2014.org ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

continued on page 142

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Bone metastases?

1

First sign of symptoms?

1

Start

to extend survival

1,2

Important Safety Information • Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

Myelosuppression—notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death.

Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigotreated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

© 2014 Bayer HealthCare Pharmaceuticals Inc. BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer.

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care • Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have

600-10-0007-14d

07/14

Printed in USA

• In the ALSYMPCAa exploratory updated analysis,b median overall survival was 14.9 months for Xofigo (95% confidence interval [CI]: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8) [hazard ratio (HR)=0.695; 95% CI: 0.581-0.832]1 • In the ALSYMPCA prespecified interim analysis, median overall survival was 14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2) [P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)]1

a

30% reduction in the risk of death vs placebo1

ALSYMPCA was a phase 3, randomized, double-blind, controlled trial that evaluated Xofigo plus best standard of care (n=614) vs placebo plus best standard of care (n=307).1

b

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1

To learn more, visit www.xofigo-us.com

not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit.

Therefore, radiation protection precautions must be taken in accordance with national and local regulations

References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013.

2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see brief summary of full Prescribing Information on following pages.

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were

radium Ra 223 dichloride INJECTION

Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).

Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations.

Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination.

Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing.

19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is Renal and urinary disorders recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo.

The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy.

Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression.

In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo.

The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized.

In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)].

Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.

The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle.

As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.

Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.

Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.

Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)].

However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.

Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed.

3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go.

8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established.

In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight.

8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go.

Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation

by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies.

There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats.

Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation.

Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers.

Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination.

When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. Š 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Revised: 05/2013 "3

The ASCO Post | AUGUST 15, 2014

PAGE 142

2014-2015 Oncology Meetings continued from page 137

December

37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org 11th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

February

The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 19-21 • San Diego, California For more information: www.imedex. com/anti-angiogenesis-andimmune-therapies/ Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: http://www. gotoper.com/conferences/mbcc/ meetings/32nd-Annual-MiamiBreast-Cancer-Conference

March 13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org 16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: http://imedex.com/lung-cancercongress-europe/index.asp Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11-15 • San Diego, California For more information: www.asbmt.org 5th International Conference on Innovative Approaches in Head & Neck Oncology February 12-14 • Nice, France For more information: http://www.estro.org/congressesmeetings/items/5th-ichno

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp

2014-2015

8th Annual Interdisciplinary Prostate Cancer Congress™ March 14 • New York, New York For more information: http:// www.gotoper.com/conferences/ ipcc/meetings/8th-AnnualInterdisciplinary-Prostate-CancerCongress

3rd ESTRO Forum April 23-28 - Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum

May

ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp State-of-the-Art Neuro-Oncology Conference: 3rd Annual Meeting March 19-20 • Clearwater Beach, Florida For more information: http://moffitt. org/for-physicians-healthcareprofessionals/conferences/ conferences 21st Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/ 46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

April American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: http://www.esmo.org/Conferences/ ELCC-2015-Lung-Cancer American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

June Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28–August 1 • Washington, DC For more information: http://www.apos-society.org/ professionals/meetings-ed/ annualconference.aspx Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

ASCOPost.com | AUGUST 15, 2014

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Patient’s Corner

Taking Charge of Your Care

A diagnosis of advanced pancreatic cancer sent me reeling. Taking part in my health-care decision-making kept me positive and was key to my survival.

By Dawn Gill, as told to Jo Cavallo

T

he first sign I had that something might be wrong was an uncontrollable itch all over my body. Although I had never had anything like that before, the problem was easy to initially dismiss. I’m a respiratory therapist and visit patients in their homes daily, so I chalked up the itchiness to an allergen I had come in contact with while treating a patient.

By the next week, I noticed that both my urine and stool were a different color and had a strange odor, but I didn’t think any of these symptoms were related and, again, dismissed them. By the third week, I had stomach pains that were so severe they kept me in bed for a couple of days.

Emergency Room Visit Two weeks later my eyes and skin were jaundiced, and I knew something was very wrong. I made a trip to the emergency room, and the images from a series of tests, including an abdominal ultrasound and an endoscopy, showed that I had a mass the size of a tennis ball on my pancreas.

The doctor said there was so much damage to the organ it looked like the pancreas of a 60-year-old alcoholic. I’m only 41, a nonsmoker, and rarely drink, and I’ve never had stomach problems or pancreatitis, so getting this news was especially shocking.

What came next was even scarier. A tissue biopsy of the tumor was negative for a malignancy, but the doctor said he didn’t trust the test results and felt

certain that I had pancreatic cancer. Because the pancreas was so inflamed, the doctor said he wanted to wait a month to do another biopsy and then start treatment if it was cancer.

If this really was pancreatic cancer, I knew I didn’t have the luxury of waiting another month, so I sought a second opinion. Again I ran into delays.

Even though I have good health insur-

bile duct, enlarging my gallbladder and causing it to malfunction, I couldn’t tolerate the full course of the chemotherapy and had to be hospitalized seven times for infections.

Finally, a stent was placed in the bile duct to keep it open, and I was able to complete the course of chemotherapy and have the surgery.

Overcoming the Odds

You can be young, vigilant about your health, do all the right things, and still get cancer. What really matters is how you deal with the aftermath of the diagnosis. I know that for me, staying positive and being my own health advocate were key to my survival.

—Dawn Gill

ance coverage, two medical institutions turned me away because they didn’t accept my plan, and I had to travel from my home in Illinois to Missouri to see an oncologist.

Advanced Cancer Diagnosis I was finally given the devastating diagnosis of stage III adenocarcinoma of the pancreas. I was prescribed a cocktail of chemotherapies, including gemcitabine, irinotecan, fluorouracil, and leucovorin, to shrink the tumor prior to having Whipple surgery. But because the cancer was blocking my

damage to my gallbladder and liver, I’ve had to change my diet to accommodate a modified digestive system.

Despite these challenges, I know how lucky I am. The chances of surviving advanced pancreatic cancer are slim, and I’m grateful just to be alive, to go about the normal activities of my day, and, most of all, to take care of my son.

Lingering Effects of Cancer After finishing adjuvant chemotherapy with gemcitabine in March, I am now cancer-free, but I’m still reeling from the physical, emotional, and financial ramifications of having pancreatic cancer.

My illness had a profound effect on my teenage son, and we’re still working through the emotional toll it has taken on him. I had to quit my job when I became ill, and have just started a new one, so overcoming the financial burden of having cancer has been difficult as well.

And because of the surgery and all the

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

Throughout this whole experience, I stayed positive and took control of my life and health care. It’s that attitude that keeps me moving forward now. I was fortunate to have an oncologist who not only treated my cancer but also related to me on a personal level and included me in all the decision-making in my care.

She told me she was in this fight with me and said to ask questions if there was anything I didn’t understand. I felt like I was part of the medical team and that my input was as important as that of the other members on the team. That helped raise my spirit and gave me confidence that I could overcome the odds.

Having cancer has taught me that no one is immune from this disease.

You can be young, vigilant about your health, do all the right things, and still get cancer. What really matters is how you deal with the aftermath of the diagnosis. I know that for me, staying positive and being my own health advocate were key to my survival. n Dawn Gill is a respiratory therapist in Minier, Illinois.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

The ASCO Post | AUGUST 15, 2014

PAGE 144

Advocates in Oncology Hematology

Cancer Survivor and Patient Advocate Michael S. Katz, MBA, Has Helped Alter the Standard of Care for Myeloma Survivors

By Jo Cavallo

M

ichael S. Katz, MBA, has lived longer than any of his doctors thought he would. A two-time cancer survivor, Mr. Katz was diagnosed, first with multiple myeloma in 1990 and then with colorectal cancer in 2008, and has spent the past 2 decades tirelessly advocating for patients with cancer.

The 61-year-old native New Yorker was just 37 when he was diagnosed with multiple myeloma following the discovery of a large plasmacytoma in his ilium, which was causing a limp and weakness in his right leg. His doctor advised a resection of the iliac crest and an allograft, but offered no other details of the incurable cancer, which then carried a dismal survival of 3 to 5 years.

“When I was first diagnosed, I wasn’t given the full story of what myeloma was or its prognosis. The focus was on the orthopedic crisis,” said Mr. Katz.

And with the Internet still in its infancy, there were no online patient support groups or myeloma advocacy organizations to turn to for information.

When the disease appeared to be progressing 1½ years later, he was offered an allogeneic bone marrow transplant, which is associated with an overall mortality rate between 25% and 50%.1 “That statistic got my attention,” said Mr. Katz, who then crisscrossed the country meeting with specialists to learn more about myeloma and explore his treatment options, which were limited to chemotherapy, bone marrow transplantation, and radiation therapy.

“It was a very scary and lonely time,” said Mr. Katz. It was that experience that would become the catalyst for Mr. Katz’ advocacy on behalf of myeloma survivors.

Living With Chronic Cancer Like many patients with myeloma, Mr. Katz has seen his cancer seesaw between stable and active disease over the years. He credits the advances in myeloma treatment, including the immunomodulatory agents thalidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide (Pomalyst) and the proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis)—which have transformed the management of myeloma—with keeping him alive for 24 years. During that time, Mr. Katz rose in his career as a management consultant, raised three sons with

his wife, Susie, and saw the birth of seven grandchildren.

These were also years that led Mr. Katz to advocacy, a calling he attributes to his desire to pay forward the help he received early in his diagnosis from the late Francesca M. Thompson, MD, a renowned orthopedic surgeon, who was diagnosed with multiple myeloma in 1987 and was among the first patients with the disease to undergo an autologous bone marrow transplant.

Dr. Thompson later chronicled her struggle with myeloma in her book,

cluding an appointment as Chair of the Director’s Consumer Liaison Group at the National Cancer Institute and selection on the Drug Development Patient Consultant Program at the U.S. Food and Drug Administration.

But it was Mr. Katz’ involvement with ECOG’s E4A03 clinical trial that changed his life—and the lives of virtually all myeloma survivors.3 E4A03 was a randomized phase III trial that compared lenalidomide and standard-dose dexamethasone (40 mg for 4 consecutive days with 4 days rest for 28 days)

I’ve always chosen to live my life as if I didn’t have cancer. I just face forward and try to do everything I want to do, working around symptoms and treatment side effects.

—Michael S. Katz, MBA

Going for the Cure.2 Dr. Thompson provided Mr. Katz with basic information on myeloma that helped him reach a decision on how to treat serious bone lesions.

“The impact of talking with Dr. Thompson was so powerful and I felt so grateful, it got me thinking that I could do the same for others,” said Mr. Katz.

Making a Difference After reaching out to Susie Novis, a cofounder and President of the International Myeloma Foundation (IMF), to see how he could help the organization, Mr. Katz offered to set up the IMF’s patient database and began speaking at the organization’s Patient & Family Seminars, which led to one-on-one patient counseling. He also helped develop the IMF’s Myeloma Manager, which allows patients to track their laboratory results.

He is now an Executive Board Member of the IMF. It was his involvement in the IMF that led to his work as a patient advocate for the Eastern Cooperative Oncology Group (ECOG), where he was elected Chair of its Patient Representative Committee and was later made Chair of the Coalition of Cancer Cooperative Groups’ Patient Advisory Board.

Other influential positions followed, in-

and lenalidomide and low-dose dexamethasone (40 mg once every 7 days for 28 days) in newly diagnosed patients with multiple myeloma.

Based on his experience with lowerdose dexamethasone, which had been successful in keeping his myeloma from progressing, and the similar feedback he was getting from patients in the IMF’s support groups and on the listservs of the Association of Cancer Online Resources he was overseeing, Mr. Katz convinced the Chair of the ECOG Myeloma Committee to launch a comparison of the low- and standarddose dexamethasone and lenalidomide regimens.

Because a clear survival advantage was found in the lower-dose dexamethasone arm (96% of patients in the low-dose arm were alive at 1 year vs 87% for those on the standard dose), the trial was halted early. Although the clinical trial tested the lower-dose regimen in the upfront setting, the study’s results led to a change in the standard of care for the use of dexamethasone in all disease stages and in virtually all dexamethasone-containing combination drug regimens.

“E4A03 was a huge win and significantly reduced early deaths and steroid toxicities [in patients with

myeloma],” said Mr. Katz.

Mr. Katz was also instrumental in raising awareness of bisphosphonaterelated osteonecrosis of the jaw, a rare but serious condition that has been linked to the use of pamidronate (Aredia) and zolendronic acid. In 2004, after the IMF received numerous reports from myeloma patients of osteonecrosis of the jaw and tooth loss after taking bisphosphonates, the organization conducted a Web-based survey to assess the risk factors involved.

According to the published results,4 over 1,200 people responded to the survey—904 with myeloma and 299 with breast cancer. The findings showed that 152 of the patients had either osteonecrosis of the jaw or suspicious findings.

Of the patients with myeloma, 71% had received zoledronic acid and 29% had received only pamidronate.

In 2007, in response to concern over bisphosphonate-related side effects, ASCO updated its clinical practice guideline on bisphosphonate treatment for multiple myeloma5 to include a discussion of osteonecrosis of the jaw, recommending that most patients receive bisphosphonate treatment for no longer than 2 years.

Rewarding Patient Advocacy During the 2014 ASCO Annual Meeting, Mr. Katz was recognized for his advocacy with ASCO’s Partners in Progress Award, which honors individuals who have made valuable contributions in cancer awareness and public advocacy.

“The news of the award came out of the blue and I was shocked,” said Mr. Katz. “I have ‘broken a lot of china’ in my public policy work, being very vocal in public forums about the lack of discipline evident in some of the regulation and management of research and clinical trials, so I wasn’t expecting this kind of recognition. It means a lot to me to know that people appreciate what I do.”

In addition to his advocacy work, Mr. Katz is also a lay leader of his synagogue and does volunteer work for Lifeline for the Old, an organization in Israel that provides employment and social services for the elderly.

Facing the Future Controlling his myeloma has become more challenging in recent years, and Mr. Katz is now dependent on a

ASCOPost.com | AUGUST 15, 2014

PAGE 145

Advocates in Oncology mobility scooter to get around. Nevertheless, he remains confident the continued advancements in myeloma treatment will keep his cancer manageable for years to come.

Although now retired from his consulting career, Mr. Katz shows no signs of slowing down on his cancer advocacy work. That work now includes serving as a reviewer of federal- and state-funded research grant programs supporting a spectrum of cancers and developing a methodology for measuring the accrual performance of underrepresented minorities in publicly funded clinical trials.

“I’ve always chosen to live my life as if I didn’t have cancer. I just face forward and try to do everything I want to do, working around symptoms and treatment side effects,” said Mr. Katz. “I’ve been a patient for so long, I’m much

Contact

The ASCO Post

better now at managing those things.” n

Disclosure: Dr. Katz reported no potential conflicts of interest.

References 1. Bensinger WI: Is there still a role for allogeneic stem-cell transplantation in multiple myeloma? Best Pract Res Clin Haematol December 20:783-795, 2007.

2. Thompson FM: Going for the Cure.

New York, St. Martins Press, 1989.

3. Rajkumar SV, Jacobus S, Callender N, et al: Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol

25(18S):Abstract LBA8025, 2007.

4. Durie B, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99-102, 2005.

5. Kyle RA, Yee GC, Somerfield MR, et al: American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 25:2464-2472, 2007.

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PAGE 146

Issues in Oncology Who Will Care for Patients? continued from page 1

by population growth, an aging population, and health insurance expansion will drive the demand for additional primary care physicians to a staggering 52,000 by 2025. In addition, the already significant shortage of nurses in the United States is expected to top 1 million in just the next 5 years.3 The impending increasing demand for oncology services—by 2030, the number of new cancer cases will rise by 45% to 2.3 million a year, and by 2022, the number of cancer survivors, now at 14 million, will grow to 18 million4— coupled with the looming shortfall of oncologists as well as specialists from other medical disciplines raises the unsettling question: Who will take care of people will cancer?

Finding Solutions “That is the key question, and the medical community at large has to figure out a solution to this issue,” said Richard L. Schilsky, MD, FACP, ­FASCO, Chief Medical Officer of ASCO. “What can we do? There are really only two kinds of solutions that can be pursued. One is hiring and using advanced practice providers in our offices and clinics. We need help to train these professionals in the practice of oncology, and it is ASCO’s responsibility to work with the professional societies that support advanced practice providers to provide a training program and curricula so they are well trained in the needs of cancer patients. And the other solution is to encourage more doctors to enter the field of oncology.”

To provide advanced practice providers with the educational resources necessary to meet the increasing demand for team-based oncology care and help mitigate the shortage of oncologists, ASCO University ® issued ASCO’s Curricula for Advanced Practice Providers (ACAPP ™) in 2013 and updated the program’s courses earlier this year.5 The program also includes an important module for oncologists on teambased care. ASCO is also working with medical schools to help them develop comprehensive curricula in cancer care.

“We had a meeting with the deans of medical education at many of the medical schools as well as with the Association of American Medical Colleges to explore the idea of working together to develop a better, more comprehensive, and more organized cancer curriculum, and they were receptive to the idea,” said Dr. Schilsky.

“We are optimistic that we will be

able to continue to work with them to achieve that goal,” he continued. “We hope working with the medical schools this way will expose more medical students to patients with cancer during the course of their training and perhaps stimulate their interest in pursuing careers in oncology.”

Bridging the Knowledge Gap According to Dr. Schilsky, ASCO is also reaching out to other medical societies to encourage the development of continuing education programs on the specific needs of patients with cancer to provide primary care physicians and specialists from various medical disciplines with the knowledge to better manage the health care of cancer survivors. This effort may help reverse findings showing that many internists feel ill-equipped to care for cancer survivors.

In a survey of 1,100 general internists across the United States to determine their attitudes and knowledge

follow-up program, or another primary care physician. A large majority (72%) of survey participants said they had never received a survivorship care treatment summary—perhaps a contributing factor to their discomfort level.

“General internists are very thoughtful and knowledgeable about medicine, but I don’t think we are given the proper education, either in medical school or during residency, to learn about cancer survivorship care or the late effects from treatment,” said Eugene Suh, MD, first author of the study and Assistant Professor in the Division of Pediatric Hematology & Oncology at Loyola University Chicago Stritch School of Medicine. “In terms of the resources [internists] are provided, it is partly our fault as oncologists for not consistently providing the proper guidelines [for survivorship care] or the proper communication.”

Dr. Schilsky agrees. “We have an obligation as oncologists to complete and provide treatment summary survivor-

Many of the newer therapeutics are oral medications that patients can self-administer at home, so that means less demand on nursing time for the administration of therapy in an office practice or clinic.

—Michael P. Kosty, MD, FACP, FASCO

about the care of adult survivors of childhood cancer, on average, internists reported being “somewhat uncomfortable” caring for childhood cancer survivors and only 36.9%, 27%, and 25% of respondents said they were “somewhat comfortable” or “comfortable” caring for survivors of Hodgkin lymphoma, acute lymphoblastic leukemia, and osteosarcoma, respectively.6 Only 61 respondents said they preferred to care for childhood cancer survivors independently, with 84% preferring to work in collaboration with a cancer center–based physician or a long-term follow-up clinic. And 10.5% said they would refer survivors to a cancer center–based physician, long-term

Eugene Suh, MD

ship care plans to our patients so they can carry that information to their primary care physicians,” he said.

Following Survivors for Life Although every patient with cancer treated at the Greenville Health System’s Cancer Institute in Greenville, South Carolina, gets a survivorship care plan once treatment is completed, Medical Director W. Larry Gluck, MD, said it is the hospital’s intention to follow survivors for their “entire lifetime” to monitor long-term treatment side effects and the initiation of secondary cancers. The ongoing surveillance is among myriad services provided by the health system’s Center for Integrative Oncology and Survivorship, a patient-centered program Dr. Gluck launched in 2011 to integrate evidenced-based complementary therapies with traditional oncology care to meet the physical and psychosocial needs of cancer survivors.

“I tell all my patients that the cancer institute will follow them for life, and this notion is a paradigm shift for me,” said Dr. Gluck. “I saw patients returning

W. Larry Gluck, MD

to their primary care providers who had varying degrees of interest in their care.

Primary care physicians do not have the training to look for delayed side effects that are common with the complex therapies we deliver today, so it is incumbent upon oncologists to take care of any health issue that is cancerrelated. My philosophy is that we own that cancer for life.”

To ensure that the Cancer Institute is adequately staffed to manage the care of both newly diagnosed patients and long-term survivors, Dr. Gluck is using greater numbers of highly trained certified nurse practitioners and physician assistants to meet the demand of a more team-based model of oncology care.

He is also working with local universities and medical schools on building comprehensive oncology curricula to increase the supply of oncologists and advanced practice providers.

Improving Efficiency of Care The way cancer therapies are delivered in the future may also help offset the projected oncology workforce shortage. “Many of the newer therapeutics are oral medications that patients can self-administer at home, so that means less demand on nursing time for the administration of therapy in an office practice or clinic,” said Michael P. Kosty, MD, FACP, FASCO, a member of ASCO’s Workforce Advisory Group and Director of the Scripps Green Cancer Center in La Jolla, California.

“Certainly, physicians and nurses are needed to manage treatment toxicities,” he said. “But the increasing development of oral agents was something we couldn’t have predicted 5 years ago when we started examining the workforce shortage issue.”

Striking a Geographic Balance Perhaps an even more challenging problem to solve than the overall shortage of medical oncologists to preserve access to quality care is the imbalance in the geographic distribution of absolute numbers of oncologists throughout the country. According to ASCO’s report, The State of Cancer Care in America: 2014, nearly 97% of oncologists prac-

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Issues in Oncology

tice in urban areas of the country and about 3% practice in rural regions,4 where the U.S. Census Bureau estimates 20% of Americans live. The report also noted that more than 70% (2,067) of the U.S. counties ASCO analyzed had no medical oncologists at all.

“The real threat to access to care is the dwindling numbers of oncology practices in smaller communities,” said Dr. Schilsky.

2. Petterson SM, Liaw WR, Phillips RL, et al: Projecting US primary care physician workforce needs: 2010-2025. Ann Fam Med 10:503-509, 2012.

3. Health Resources and Services Administration: What is behind HRSA’s projected supply, demand, and shortage of registered nurses? Rockville, Maryland; U.S. Department of Health and Hu-

man Services, 2006.

4. American Society of Clinical Oncology: State of Cancer Care in America: 2014. Available at www.asco.org/practiceresearch/cancer-care-america. Accessed July 28, 2014.

5. American Society of Clinical Oncology: ASCO University®’s 2014 Curricula for Advanced Practice Practitioners

(ACAPP ™). ASCO Daily News, May 30, 2014. Available at am.asco.org/asco-university’s-2014-curricula-advanced-practiceproviders-acapp. Accessed July 28, 2014.

6. Suh E, Daugherty CK, Wroblewski K, et al: General internists’ preferences and knowledge about the care of adult survivors of childhood cancer: A cross-sectional survey. Ann Intern Med 160:11-17, 2014.

Leveraging Available Interventions Since the causes of the projected oncology workforce shortage are many (including changes in physician retirement rates—in 2008, the proportion of oncologists 64 years of age and older surpassed the proportion under 40 years of age for the first time4—and physician burnout), it will take a multifaceted approach to solve the problem, said Dr. Schilsky.

“This is a complicated issue from so many angles, and the problem is not going to be solved by ASCO alone. It is going to be solved by ASCO working in concert with the whole medical community, because at some point every doctor will come in contact with a cancer survivor in his or her practice,” said Dr. Schilsky.

He continued, “We will need to have better communication among all medical professionals and the development of a comprehensive, interconnected, interoperable electronic medical record system to ensure that wherever a cancer survivor goes for care, the physician will have complete details of that patient’s cancer and its treatment.”

By leveraging myriad interventions, including expanding the use of advanced practitioners in oncology practices and clinics, encouraging more medical students to specialize in oncology, collaborating with primary care physicians for the coordination of care of patients with cancer, monitoring and developing strategies for preventing physician burnout, and utilizing big data technology to advance quality of care, it will be possible to ensure that the growing numbers of patients with cancer and long-term survivors receive the care they need from qualified and knowledgeable providers, said Dr. Schilsky. n

Disclosure: Dr. Schilsky reported no potential conflicts of interest.

References 1. Yang W, Williams JH, Hogan PF, et al: Projected supply of and demand for oncologists and radiation oncologists through 2025: An aging, better-insured population will result in shortage. J Oncol Pract 10:39-45, 2014.

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The ASCO Post | AUGUST 15, 2014

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News

Surgeon General Call to Action to Prevent Skin Cancer

O

n July 29, 2014, the Surgeon General issued a Call to Action urging immediate action steps to prevent skin cancer.

The report encourages increased awareness of the disease and calls for immediate and collaborative actions to reduce its risk.

Nearly 5 million people are treated for skin cancer in the United States each year, estimated to cost $8.1 billion annually. According to the report, the rates of skin cancer continue to increase in the United States and worldwide de-

deadly,” writes Howard K. Koh, MD, MPH, Assistant Secretary for Health.

The report emphasizes universal susceptibility to the disease, encouraging all to understand and implement strategies to reduce risk. More than 400,000 cases of skin cancer, 6,000 of which are melanomas, are estimated to be related to indoor tanning in the United States each year.

“It’s important to shatter the myth that tanned skin is a sign of health…

Tanned skin is damaged skin. Understanding the risk of UV exposure is crucial to protecting ourselves and our loved ones,” Dr. Koh said. The report provides a series of comprehensive action steps to increase awareness of the disease and its risk factors.

Partners in Prevention From All Sectors Howard K. Koh, MD, MPH

spite efforts to address risk factors such as inadequate protection from the sun and intentional tanning behaviors. More than 63,000 new cases of melanoma, the deadliest form of skin cancer and the most common type of cancer among U.S. teens and young adults, are diagnosed in the United States each year.1 “While those with lighter skin are more susceptible, anyone can get skin cancer—and it can be serious, even

Furthermore, the Call to Action urges partners in prevention from all sectors across the United States, including the business, health care, education, government and nonprofit sectors in addition to families and individuals, to address skin cancer as a major public health problem and to do more to prevent the disease.

“As both a medical doctor and a public health official, I see that now is the time for a comprehensive approach to prevent skin cancer, bringing together community partners, business leaders, government agen-

As both a medical doctor and a public health official, I see that now is the time for a comprehensive approach to prevent skin cancer, bringing together community partners, business leaders, government agencies, and individuals for a common cause.

—Boris D. Lushniak, MD, MPH, Acting Surgeon General

cies, and individuals for a common cause,” said Boris D. Lushniak, MD, MPH, Rear Admiral of the U.S. Public Health Service and Acting Surgeon General.

The report recommends, for instance, that communities provide shade in recreational and play areas, that businesses increase availability of sun protection to outdoor works, that policy makers promote policies for shade planning in land use development, and that health providers counsel patients on the importance of using sun protection.

effects of exposure from the sun and from indoor tanning. According to the Statement, consumers today can rely on more accurate information on the labels of all sunscreen products on the market, particularly in claims regarding “Broad Spectrum” and resistance to water. Furthermore, the FDA recently changed its risk classification for sunlamp products, and imposed increased regulatory controls on these products including age restrictions and boxed warnings. See the full text of this statement below. n

FDA Weighs In

Reference 1. U.S. Department of Health and Human Services. The Surgeon General’s Call to Action to Prevent Skin Cancer. Washington, DC: U.S. Department of Health and Human Services, Office of the Surgeon General, 2014.

In response, FDA Commissioner Margaret A. Hamburg, MD, issued a statement regarding recent steps taken by the FDA designed to allow consumers to better understand the harmful

FDA Commissioner Margaret A. Hamburg’s Statement on the Surgeon General’s Call to Action to Prevent Skin Cancer Statement issued by the Food and Drug Administration, July 29, 2014

Margaret A. Hamburg, MD

E

ach year, thousands of Americans are diagnosed with some form of skin cancer. The Surgeon General’s Call to Action to prevent skin cancer is important especially during these hot summer months when many of us spend extra time in the sun.

Over the last few years, the FDA has taken a number of important steps designed to help consumers better understand the harmful effects of exposure from the sun and from indoor tanning.

Today, consumers going to a beach or pool can rely on more accurate information on the labels of all sunscreen products on the market.

In 2011, the FDA made changes that help consumers buy and use sunscreen. Consumers now see accurate labels that may include “Broad Spectrum” claims and water resistance claims (how long a sunscreen remains effective while swimming or sweating).

Earlier this year, the agency

changed its risk classification for sunlamp products (eg, tanning beds, tanning booths), imposing increased regulatory controls on these products. The products now must be labeled with boxed warnings stating that they should not be used on anyone younger than 18 years, and specific contraindications and warnings must be included in certain promotional materials for these products.

These were important actions and steps that the FDA hopes will help address the harmful effects of the sun and UV radiation exposure.

• Spending time in the sun increases a person’s risk of skin cancer and early skin aging. To reduce these

risks, the FDA encourages consumers to take an active role in sun safety and understand how to responsibly spend time in the sun.

Consumers should use a Broad Spectrum sunscreen with an SPF value of 15 or higher in combination with other protective measures. Find more sun safety tips here: http://www.fda.gov/drugs/ resourcesfor you/consumers/ buyingusingmedicinesafely/understandingover-the-countermedicines/ucm239463.htm • There are risks associated with sunlamp product use. More information can be found here http://www. fda.gov/ForConsumers/ConsumerUpdates/ucm350790.htm n

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Lab Notes

Ongoing Molecular Research in the Science of Oncology TARGETED THERAPY Spleen Tyrosine Kinase Inhibition Has Promise in High-Risk Precursor B-Cell ALL In a study reported in Science Translational Medicine, Perova and colleagues found that pre–B-cell receptor–independent spleen tyrosine kinase signaling was necessary for leukemic B-cell survival and proliferation in a mouse model. Investigation of samples from pediatric and adult B-cell acute lymphoblastic leukemia (ALL) showed that spleen tyrosine kinase and downstream targets were phosphorylated independently of pre–B-cell receptor expression or genetic subtype.

Studies with two small-molecule spleen tyrosine kinase inhibitors showed reduced growth in vitro of B-cell ALL subtypes, including high-risk subtypes. Treatment of immunodeficient mice with one of the inhibitors reduced disease burden in high-risk B-cell ALL xenografts and decreased dissemination of leukemia into the spleen, liver, kidney, and central nervous system.

The investigators concluded, “[Spleen tyrosine kinase] activation sustains the growth of multiple [high-risk] B-ALL subtypes, suggesting that [spleen tyrosine kinase] inhibitors may improve outcomes for [high-risk] and relapsed B-ALL.” Perova T, et al: Sci Transl Med 6:236ra62, 2014.

ONCOGENESIS BRCA2 Inhibits Genome Instability by Preventing R-Loop Accumulation Genome instability and DNA damage in cancer can be induced by mutations in genes involved in pre-mRNA splicing and biogenesis and export of messenger ribonucleoprotein (mRNP).

Instability can be mediated by R-loops formed by DNA-RNA hybrids and displaced single-stranded DNA. The TREX-2 complex is involved in mRNP biogenesis and export. In a study reported in Nature, Bhatia and colleagues found that the TREX-2 complex acts to prevent genome instability as shown by accumulation of γ-H2AX and 53BP1 foci as well as by single-cell electrophoresis in cells depleted of the TREX-2 subunits

PCID2, GANP, and DSS1.

The investigators showed that BRCA2 repair factor binds to DSS1 and also associates with PCID2 within cells.

Whereas R-loops were not detected in TREX-2–depleted cells, they were observed to accumulate in BRCA2-depleted cells. The findings indicate both that R-loops are frequently formed in cells and that BRCA2 is required for their processing.

The investigators concluded, “This link between BRCA2 and RNA-mediated genome instability indicates that R-loops may be a chief source of replication stress and cancer-associated instability.”

Bhatia V, et al: Nature 511:362-365, 2014.

NOVEL STRATEGIES Prolyl Hydroxylase Inhibition Protects Against Gastrointestinal Radiation Toxicity In a study reported in Science Translational Medicine, Taniguchi and colleagues found that inhibition of prolyl hydroxylase by genetic knockout or inhibition of all prolyl hydroxylase domain isoforms by the small-molecule dimethyloxallyl glycine (DMOG) resulted in promotion of protection against radiationinduced gastrointestinal toxicity. The protective effects observed in animal models included increased hypoxiainducible factor (HIF) expression, improved epithelial integrity, reduced apoptosis, and increased intestinal angiogenesis.

It was shown that HIF2 but not HIF1 is both necessary and sufficient to prevent radiation-induced gastrointestinal toxicity and death. Increased vascular endothelial growth factor (VEGF) expression was found to contribute to the protective effects of HIF2, with VEGF inhibition reversing the protective effects induced by DMOG. Mortality from abdominal or total body irradiation was reduced even when DMOG was given 24 hours after exposure.

The investigators concluded, “[P] rolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate [gastrointestinal] toxicity from both therapeutic radiation and potentially lethal radiation exposures.”

Taniguchi CM, et al: Sci Transl Med 6:236ra64, 2014.

FBXW7 as Tumor Suppressor and NOTCH1 Inhibition as Potential Strategy in Melanoma In a study reported in the Journal of the National Cancer Institute, Aydin and colleagues found that mutation in and inactivation of FBXW7 and accumulation of NOTCH1, a substrate of FBXW7, were associated with melanoma tumorigenesis.

FBXW7 was found to be mutated in 8% of 103 melanoma patients, and protein expression analysis in 96 human tissue samples and 20 melanoma cell lines showed that FBXW7 inactivation was a common event (40% of cell lines). FBXW7 loss was associated with accumulation of NOTCH1 and other substrates.

Tumor formation in vivo was increased 2.4-fold with ectopic expression of mutant forms of FBXW7 and 3.9-fold with silencing of FBXW7 in immortalized melanocytes. Inactivation of FBXW7 resulted in NOTCH1 activation, a 2.6-fold upregulation of NOTCH1 target genes, and increased tumor angiogenesis. NOTCH1 inhibition resulted in a 5-fold increase in tumor shrinkage.

The investigators concluded, “Our data provides evidence on FBXW7 as a critical tumor suppressor mutated and inactivated in melanoma that results in sustained NOTCH1 activation and renders NOTCH signaling inhibition as a promising therapeutic strategy in this setting.”

Aydin IT, et al: J Natl Cancer Inst 106:dju107, 2014.

Mesenchymal Stem Cells With Oncolytic HSV Variants Promising in Glioblastoma Multiforme Although oncolytic herpes simplex virus (HSV) has been found to be safe in clinical trials in malignant glioblastoma multiforme, its efficacy is limited by insufficient viral spread after tumor resection. In a study reported in the Journal of the National Cancer Institute, Duebgen and colleagues showed that loading of human mesenchymal stem cells with multimechanistic oncolytic HSV variants represents a promising approach in treatment of glioblastoma multiforme.

Mesenchymal stem cell–oncolytic HSVs successfully produced oncolytic HSV progeny, resulting in killing of

glioblastoma multiforme cells in vitro and in vivo. Mesenchymal stem cell– oncolytic HSVs encapsulated in biocompatible synthetic extracellular matrix produced a significant increase in anti–glioblastoma multiforme efficacy compared with direct injection of purified oncolytic HSV in a mouse model of glioblastoma multiforme resection, resulting in prolonged median survival (P < .001). In a model of resistant tumors, mesenchymal stem cells loaded with the proapoptotic variant oncolytic HSV–TRAIL induced apoptosis-mediated killing and prolonged median survival in mice with oncolytic HSV– and TRAIL-resistant glioblastoma multiforme (P < .001).

The investigators concluded, “Human [mesenchymal stem cells] loaded with different [oncolytic] HSV variants provide a platform to translate oncolytic virus therapies to clinics in a broad spectrum of [glioblastoma multiforme] after resection and could also have direct implications in different cancer types.”

Duebgen M, et al: J Natl Cancer Inst 106:dju090, 2014.

OUTCOME PREDICTORS Mutations in IGF Pathway Genes Associated With Prostate Cancer Mortality In a study reported in the Journal of the National Cancer Institute, Cao and colleagues identified mutations in insulin-like growth factor (IGF) pathway genes that were significantly associated with mortality in prostate cancer.

Analysis of 530 single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes in 5,887 European-ancestry prostate cancer patients, including 704 who died from the disease, showed that mutations in the IGF signaling pathway overall were significantly associated with prostate cancer mortality (P = .03), with mutation in IGF2-AS and SSTR2 being the main contributors to the association (both P = .04).

In SNP-specific analysis, 36 SNPs were associated with prostate cancer mortality (P < .05 for trend). However, only three SNPs in IGF2-AS remained significant after gene-based corrections; two were in linkage disequilibrium (rs1004446 and rs3741211) and one (rs4366464) was independent.

The hazard ratios per each additional

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Lab Notes

risk allele were 1.19 (P = .003 for trend) for rs3741211 and 1.44 (P < .001 for trend) for rs4366464, with the effect of rs4366464 remaining significant after correction for all SNPs (P = .04 for trend). In 2,424 patients, including 313 who died, prediagnostic circulating IGF1 and IGFBP3 levels were not significantly associated with mortality.

The investigators concluded, “The IGF signaling pathway, primarily IGF2AS and SSTR2 genes, may be important in [prostate cancer] survival.”

Cao Y, et al: J Natl Cancer Inst 106:dju085, 2014.

TUMOR MICROENVIRONMENT Melanoma Metastases Exhibit Site-Specific Antigen Heterogeneity Correlating With T-Cell Infiltration In a study reported in Clinical Cancer Research, Bartlett and colleagues found that melanoma metastases exhibit sitespecific antigen heterogeneity that correlates with T-cell infiltration.

A total of 3,086 metastatic tumors involving various anatomic sites were assessed for a panel of melanocyte differentiation antigens, which revealed a site-specific pattern of antigen expression that was highest in the brain, intermediate in soft tissues/lymph nodes, and lowest in visceral metastases. Hierarchical clustering analysis supported the finding of a phylogenetically determined pattern of antigen expression varying by anatomic site of the metastases. Expression of the melanocyte differentiation antigen tyrosinase was more frequently lost in metastatic sites other than the brain and was correlated with endogenous CD8-positive and CD4-positive T-cell infiltrates.

The investigators concluded, “Sitespecific antigen heterogeneity rep-

resents a novel attribute for human melanoma metastases that should be considered in future therapy development and when assessing the responsiveness to antigen-specific immunotherapies.”

Bartlett EK, et al: Clin Cancer Res 20:2607-2616, 2014.

BIOMARKERS Plasma Tumor DNA Detectable Before and After Surgery in Patients with Early-Stage Breast Cancer Detecting circulating plasma tumor DNA in patients with early-stage cancer has the potential to influence selection of adjuvant systemic therapy. In a study reported in Clinical Cancer Research, Beaver and colleagues found that plasma tumor DNA could be detected both before and after surgery in patients with early-stage breast cancer.

Sanger sequencing of 30 tumors from 29 patients for PIK3CA mutations tumors identified 7 exon 20 and 3 exon 9 mutations. Analysis of tumors by droplet digital polymerase chain reaction, a new sensitive and specific method for mutation detection, confirmed these mutations and identified 5 additional mutations.

Droplet digital polymerase chain reaction analysis of presurgery plasma samples from the 29 patients identified 14 of the 15 PIK3CA mutations detected in the tumors, with no mutations being found in plasma from patients with PIK3CA wild-type tumors (sensitivity = 93.3%, specificity = 100%).

Analysis of postsurgery plasma from 10 patients with presurgery mutationpositive plasma tumor DNA showed that 5 still had detectable plasma tumor DNA. The investigators concluded, “This prospective study demonstrates accu-

rate mutation detection in tumor tissues using [droplet digital polymerase chain reaction], and that [plasma tumor DNA] can be detected in blood before and after surgery in patients with earlystage breast cancer. Future studies can now address whether [plasma tumor DNA] detected after surgery identifies patients at risk for recurrence, which could guide chemotherapy decisions for individual patients.”

Beaver JA, et al: Clin Cancer Res 20:2643-2650, 2014.

MECHANISMS OF ACTION IGF-2/IGF-1R Inhibition Shows Promise in Esophageal Cancer In a study reported in Clinical Cancer Research, Li and colleagues found that overexpression of Id1 protein resulted in insulin-like growth factor (IGF)-2 production, which, in turn, resulted in esophageal cancer cell proliferation, survival, and invasion via autocrine activation of AKT. Overexpression of IGF-2 was identified in 60% of tumor samples from patients with esophageal cancer and was associated with upregulation of Id1 and phosphorylated AKT. In Id1-overexpressing xenografts, secreted IGF-2 promoted growth of distant esophageal tumors and metastasis of circulating cancer cells.

Intratumoral injection of IGF-2 antibody and intraperitoneal injection of the IGF-1 receptor (IGF-1R) antibody cixutumumab resulted in significant suppression of tumor growth and metastasis in mice. Further, cixutumumab increased the sensitivity of tumor xenografts to fluorouracil and cisplatin.

The investigators concluded, “The Id1–[IGF-2–IGF-1R]–AKT signaling cascade plays an important role in esophageal cancer progression. Block-

ade of [IGF-2/IGF1R] signaling has therapeutic potential in the management of esophageal cancer.”

Li B, et al: Clin Cancer Res 20:26512662, 2014.

CANCER PROMOTERS Centrosome Amplification Promotes Cellular Invasion in Mammary Epithelial Cells Centrosomes, the primary microtubule organizing centers within cells, are commonly amplified in tumors, but the role of centrosome amplification in tumorigenesis is unclear. Centrosome amplification is not favored in nontransformed cells, with extra centrosomes being spontaneously lost in the absence of selection pressure. It is thus possible that extra centrosomes confer cellular alterations advantageous to tumor progression.

In a study reported in Nature, Godinho and colleagues showed that centrosome amplification induced cell invasion in human mammary epithelial cells. They found that the invasiveness was similar to that induced by ERBB2 and that amplification resulted in enhanced ERBB2-related invasiveness.

Overall, the findings suggested that centrosome amplification increases Rac1 activity via increased centrosome microtubule nucleation, resulting in abnormal cell-cell adhesion that promotes invasion.

The investigators concluded, “These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.”

Godinho SA, et al: Nature 510:167171, 2014.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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Now FDA Approved For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed after prior fluoropyrimidine- or platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo.

Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred

in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery.

Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly improved progression-free survival (PFS)1 MAJOR OUTCOME MEASURE

OS PROBABILITY

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)1 1.0

CYRAMZA

Placebo

0.8

months

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.6

The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. Major efficacy outcome measure was overall survival. Supportive efficacy outcome measure was progression-free survival. All patients were ECOG PS 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy. Patients were randomized 2:1 to CYRAMZA 8 mg/kg q2w + BSC (n=238) or placebo + BSC (n=117).1

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

1

2

3

238 117

5

6

7

8

9

10 11 12 13

14 15 16 17 18 19

20

26

27

28

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

4

154 66

92 34

49 20

17 7

7 4

3 2

37%

• Median PFS with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1

CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; PS=performance status; BSC=best supportive care.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%).

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

• The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

• As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZA-treated patients with post-baseline serum samples tested positive for antiramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting antiramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

• Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page.

RB HCP ISI 21APR2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

RB89001 05/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. CYRAMZA™ is a trademark of Eli Lilly and Company.

Visit CYRAMZANowApproved.com

CYRAMZATM (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

INDICATIONS AND USAGE CYRAMZA as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single-agent in clinical trials experienced gastrointestinal perforation.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 a (MedDRA) All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates.

Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single-agent.

Geriatric Use Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over.

Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab.

Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab.

Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility.

Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes.

Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Of increased risk of an arterial thromboembolic event.

• To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

Additional information can be found at www.CYRAMZAhcp.com.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZAtreated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal drug interaction studies have been conducted.

TM

CYRAMZA (ramucirumab) injection

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2014, Eli Lilly and Company. All rights reserved.

RB HCP BS 21APR2014

PA000IPAM00 – BS 9.25x13.25

CYRAMZATM (ramucirumab) injection

PA000IPAM00 – BS 9.25x13.25

ASCOPost.com | AUGUST 15, 2014

PAGE 155

MASCC/ISOO International Symposium Supportive Care

Dignity, Personhood, and the Culture of Medicine

By Meg Barbor

C

T:14 in

B:14.25 in

S:13 in

ancer patients need more than good health care: they need health caring, according to palliative care specialist Harvey M. Chochinov, MD, PhD, Distinguished Professor of Psychiatry at the University of Manitoba and Director of the Manitoba Palliative Care Research Unit, CancerCare Manitoba.

Health care pertains to cognition, knowledge, technical procedures, and prowess, whereas health caring pertains to things that are going to cause patient satisfaction or dissatisfaction, explained Dr. Chochinov during the Plenary Session at the 2014 Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology (MASCC/ISOO) Symposium, held recently in Miami.

“We have a system designed to provide health care as distinct from a system that is about health caring,” he said. “Like our patients, we need to see ourselves as vulnerable.... There is very little that separates us from our patients other than time and luck…. And if we can see ourselves in that way, we are more likely to be able to practice caring and compassionate medicine,” he suggested.

The idea of health caring is the gateway to disclosure. When patients feel that caring is present and that they matter as a whole person, they’re much more likely to be forthcoming with their physicians. This disclosure leads to greater honesty and a greater likelihood that treatment plans will be consistent with patients’ goals of care, he said.

The Dignity Model Dr. Chochinov and colleagues published a study in 2006 that examined dignity in the terminally ill in a population of 211 patients with endstage cancer and less than a 6-month life expectancy.1 Patients were given a list of variables and asked which issues would have an influence on their

sense of dignity. For nearly 75%, “no longer feeling like who you were” was found to be a profound dignityrelated and existential issue.

“The psychology of illness is the psychology of loss,” he explained. “When you’re a little ill, you encounter inconvenience or annoyance. When you’re very ill, you start to lose your sense of self, your sense of person. There’s a notion of no longer feeling like who you were.”

Other important issues cited by patients and associated with sense

that patients figuratively look into the eyes of health-care providers for a reflection that will either affirm or disaffirm their sense of person.

“If they only see their illness, they feel that they have been reduced to their ailment and nothing else has registered. On the other hand, if they see that the reflection in the eye of the beholder is one that contains a picture of the entire person—not just the patient—they feel affirmed,” he suggested.

We need to understand that like our patients, we too are vulnerable.... If we can see ourselves in that way, we are more likely to be able to practice caring and compassionate medicine.

—Harvey M. Chochinov, MD, PhD

of dignity were “feeling a burden to others” and “not being treated with respect or understanding.”

Respect and Understanding “We need to think of ourselves as people who are in a position to provide affirmation. That’s not a word frequently used in health care, but it’s an important word,” he emphasized.

“The irony is that we spend our entire professional lives studying how to look after patients, when the reality is that no one wants to feel like just a patient,” he said. The issue of affirmation is the ability to see patients as whole human beings. The notion of respect is something that clinicians can provide or withhold, he added.

Ten years ago, in an article titled “Dignity and the Eye of the Beholder,” Dr. Chochinov explored the notion of how patients perceive themselves as seen by others.2 He asserted

Patient Dignity Question Seeing patients in a way that affirms their dignity and personhood is of utmost importance. According to Dr. Chochinov, the easiest and most straightforward way to put personhood on the clinical radar is to ask patients, “What should I know about you as a person to help me take the best care of you that I can?” Dr. Chochinov and colleagues coined this the Patient Dignity Question, or PDQ, due to the positive correlation between affirming personhood and preserving dignity.

Dr. Chochinov and colleagues examined the importance and significance of this question to patients, family members, and health-care providers in a study.3 They found that nearly all patients wanted their answers to the Patient Dignity Question to be included on their charts, and in many cases they wanted copies for themselves or family members. Nearly

all participants felt their answers had been accurately represented, deemed this information important for healthcare providers, thought this information could affect their health care, and would recommend use of the Patient Dignity Question for other patients and families.

When health-care providers were asked about the influence of the information gathered from the Patient Dignity Question, the vast majority said they had learned something new about their patients. Over half said they were emotionally affected by the information and felt it had changed their attitude. The majority said it had influenced their care or sense of respect, empathy, and their sense of connectedness with that individual.

In general, female practitioners were more likely to be responsive to issues surrounding personhood than their male counterparts. Additionally, health-care providers with the most experience were most likely to be open to issues of personhood, followed by those with no experience at all.

“This is likely due to the fact that those with the most experience know the importance of personhood,” Dr. Chochinov suggested, “and those with no experience—students—had the humility to know how little they actually knew.” n Disclosure: Dr. Chochinov reported no potential conflicts of interest.

References 1. Chochinov HM, Krisjanson LJ, Hack TF, et al: Dignity in the terminally ill: Revisited. J Palliat Med 9:666-672, 2006.

2. Chochinov HM: Dignity and the eye of the beholder. J Clin Oncol 22:13361340, 2004.

3. Chochinov HM, McClement S, Hack T, et al: Eliciting personhood within clinical practice: Effects on patients, families and healthcare providers. Under review.

For more from the Multinational Association of Supportive Care in Cancer, see pages 23, 26–29 in this issue of The ASCO Post.

The ASCO Post | AUGUST 15, 2014

PAGE 156

In the News Genitourinary Oncology

‘Reasonable’ to Advise Men Who Have Had Vasectomies That They Have a Small Increased Risk for Lethal Prostate Cancers

By Charlotte Bath

L

ong-term results from the Health Professionals Follow-up Health Study have shown a 20% increased risk of advanced prostate cancer and a 19% increased risk of lethal prostate cancer among men who had vasectomies.1 According to the study’s lead author, Mohummad Minhaj Siddiqui, MD, it is “reasonable” to advise men of the asso-

Major Study Findings The findings, published ahead of print online by the Journal of Clinical Oncology,1 involved 49,405 men in the Health Professionals Follow-up Study who were aged 40 to 75 years old at baseline in 1986 and were followed for up to 24 years. The vasectomy status of the men was updated every 2 years,

The risk [of lethal prostate cancer associated with vasectomy] is pretty small in the grand scheme of things….

Having that discussion [with concerned patients] is probably good, but only in the context of the magnitude of the risk that is discussed.

—Mohummad Minhaj Siddiqui, MD

ciation between vasectomy and prostate cancer, but that should be in the context of their overall risk.

“The thing to keep in mind,” Dr. Siddiqui said in an interview with The ASCO Post, “is that although there is an increase of 10% in overall prostate cancer risk, and 19% in the lethal cancer subset, the absolute incidence of lethal prostate cancer within the overall population was relatively rare—1.6%. So if you have a 19% increase on 1.6%, that translates essentially to a 0.3% increase overall,” he explained.

“The risk is pretty small in the grand scheme of things,” he continued. “If a physician senses that some patients are really worried about prostate cancer, those patients may appreciate being advised that there is a small increased risk from vasectomy that may be present,” Dr. Siddiqui said. “Having that discussion is probably good, but only in the context of the magnitude of the risk that is discussed.”

Dr. Siddiqui is Director of Urologic Robotic Surgery, and Assistant Professor of Surgery-Urology, at the University of Maryland School of Medicine in Baltimore, although his work on the study was conducted while he was completing his residency training at Massachusetts General Hospital in Boston. The study coauthors are affiliated with Massachusetts General, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard School of Public Health, all in Boston.

and 12,321 men (25%) reported having vasectomies by the year 2000. During the study period, 6,023 men were diagnosed with prostate cancer, including 811 lethal prostate cancers.

Multivariate analysis showed a 10% increased risk of prostate cancer overall in men who had a vasectomy. Vasectomy was not significantly associated with risk of low-grade prostate cancer, but the procedure was associated with a 20% increased risk of advanced-stage prostate cancer and a 19% increased risk of lethal prostate cancer.

“We defined advanced prostate cancer as stage T3b, T4, N1, or M1 at diagnosis; development of lymph node or distant metastasis; or death as a result of prostate cancer before the end of follow-up. Lethal cancers, a subset of advanced cancers, were those that caused death or metastasis to bone or other organs before the end of follow-up,” the authors explained.

“There was a suggestion that the increased risk was more pronounced among men who were younger at the time of vasectomy,” the investigators reported, but “this pattern was not apparent when we examined age at vasectomy in quartiles,” they added.

“The relative risk seems slightly higher, but it is not statistically significant,” Dr. Siddiqui said. “That story seems to have picked up a little bit of traction, but I don’t think it is something to emphasize, and I think it is actually incor-

rectly being emphasized.”

An earlier 1993 report from the Health Professionals Follow-up Study also found an increased risk of prostate cancer in men with vasectomies, although it was based on only 300 new cases of the disease from 1986 to 1990 (age-adjusted relative risk = 1.66; 95% confidence interval = 1.25–2.21; P = .0004).2 The recently updated data include 19 additional years of follow-up.

Not Decision-Changing Dr. Siddiqui agreed with comments in some news reports that the study findings should not be considered practice-changing. A CBS News report quoted Louis R. Kavoussi, MD, Chairman of Urology at North Shore– LIJ Health System, New Hyde Park, New York, as saying, “I would be cautious about applying these findings to

Louis R. Kavoussi, MD

clinical practice right now. This is not like cigarette smoking causing a large number of people to develop lung cancer. This is a small increase in the risk of prostate cancer.”3 James M. McKiernan, MD, Interim Chairman of the Department of Urology at New York Presbyterian Hospital/ Columbia University Medical Center, commented in The New York Times,4 “If someone asked for a vasectomy, I would have to tell them that there is this new

The study authors concluded: “The decision to opt for a vasectomy remains a highly personal one in which the potential risks and benefits must be considered.” For men contemplating a vasectomy, it “would be reasonable,” to consider the association between vasectomy and prostate cancer as one of the many potential risks and benefits, Dr. Siddiqui told The ASCO Post, although it should also be noted that no biologic explanation for that association has yet been found.

Biologic Mechanisms “If we can figure out the biologic mechanisms” for the association between vasectomy and lethal prostate cancer, “that may actually have wider implications beyond vasectomy. The increased risk associated with vasectomy itself is probably modest and not decision-changing for most patients, although it may be for some,” Dr. Siddiqui added.

“We have been working on trying to see what kind of biologic explanations there might be. There are a lot of theories, but nothing has been proven,” Dr. Siddiqui stated. “Vasectomy leads to hormonal changes and changes in the contents of semen, such as different proteins that are present in the semen, and even immune changes in the body. It is feasible—and it has been shown in other studies—that these changes could be linked to prostate cancer pathogenesis, but it has not been definitively shown with vasectomy.”

As the study report states, “the challenge lies in the fact that there is usually a 20- to 30-year interval between vasectomy and detection of prostate cancer.”

The study group is continuing to look at the data and at underlying biologic reasons. “We have some good geneexpression data on subsets of patients, and we are trying to study differences in the different groups.” Dr. Siddiqui said

Impact of PSA Testing

James M. McKiernan, MD

data in this regard, but it’s not enough for me to change the standard of care.

I would not say that you should avoid vasectomy.”

The study report estimates that about 15% of men now get vasectomies, although the rate for the study population was 25%. Dr. Siddiqui said that the research team suspects the reason for the higher rate in the study population was that the men were all health professionals and relatively well off. “It continued on page 158

ENESTgoal

US treatment-free remission after switch to nilotinib on study

Evaluating Nilotinib Efficacy and Safety in Clinical Trials

A Phase II, randomized, multicenter study of treatment-free remission (TFR) in Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Philadelphia chromosome-positive CML-CP) patients who achieve and sustain molecular response (MR4.5) after switching to nilotinib ENESTgoal: Evaluating Nilotinib Efficacy and Safety in Clinical Trials—TFR in Ph+ CML-CP patients who switched from imatinib to nilotinib and achieved sustained MR4.5 while on nilotinib for 1 or 2 years Multicenter, open-label study of adult patients with Ph+ CML-CP with sustained MR4.5 after switching from imatinib to nilotinib

Monitoring Phase (2 years, n=300) Nilotinib 300 mg bid

• Monitor for confirmed MR4.5*

Consolidation Phase† (1 or 2 years, n=48 in each arm) • 1:1 randomization of patients to 1 or 2 years of sustained MR4.5

TFR Phase (3 years) • Stop nilotinib treatment after 1 or 2 years of sustained MR4.5 • Monitor for 3 years

*Patients who achieve MR4.5 will have the sample confirmed by a second sample drawn 4 weeks later.

Patients will be stratified based on the duration of imatinib treatment (<3 years vs ≥3 years).

†

Primary Endpoint • Molecular relapse–free rate at 6 months after stopping nilotinib treatment in patients with MR4.5 – Molecular relapse is defined as having a confirmed BCR-ABL1 ratio above MR4 (2 consecutive BCR-ABL1 levels >0.01% on the international scale [IS])

Secondary Endpoints • Relapse-free survival • Molecular relapse–free rates at 12 months, 18 months, and 36 months after stopping nilotinib treatment • Proportion of patients who achieve MR4.5 after restarting nilotinib following relapse • Proportion of patients who progress to accelerated phase (AP) or blast crisis (BC) CML, and number of CML-related deaths

Select Inclusion Criteria • Male or female patients ≥18 years of age with Ph+ CML-CP • Received imatinib for ≥1 year • BCR-ABL1 levels ≤0.1% IS (MR3) and >0.0032% IS (MR4.5) • Adequate end organ function

Select Exclusion Criteria • Prior imatinib failure, CML-AP, -BC, or allogeneic stem cell transplant • Previously documented T315I mutation • Prior attempt to permanently discontinue imatinib or nilotinib • Known impaired cardiac function

Currently Enrolling For more information about ENESTgoal: • Visit www.clinicaltrials.gov and type ENESTgoal or NCT01744665 into the search field Treatment-free remission is not an FDA-approved indication for nilotinib, and there is no guarantee it will be approved for this use.

For more information, please visit www.tfrtrials.com

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2014 Novartis

7/14

AM7-1095165

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In the News Vasectomy and Prostate Cancer Risk continued from page 156

is possible that with that background,” he speculated, “more of them opted for vasectomy as their method of birth control. This is a unique subset of patients; that is important to remember.”

They were also more likely to have had PSA testing during the study years, 1986 to 2010. “Having said that, since PSA testing is so closely related to prostate cancer diagnosis, we controlled for PSA testing using multiple methods. We controlled for that in the baseline analysis, but we also did subanalyses of only patients with highly screened behaviors,” Dr. Siddiqui explained. In a cohort of 13,901 “highly screened men”—those getting PSA testing on a regular basis—27% reported having had a vasectomy by the year 2000, and “the overall findings were essentially the same as in the general cohort,” Dr. Siddiqui reported.

“That is one of the issues that has been historically challenging,” Dr. Siddiqui stated. “Patients who get vasectomies may be more plugged into their medical care. They have a relationship with a urologist, and they may be more likely to undergo prostate cancer screening than patients who do not get a vasectomy. So the detection of prostate cancer could be biased by the fact that you are checking for prostate cancer more often in men with vasectomy vs those who do not have vasectomy. The way to control for that is to look at all men who are regularly checking for prostate cancer, and exclude the ones who don’t look for prostate cancer as regularly. That was a new dimension to this study that built on previous studies.”

Effect of 2012 Screening Recommendations The study follow-up ended in 2010, which was 2 years before the U.S. Preventive Services Task Force updated

its prostate cancer screening recommendation—the Task Force now advocates against PSA-based screening for prostate cancer.5 “It is unclear” what if any effect this updated recommendation will have on PSA screening among men who have had vasectomies. Follow-up is continuing, but the recommendation probably won’t affect men in the study because “many of them have already been getting PSA tested for a while,” Dr. Siddiqui noted. “These are men who were enrolled in the 1980s and 1990s; we are not enrolling additional men now. So there won’t be many men who are getting PSA testing in 2012 for the first time. Most of them have already passed the point at which they were going to get PSA testing anyway.”

Dr. Siddiqui said that while “it is a subjective finding,” he thinks that the routine administration of PSA testing

“has really dropped off.” Among urologists, “we see fewer and fewer people coming in with elevated PSAs as the primary complaint,” he said. “Men with a family history or some other reason for concern about prostate cancer are not denied PSA testing,” he said. “It is just not a routine part of a yearly physical exam anymore.”

Confounding Factors Unlikely The study also notes that confounding by infections or cancer treatment is unlikely. “Studies have actually shown that prostate cancer is associated with sexually transmitted infections, in particular, Trichomonas vaginalis and herpesvirus,” Dr. Siddiqui explained.

“Some people suggest that perhaps men with vasectomy are more prone to sexually transmitted infections because of behavioral changes, so that could be a reason for the increased risk of pros-

Expect Questions From Patients

A

n updated study reporting a 20% increased risk of advanced prostate cancer and a 19% increased risk of lethal prostate cancer among men who have had vasectomies generated coverage by the medical and major media, including CBS News and The New York Times, and can be expected to prompt questions from patients. The study, published ahead of print online by the Journal of Clinical Oncology, involved 49,405 men in the Health Professionals Follow-up Study who were aged 40 to 75 years at baseline in 1986 and were followed for up to 24 years.

The study’s lead author, Mohummad Minhaj Siddiqui, MD, Director of Urologic Robotic Surgery, and Assistant Professor of Surgery-Urology, at the University of Maryland School of Medicine in Baltimore, noted several points that should be communicated to patients: • The 19% increase in lethal prostate cancers among men who had vasectomies is on top of a 1.6% cumulative incidence in the overall population, which translates to a very small increase in absolute risk.

• Previous reports have shown conflicting results about a possible link between vasectomy and prostate cancer. The recently updated data strengthens the conclusion that there likely is some kind of association, even if it is small.

• The future direction of research is probably best served by trying to figure out what the biologic explanation might be for the association between vasectomy and prostate cancer, he added.

tate cancer. But we didn’t see any association with infections in our study, and we had pretty good data on histories of sexually transmitted infections.”

Cancer treatments were considered as confounding factors because of concerns that differing treatments could affect whether particular cases were lethal or not. “Perhaps some men are getting lethal prostate cancer because they are getting treated differently…. Theoretically, it is possible that men with vasectomies have relationships with their urologists, so maybe they prefer treatments that the urologist offers, such as surgery, as opposed to men who haven’t had a vasectomy,” Dr. Siddiqui explained.

“Maybe those men fear surgery in general and so they opt for radiation or other treatments,” he continued. “But what we found was that there was no difference in the vasectomy and nonvasectomy group with regard to what treatments were used to treat the prostate cancer. So that does not explain the observed risk either.” n Disclosure: Dr. Siddiqui reported no potential conflicts of interest.

References 1. Siddiqui MM, Wilson KM, Epstein MM, et al: Vasectomy and risk of aggressive prostate cancer. J Clin Oncol. July 7, 2014 (early release online).

2. Giovannucci E, Ascherio A, Rimm EB, et al: A prospective cohort study of vasectomy and prostate cancer in US men.

JAMA 269:873-877, 1993.

3. Preidt R: Vasectomy linked to aggressive prostate cancer. Available at www. cbsnews.com. Posted July 11, 2014. Accessed July 14, 2014.

4. Bakalar N: A vasectomy may increase prostate cancer risk. New York Times, July 17, 2014.

5. U.S. Preventive Services Task Force: Screening for prostate cancer. Available at http://www.uspreventiveservicestaskforce.org/prostatecancerscreening.htm.

Accessed July 17, 2014.

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Clinical Trials Thoracic Oncology

New Clinical Study Aims to Investigate the Genomics of Young Lung Cancer

T

he Addario Lung Cancer Medical Institute (ALCMI) recently launched a new study, the Genomics of Young Lung Cancer, to understand why lung cancer occurs in young adults, who quite often are athletic, never smokers and do not exhibit any of the known lung cancer genetic mutations. ALCMI, a patient-centric, international research consortium and partner of the Bonnie J. Addario Lung Cancer Foundation (ALCF), is facilitating this first-of-its-kind, multiinstitutional, prospective genomic study in order to identify new genome-defined subtypes of lung cancer and accelerate delivery of more effective targeted therapies.

cancer patients under 40,” Dr. Gitlitz said. “We’ll be evaluating 60 patients in this initial study and hope to apply our findings to a larger follow-up study in the future.”

Other investigators include ­Geoffrey Oxnard, MD, of Dana-Farber Cancer Institute, David Carbone, MD, PhD, of The Ohio State University, and Giorgio Scagliotti, MD, PhD and

TELL YOUR ADVANCED PRACTICE COLLEAGUES TO

Silvia Novello, MD, both at the University of Torino in Italy. Patients may enroll in the study regardless of where they live, and will not need to travel to any of the above institutions. n

SAVE THE DATE

Groundbreaking Study “This groundbreaking study will investigate why young adults under the age of 40 are getting lung cancer and whether they have a unique cancer subtype, or genotype, that can be treated differently,” said Bonnie J. Addario, stage IIIB lung cancer survivor and founder of ALCMI and the ALCF. Our evolving understanding of the disease and new molecular tools suggest that young age may be an under-appreciated clinical marker of new genetic subtypes. An important goal for this research study is to reveal new lung cancer subtypes of lung cancer requiring distinct treatment strategies.

“Leveraging this study as a proof of principle, ALCMI is also characterizing other specific patient populations to support emerging data that lung cancer diagnostic and therapeutic interventions are more effective when individualized, and personalized approaches are brought to bear,” Steven Young, President and COO of ALCMI, who also points out this study represents a unique public-private collaboration between the ALCMI consortium and Foundation Medicine, Inc. The Genomics of Young Lung Cancer study is centrally managed by ­ALCMI while the Principal Investigator is Barbara Gitlitz, MD, Associate Professor of Medicine, University of Southern California, Norris Comprehensive Cancer Center.

“This study lays the groundwork for discovery of novel targetable genotypes as well as heritable and environmental risk factors for lung

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October 30 – November 2, 2014 Loews Royal Pacific Hotel at Universal Orlando, FL

This CE/CME/CEU accredited conference is jointly sponsored by:

For more information, visit apsho.org/jadprolive

The ASCO Post | AUGUST 15, 2014

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Clinical Trials Resource Guide Genitourinary Oncology

Ongoing Clinical Trials Actively Recruiting Patients With Bladder Cancer Compiled by Jo Cavallo

T

he information in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with bladder cancer. The list includes randomized and nonrandomized phase 0 to III studies as well as observational clinical trials evaluating new therapies, surgical techniques, and devices; image-guided radiation and radiation doses; noninvasive assays to detect bladder cancer cells; molecular profiling; and quality of life. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

BLADDER CANCER Study Type: Phase 0/interventional/randomized Study Title: An Immunopharmacodynamic Phase 0/I Study of Rapamycin in Patients Undergoing Radical Cystectomy for Bladder Cancer Study Sponsor and Collaborators: The University of Texas Health Science Center at San Antonio Purpose: To evaluate the effects of rapamycin directly on bladder tumors and the effects of rapamycin on the immune system of patients with bladder cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Tissue pharmacodynamic response to TORC1 inhibition (time frame: 30 days) Principal Investigator: Robert S. Svatek, MD, MSCI, UT Health Science Center San Antonio; 210-567-5676 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01827618 Study Type: Phase 0/interventional/single-group assignment Study Title: Impact of Valproate on Angiogenesis and Histone Deacetylation in Bladder Cancer Study Sponsor and Collaborators: State University of New York-Upstate Medical University Purpose: To test whether the drug valproic acid can cause changes in bladder tumors that might inhibit their growth Ages Eligible for Study: 21 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No

Primary Outcome Measures: Thrombospondin-1 gene expression (time frame: 1 day) Principal Investigator: Oleg Shapiro, MD, State University of New YorkUpstate Medical University. Contact: Barbara McConnell; 315-464-4473; mcconneb@upstate.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01738815 Study Type: Phase 0/interventional/single-group assignment Study Title: Noninvasive Vibrational Device to Improve Sensitivity of Urine Cytology for Bladder Cancer Study Sponsor and Collaborators: Johns Hopkins University Purpose: To test whether a commercially available vibrating chair can increase the number of urothelial cells in a urine sample of healthy participants noninvasively.

Ages Eligible for Study: 18 to 80 years Genders Eligible for Study: Male Accepts Health Volunteers: No Primary Outcome Measures: Number of cancer cells (time frame: up to 24 weeks) Principal Investigator: Trinity Bivalacqua, MD, PhD, Johns Hopkins University. Contact: John J. Kim, BS; 805-220-8765; jkim324@jhu.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01826097 Study Type: Interventional/nonrandomized/single-group assignment Study Title: Pilot Pre-cystectomy Trial of Broccoli Extract in Patients With Superficial or Locally Advanced Bladder Cancer Study Sponsor and Collaborators: Roswell Park Cancer Institute; Johns Hopkins University Purpose: To study the side effects of broccoli sprout extract in treating patients with transitional cell bladder cancer undergoing surgery Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Toxicity as assessed by National Cancer Institute Common Toxicity Criteria version 3.0 (time frame: 14 days) Principal Investigator: Roberto Pili, MD, Roswell Park Cancer Institute.

Contact: AskRPCI, MD 877-275-7724; askrpci@roswellpark.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01108003

Washington Cancer Consortium; 206616-8289 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01938573

Study Type: Phase I/interventional/nonrandomized Study Title: Phase I Dose-Escalation Study of Image-Guided Radiation Therapy for Bladder-Cancer Patients Undergoing Radiotherapy and Concurrent Gemcitabine Chemotherapy Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center Purpose: To test the safety of different doses of external-beam radiation therapy combined with chemotherapy Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To determine the dose limiting toxicity and establish the maximal tolerated dose (time frame: 2 years) Principal Investigator: Marisa Kollmeier, MD, Memorial Sloan Kettering Cancer Center; 212-639-3952 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01104350

Study Type: Phase II/interventional/randomized Study Title: A Multicenter Phase II Study of Enhancement of Immune Reconstitution and Vaccine Responses With Administration of Glyco-Recombinant Human IL-7 in Older Subjects Following Chemotherapy Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the effects of IL-7 on immune system function in two different groups of older people. One group will be people who have completed chemotherapy treatment for breast, colon, or bladder cancer. The other group will be people who have never received chemotherapy.

Ages Eligible for Study: 60 years and older Genders Eligible for Study: Both Accepts Health Volunteers: Yes Primary Outcome Measures: Vaccines responses (time frame: up to 1 year); quality of immune responses (time frame: 8 weeks); safety of rhIL-7 (time frame: up to 1 year) Principal Investigator: Ronald E. Gress, MD, National Cancer Institute; 301-496-1791; gressr@mail.nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01339000

Study Type: Phase I/II/interventional/single-group assignment Study Title: A Phase I-II Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Bladder Cancer Study Sponsor and Collaborators: University of Washington; National Cancer Institute Purpose: To investigate the side effects and the best dose of sirolimus when given together with cisplatin and gemcitabine hydrochloride and how well it works in treating patients with bladder cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose of sirolimus based on the incidence of dose-limiting toxicity graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 (phase 1) (time frame: up to 28 days) Principal Investigator: Robert B. Montgomery, MD, Fred Hutchinson Cancer Research Center/University of

Study Type: Phase II/interventional/nonrandomized Study Title: A Multi-Histology Phase II Study of 5-Fluoro-2’-Deoxycytidine With Tetrahydrouridine (FdCyd + THU) Study Sponsor and Collaborators: National Cancer Institute Purpose: To determine the effectiveness, safety, and tolerability of FdCyd and THU when given together to control tumor growth in patients with bladder cancer, non–small cell lung cancer, breast cancer, or head or neck cancer that has progressed after receiving standard treatment or for which no effective therapy exists Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Determine progression-free survival and/ or the response rate (complete plus pari-

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Clinical Trials Resource Guide

tal responses) of FdCyd administered 5 days/week for 2 weeks, in 28-day cycles, by intravenous infusion with THU in patients with breast cancer, head and neck cancer, non–small cell lung cancer, and bladder cancer.

Principal Investigator: James H. Doroshow, MD, National Cancer Institute; 301-496-4291; doroshoj@mail.nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00978250 Study Type: Phase II/interventional/single-group assignment Study Title: Phase II Study of Neoadjuvant Dose Dense Gemcitabine and Cisplatin (DD GC) In Patients With Muscle-Invasive Bladder Cancer Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center; University of North Carolina, Chapel Hill; New York University Purpose: To determine if standard chemotherapy (gemcitabine and cisplatin) given on a dose-dense treatment schedule (with less time between treatments) can help shrink the tumor better than standard chemotherapy given on a standard treatment schedule before the patient undergoes surgery for bladder cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Pathologic response rate (time frame: 1 year) Principal Investigator: Dean Bajorin, MD, Memorial Sloan Kettering Cancer Center; 646-422-4333 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01589094 Study Type: Phase II/interventional/single-group assignment Study Title: Phase II Study of Adjuvant Conformal Radiotherapy in High Risk Bladder Cancer Study Sponsor and Collaborators: Emory University Purpose: To study how well modern, conformal radiation therapy after surgery works in treating patients with high-risk bladder cancer. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue.

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Gastrointestinal late effects, assessed using Radiation Therapy Oncology Group

Late Effects in Normal Tissues Subjective, Objective, Management and Analytic Scales (time frame: 3 months) Principal Investigator: Joseph W. Shelton, MD, Emory University; 404616-6343; jwshelt@emory.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01954173

Study Type: Phase II/interventional/single-group assignment Study Title: A Phase II Protocol for Patients With Stage T1 Bladder Cancer to Evaluate Selective Bladder Preserving Treatment by Radiation Therapy Concurrent With Radiosensitizing Chemotherapy Following a Thorough Transurethral Surgical Restaging

Study Sponsor and Collaborators: Radiation Therapy Oncology Group; National Cancer Institute; NRG Oncology Foundation, Inc Purpose: To study how well radiation therapy given together with chemotherapy works in treating patients with stage I bladder cancer continued on page 162

Trim: 7.625 X 10.5

After progression following initial antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer...

Go with FASLODEX.

Primary Endpoint: Progression-Free Survival (PFS)1,*

Secondary Endpoint: Overall Survival (OS)1

Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg in CONFIRM2,†

Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg in CONFIRM2

At minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2

• Not statistically signifcant as no adjustments were made for multiplicity2

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2

Important Safety Information About FASLODEX • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) Please see additional Important Safety Information on reverse and brief summary of full Prescribing Information for FASLODEX on adjacent pages. * PFS is defned as the time between randomization and the

earliest evidence of progression or death from any cause. 2 † COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer.1

Go with Confdence Learn more at www.faslodex.com/hcp

The ASCO Post | AUGUST 15, 2014

PAGE 162

Clinical Trials Resource Guide Bladder Cancer continued from page 161

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Rate of freedom from radical cystectomy at 3 years (time frame: 3 years

from date of registration) Principal Investigator: William U. Shipley, MD, FACR, Massachusetts General Hospital. See individual clinical trial locations for contact ­information.

For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00981656

Study Type: Phase III/interventional/ randomized Study Title: A Phase III Surgical Trial to Evaluate the Benefit of a Standard Versus an Extended Pelvic Lymphadenectomy Performed at Time of Radical Cystectomy for Muscle Invasive Urothelial Cancer Study Sponsor and Collaborators: Southwest Oncology Group; National

Trim: 7.625 X 10.5

Cancer Institute Purpose: To study standard pelvic lymphadenectomy to see how well it works compared to extended pelvic lymphadenectomy in treating patients undergoing surgery for invasive bladder cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both

FASLODEX is indicated for the treatment of hormone receptor-positive (HR+) metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,†

FASLODEX 500 mg Showed a Comparable Safety Profle to FASLODEX 250 mg in CONFIRM1

• Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2

Additional Important Safety Information About FASLODEX (continued)

• Objective response rates (ORRs)‡ were not signifcantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2

• Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX

— Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

FASLODEX 500 mg vs 250 mg in the updated OS analysis in CONFIRM2,§ • Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg at minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2 Not statistically signifcant as no adjustments were made for multiplicity.2 • In the initial OS analysis after a minimum duration of 18 months, there was no statistically signifcant difference in OS between the 2 treatment groups2

• The most common, clinically signifcant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot fash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent

Indication For FASLODEX • FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

* The CONFIRM trial was a randomized, double-blind, controlled phase III

study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 † PFS was the primary endpoint.1 ‡ ORR is defned as the number of patients with complete response or partial response.2 § OS was a secondary endpoint.1

Please read brief summary of full Prescribing Information for FASLODEX on adjacent pages.

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Go with Confdence FASLODEX is a registered trademark of the AstraZeneca group of companies.

©2013 MedImmune, Specialty Care Division of AstraZeneca.

All rights reserved.

2873001

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Clinical Trials Resource Guide

Accepts Health Volunteers: No Primary Outcome Measures: Disease-free progression Principal Investigator: Seth P. Lerner, MD, Baylor College of Medicine; 713-798-6841 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01224665

Study Type: Observational/patient registry Study Title: Pilot Study of Role of MRI in Neoadjuvant Chemotherapy for Bladder Cancer Study Sponsor and Collaborators: New York University School of Medicine Purpose: This is a prospective study of pretreatment DW-MRI Trim: 7.625 X 10.5 to identify

FASLODEX® (fulvestrant) Injection

potential imaging biomarkers predictive of response to neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures:

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients Fulvestrant 500 mg N=361

Fulvestrant 250 mg N=374

Injection Site Pain

42 (11.6)

34 (9.1)

Headache

28 (7.8)

25 (6.7)

DOSAGE AND ADMINISTRATION

Back Pain

27 (7.5)

40 (10.7)

Recommended Dose

Fatigue

27 (7.5)

24 (6.4)

Pain in Extremity

25 (6.9)

26 (7.0)

Asthenia

21 (5.8)

23 (6.1)

24 (6.6)

22 (5.9)

Nausea

35 (9.7)

51 (13.6)

Vomiting

22 (6.1)

21 (5.6)

Anorexia

22 (6.1)

14 (3.7)

Constipation

18 (5.0)

13 (3.5)

Bone Pain

34 (9.4)

28 (7.5)

Arthralgia

29 (8.0)

29 (7.8)

Musculoskeletal Pain

20 (5.5)

12 (3.2)

Cough

19 (5.3)

20 (5.3)

Dyspnea

16 (4.4)

19 (5.1)

BRIEF SUMMARY For full Prescribing Information, see package insert.

INDICATIONS AND USAGE FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter [see Clinical Studies (14) in full Prescribing Information].

Dose Modification Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter.

FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Specific Populations].

Administration Technique

The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged.

2. Remove perforated patient record label from syringe.

3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.”

4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap.

5. Twist to lock the needle to the luer connector.

6. Remove needle sheath.

7. Remove excess gas from the syringe (a small gas bubble may remain).

8. Administer intramuscularly slowly in the buttock.

9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered.

10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector.

11. Repeat steps 1 through 10 for second syringe.

For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

CONTRAINDICATIONS FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX.

WARNINGS AND PRECAUTIONS Blood Disorders Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.

Hepatic Impairment The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.

Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration].

FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations].

Use in Pregnancy Based on its mechanism of action and findings in animals, FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area. There are no adequate and wellcontrolled studies in pregnant women using FASLODEX. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).

Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

and Adverse Reaction Body as a Whole

Vascular System Hot Flash Digestive System

Musculoskeletal System

Respiratory System

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms.

Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis.

Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2).

Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.

Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5% Body System FASLODEX 250 mg Anastrozole 1 mg N=423 N=423 and Adverse Reactiona (%) (%) Body as a Whole Asthenia Pain Headache Back Pain Abdominal Pain Injection Site Painb Pelvic Pain Chest Pain Flu Syndrome Fever Accidental Injury Cardiovascular System Vasodilatation Digestive System Nausea Vomiting Constipation Diarrhea Anorexia Hemic and Lymphatic Systems Anemia

68.3 22.7 18.9 15.4 14.4 11.8 10.9 9.9 7.1 7.1 6.4 4.5 30.3 17.7 51.5 26.0 13.0 12.5 12.3 9.0 13.7 4.5

67.6 27.0 20.3 16.8 13.2 11.6 6.6 9.0 5.0 6.4 6.4 5.7 27.9 17.3 48.0 25.3 11.8 10.6 12.8 10.9 13.5 5.0 —continued

Complete pathologic response (time frame: < 1 year) Principal Investigator: Arjun Balar, MD, NYU Langone Medical Center. Contact: Simone Rainey; 212-263-2710; simone.rainey@nyumc.org For More Information: Visit ClinicalTrials.gov and refer to this study by its continued on page 164

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PAGE 164

Clinical Trials Resource Guide Bladder Cancer continued from page 165

identifier: NCT01922232 Study Type: Observational Study Title: PORCH: A Registry of Prospective Outcomes of Radical Cystectomy With or Without Chemotherapy Study Sponsor and Collaborators:

UNC Lineberger Comprehensive Cancer Center Purpose: To create a registry of older patients undergoing surgical and/ or medical treatment for bladder cancer. The registry will record side effects and outcomes related to the treatment using different surveys and biological measures.

Trim: 7.625 X 10.5

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To collect the number of changes in functional status, surgical complications, and survival status collected in a prospective database of patients undergoing a radical cystecto-

FASLODEX® (fulvestrant) Injection Body System and Adverse Reactiona

FASLODEX 250 mg N=423 (%) Metabolic and Nutritional Disorders 18.2 Peripheral Edema 9.0 Musculoskeletal System 25.5 Bone Pain 15.8 Arthritis 2.8 Nervous System 34.3 Dizziness 6.9 Insomnia 6.9 Paresthesia 6.4 Depression 5.7 Anxiety 5.0 Respiratory System 38.5 Pharyngitis 16.1 Dyspnea 14.9 Cough Increased 10.4 Skin and Appendages 22.2 Rash 7.3 Sweating 5.0 Urogenital System 18.2 Urinary Tract Infection 6.1

Anastrozole 1 mg N=423 (%) 17.7 10.2 27.9 13.7 6.1 33.8 6.6 8.5 7.6 6.9 3.8 33.6 11.6 12.3 10.4 23.4 8.0 5.2 14.9 3.5

a A patient may have more than one adverse reaction. b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American Study 2 received placebo injections.

Post-Marketing Experience For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria.

Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered.

Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONS There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics.

Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed.

Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.

Geriatric Use For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.

Hepatic Impairment FASLODEX is metabolized primarily in the liver.

The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (ChildPugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (ChildPugh class B) [see Dosage and Administration and Warnings and Precautions].

Renal Impairment Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.

OVERDOSAGE Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

Nursing Mothers It is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FASLODEX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCuneAlbright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8).

The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.

2

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.

Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known.

Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died.

Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.

In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.

SafetyGlide™ is a trademark of Becton Dickinson and Company.

FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2873001 10/13

my with or without chemotherapy (time frame: 1 year) Principal Investigator: Angela Smith, MD, University of North Carolina Lineberger Comprehensive Cancer Center For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01776138 Study Type: Observational Study Title: A Prospective Study of Quality of Life in Patients With Bladder Cancer Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center; Albert Einstein College of Medicine of Yeshiva University; North Shore Long Island Jewish Health System Purpose: To learn about the quality of life of people living with bladder cancer. The researchers are interested in learning how treatments for bladder cancer affect people. Their findings could help provide better care and information to patients with bladder cancer.

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Prospectively characterize the impact of radical cystectomy and different urinary diversions on quality of life of patients with bladder cancer Principal Investigator: Bernard Bochner, MD, Memorial Sloan Kettering Cancer Center; 646-422-4387 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00745355 n

The Value of Federally Funded Cancer Research

ASCO has created a badge to raise awareness of the importance of federally funded biomedical research that improves the lives of people worldwide.

To call attention to the value of federal funds, The ASCO Post has printed this badge alongside reports on data resulting from federally funded research, and ongoing clinical trials including some of those in this clinical trials resource guide.

ASCOPost.com | AUGUST 15, 2014

PAGE 165

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Less Than 1% Absolute Survival Benefit at 20 Years Found for Contralateral Prophylactic Mastectomy Theorizing that an exaggerated perceived benefit from contralateral prophylactic mastectomy may have led to the substantial increase in its use in recent years, researchers from the University of Minnesota in Minneapolis used a Markov simulated decision-analytic model to evaluate the magnitude of the survival benefit of contralateral prophylactic mastectomy for women with unilateral breast cancer. The investigators found that the absolute 20-year survival benefit was less than 1%.

Predicted life expectancy gains from contralateral prophylactic mastectomy “ranged from 0.13 to 0.59 years for women with stage I breast cancer and 0.08 to 0.29 years for those with stage II breast cancer. Absolute 20-year survival differences ranged from 0.56% to 0.94% for women with stage I breast cancer and 0.36% to 0.61% for women with stage II breast cancer,” the researchers reported in the Journal of the National Cancer Institute.

Contralateral prophylactic mastectomy was more beneficial among women with stage I and estrogen receptor (ER)negative breast cancer, and those who were younger. For example, a 60-year-old woman would gain less than 2 months in life expectancy from contralateral prophylactic mastectomy, whereas a 40-year-old woman would gain as much as 7 months, according to the model.

The authors explained that the model simulates long-term prognosis of hypothetical cohorts of women with newly diagnosed unilateral breast cancer under the following two scenarios: (1) contralateral prophylactic mastectomy (ie, double mastectomy) and (2) no contralateral prophylactic mastectomy (assuming that women undergo either lumpectomy with radiation therapy or unilateral mastectomy).

Using this model, they projected the benefit of contralateral prophylactic mastectomy for cohorts of women defined by age at breast cancer diagnosis (40, 50, or 60 years), stage of primary breast cancer (I, II), and ER status.

Women with BRCA mutations were excluded. Probabilities for developing contralateral breast cancer, dying from contralateral breast cancer, dying from primary breast cancer, and age-specific mortality rates were estimated from

published studies, the authors noted.

“In this analysis, we assumed that the only plausible way that [contralateral prophylactic mastectomy] improves breast cancer survival is by preventing a potentially fatal [contralateral breast cancer],” the investigators stated. In 2011, the 10year risk of contralateral breast cancer was estimated to be 4% to 5%, and the risk “may be even lower for patients diagnosed today,” the authors added.

Further Considerations The authors acknowledged that survival “is only one potential benefit of a cancer risk-reduction strategy; effects on cancer-related anxiety, cosmesis, and self-image are also important in decision-making processes. For some women, the negative impact of [contralateral prophylactic mastectomy] on quality of life may outweigh a potential survival benefit. For others who are very anxious about [contralateral breast cancer], [contralateral prophylactic mastectomy] may result in a psychological benefit even if survival benefits are minimal.”

The researchers noted that prospective randomized trials of contralateral prophylactic mastectomy vs no contralateral prophylactic mastectomy are not feasible and retrospective studies evaluating a potential survival benefit with contralateral prophylactic mastectomy “are limited by short follow-up, potential selection bias, and lack of important clinical information.” They concluded, “Survival estimates derived from our model may be useful for physicians and breast cancer patients to arrive at evidence-based informed decisions regarding [contralateral prophylactic mastectomy].”

Although the survival benefit of contralateral prophylactic mastectomy is small, “in a fraction of patients who are very troubled by a 0.7% risk of a second, contralateral cancer, [contralateral prophylactic mastectomy] might still provide an acceptable benefit,” according to an accompanying editorial. “The balance between harm and benefit depends on the patient’s preferences and highlights the importance of capturing the patient’s values and expectations before considering [contralateral prophylactic mastectomy],” wrote Stephen G. Pauker, MD, and Mohamed Alseiari, MD, of the Division of Clinical Decision Making, Department of Medicine, Tufts Medical Center, Boston.

Portschy PR, Kuntz KM, Tuttle TM: J Natl Cancer Inst 106(8):dju160, 2014.

Pauker SG, Alseiari M: J Natl Cancer Inst 106(8):dju175, 2014.

LUNG CANCER Selected Patients With Lung Cancer and Poor Performance Status May Benefit From Standard Therapy Patients with poor performance status have an increased incidence of adverse effects from therapy and worse overall outcomes than those with good performance status, but “a selected proportion may still benefit from standard therapy,” according to a review article published in the Journal of the National Comprehensive Cancer Network.

Data on optimal approaches for patients with performance status 2 are lacking, because these patients are underrepresented in conventional clinical trials due to enrollment restrictions, noted the authors, Ajeet Gahra, MD, of the Upstate Medical University and VA Medical Center in Syracuse, New York, and Alissa S. Marr, MD, and Apar Kishor Ganti, MD, MS, of the University of Nebraska Medical Center in Omaha. Available evidence shows, however, that some patients benefit from standard therapy.

“When comorbidities or poor [performance status] exclude surgical interventions for early-stage lung cancer, radiation therapy is the standard alternative” for the management of patients with non–small cell lung cancer (NSCLC).

These patients “are often treated with radiation therapy given in a definitive dosing fashion,” the authors stated.

Stereotactic ablative body radiation “is considered biologically more effective at killing cancer cells,” according to the article. “Multiple studies have provided the evidence for the role of [stereotactic ablative body radiation] for NSCLC in medically inoperable candidates” and there is also limited evidence that performance status “does not affect outcomes after [stereotactic ablative body radiation].” The available data led the authors to advocate that “patients with early-stage disease and a marginal lung function should be evaluated in a multidisciplinary setting to determine suitability for limited resection or [stereotactic ablative body radiation]. In the absence of randomized trials, whether one approach is superior to the other is unclear,” the authors added.

Concerning chemotherapy, the authors concluded, “some patients with NSCLC and poor [performance status] may be treated with combination chemotherapy. If this approach is chosen,

the preferred treatment is carboplatin with either a taxane or pemetrexed (nonsquamous histology), based on trial data. Single-agent chemotherapy is reasonable to use at the discretion of the treating physician,” the authors continued, but single-agent erlotinib (Tarceva) “should not be used in unselected patients instead of chemotherapy in the first-line setting in the absence of known EGFR mutations.”

They continued, “Patients who are candidates for targeted therapy based on mutation status should be offered a trial of the targeted agent regardless of their performance status. It is unclear how best to implement maintenance therapy strategies in these patients because mature trial data are not currently available.

Small Cell Lung Cancer Among patients with small cell lung cancer (SCLC), those with poor performance status “seem to have a worse response to chemotherapy,” the authors noted, and the role of concurrent chemoradiation is unclear. “One possible approach may be to try a couple of cycles of systemic chemotherapy, and if the patient tolerates therapy well and experiences an improvement in functional status, radiation could be added concurrently with further chemotherapy cycles,” the researchers wrote. Noting that other factors, including metastases, influence first-line therapy for patients with extensive SCLC, the authors stated that their “practice has been to try systemic chemotherapy in these individuals, because experience has shown that there is a subset of patients whose functional status improves after a decrease in tumor burden after therapy.”

Topotecan is the only therapy approved by the U.S. Food and Drug Administration for relapsed SCLC and, despite a study showing that patients with poor performance status had lower overall survival and slightly greater grade 3/4 anemia, “may be reasonable to use in this setting for this patient cohort,” the authors noted.

“To better define optimal treatment approaches for this population of patients with lung cancer, prospective results are needed for relevant end points, such as rates of treatment completion, functional outcomes, and quality-of-life data,” the authors concluded.

Gajra A, Marr AS, Ganti AK: J Natl Compr Canc Netw 12:1015-1025, 2014. continued on page 166

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In the Literature Emerging Clinical Data continued from page 165

COLORECTAL CANCER High False-Positive Rate of Elevated CEA Seen in Patients With Resected Colorectal Cancer A retrospective study finding a 49% false-positive of carcinoembryonic antigen (CEA) testing among patients with a history of resected colorectal cancer, “suggests that confirmation of an ongoing increase in CEA level should be universal practice before an extensive workup is initiated,” Anya Litvak, MD, and colleagues from Memorial Sloan Kettering Cancer Center (MSKCC) reported in the Journal of the National Comprehensive Cancer Center.

The study involved 728 patients at Memorial Sloan Kettering who underwent resection for stage I, II, or III colorectal cancer between 2003 and 2012, and who had an increase in CEA level above the normal after a normal perioperative CEA level. “Of these, 358 had a false-positive elevation of CEA level, 335 had a true-positive elevation indicative of recurrent [colorectal cancer], and 35 had a true-positive elevation indicative of the development of a new, [non–colorectal cancer] malignancy,” the researchers found.

“For the purposes of this analysis, a false-positive was described as a CEA level higher than the upper range of normal (ie, ≥ 5.1 ng/mL) with no evidence of cancer on either imaging studies or other diagnostic procedures, with either follow-up of (1) at least 1 year since the first abnormal CEA or (2) abnormal CEA elevations followed by spontaneous normalization, with at least 2 consecutive subsequent normal CEA measurements in the absence of a therapeutic intervention,” they explained.

Among patients with false elevations, “111 had a single isolated CEA level elevation (median highest CEA level of 5.5 ng/mL) with no further abnormal measurements, whereas 247 had elevations on 2 or more readings, with a median highest level of 6.7 ng/mL. Of these 247 patients with confirmed false-positive CEA level elevations, only 5 (2%) had measurements greater than 15 ng/mL, and no confirmed elevation greater than 35 ng/mL was a false-positive,” the researchers reported.

The single isolated CEA elevations “were considered either transient falsepositives from some acute process, or the result of simple laboratory or specimen labeling errors,” the researchers stated. The frequency of one-time falsepositives and the finding that 93% of them were between 5.1 and 10.0 ng/ mL “support a recommendation to re-

©Peter Steiner/The New Yorker Collection/www.cartoonbank.com

peat and confirm any abnormal CEA test results with measurements less than 10 ng/mL before embarking on further workup,” the investigators added.

False-positive results greater than 15 ng/mL were rare, and all confirmed levels greater than 35 ng/mL were associated with cancer recurrence. “Hence, CEA levels greater than 35 ng/mL seem to be virtually diagnostic of the presence of cancer,” the authors noted.

“This information is potentially useful for patients and doctors in terms of putting the meaning of the CEA elevation into context; the authors do not advocate initiation of chemotherapy or other therapeutic maneuvers based on an abnormal CEA level alone,” they wrote. “Recurrent disease should be identified based on diagnostic imaging studies and/or biopsy results before consideration is given to a therapeutic intervention.”

Litvak A, et al: J Natl Compr Canc Netw 12:907–913, 2014.

LIVER CANCER Everolimus Did Not Improve Survival in Hepatocellular Cancer After Progression on Sorafenib “Despite the strong scientific rationale and preclinical data, everolimus [Afinitor] plus best supportive care failed to improve survival over placebo plus best supportive care” among patients with advanced hepatocellular cancer that progressed during or after receiving sorafenib (Nexavar), or who were intolerant to sorafenib, Andrew X. Zhu, MD, PhD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, and colleagues reported.

The results of the phase III Everolimus for Liver Cancer Evaluation (EVOLVE-1) study were published in the Journal of the American Medical Association.

While sorafenib has been shown to significantly improve overall survival in advanced hepatocellular cancer, its benefits are mostly transient and modest, and disease progression eventually occurs. The EVOLVE-1 study compared everolimus at 7.5 mg/d to matching placebo, both in combination with best supportive care, in 546 adults with hepatocellular cancer, Barcelona Clinic Liver Cancer stage B or C, and ChildPugh A liver function.

According to the 2:1 randomization scheme, 362 patients were randomly assigned to everolimus and 184 to place-

bo. Patients continued on trial until disease progression or intolerable toxicity.

“No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group [hazard ratio [HR] = 1.05; 95% CI = 0.86–1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo]. Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively [HR = 0.93; 95% CI = 0.75–1.15], and disease control rate was 56.1% and 45.1%, respectively (P = .01),” the researchers reported.

Safety Profile “Adverse events of any grade, regardless of relationship with study drug, were experienced by 99.2% of everolimus and 94.0% of placebo recipients,” according to the study report. Grade 3/4 adverse events occurred more frequently with everolimus, 70.9% vs 52.2% with placebo. The most common grade 3/4 adverse events with everolimus vs placebo were anemia (7.8% vs 3.3%), asthenia (7.8% vs 5.5%), and decreased appetite (6.1% vs 0.5%).

“No patients experienced hepatitis C viral flare,” the investigators stated.

“Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy.” The authors noted that the adverse events profile “observed for everolimus was mostly consistent with the known safety profile of everolimus in other cancers.”

In preclinical models, inhibition of the mammalian target of rapamycin (mTOR) with everolimus and other rapamycin analogs prevented tumor progression and improved survival, and mTOR activation was associated with hepatocellular cancer recurrence, the researchers reported. In addition, everolimus demonstrated manageable safety and clinical activity in earlyphase clinical trials.

The EVOLVE-1 results extend the list of failed phase III studies in advanced hepatocellular cancer, “highlighting the challenge of developing effective therapies for this cancer,” the authors noted.

Nevertheless, EVOLVE-1 and the other failed phase III studies “have provided several important lessons,” they continued. “First, it is difficult to assess efficacy signals from [phase II] trials,” the continued on page 168

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PAGE 168

In the Literature Emerging Clinical Data continued from page 166

authors continued. “Second, surrogate end points such as time to progression, progression-free survival, and response rate inconsistently predict overall survival in [phase III] trials. Third, clinical and biologic heterogeneity likely affects the performance of targeted therapies in [hepatocellular cancer].”

Patients in the EVOLVE-1 are being assessed for relevant biomarkers that may predict clinical outcomes among patients receiving everolimus. “Future studies of targeted agents for [hepatocellular cancer] should aim to enrich patient populations based on molecular classification and predictive biomarkers,” the authors concluded.

Zhu AX, et al: JAMA 312:57-67, 2014.

HEAD AND NECK CANCER Identifying and Managing Distress in Patients With Head and Neck Cancers A quality improvement initiative at the Norris Cotton Cancer Center in Lebanon, New Hampshire, resulted in biweekly screening rates for psychological distress among patients treated at the head and neck medical oncology clinic increasing from 0% to 74% within a 2-year period. “Distress screening also became an integral component of clinic work flow,” Natalie Riblet, MD, MPH, and colleagues from the Norris Cotton Cancer Center reported in the Journal of the National Comprehensive Cancer Network.

“Furthermore, providers and patients reported that the process improvement produced meaningful changes, in that providers appreciated having a tool to identify high-risk patients and an evidence-based guideline to help inform clinical care. Patients valued the opportunity to discuss this aspect of their health and to know that the treatment plan addressed their mental and physical health needs,” the authors noted.

The importance of identifying patients at risk for psychological distress is recognized in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Distress Management and ASCO’s Quality Oncology Practice Initiative (QOPI) measures, the authors noted. However, few U.S. cancer centers have adopted formalized screening programs for distress.

The process for identifying and managing psychosocial distress at the head and neck cancer medical oncology clinic at Norris Cotton Cancer Center involved a two-component quality im-

provement intervention: the validated NCCN Distress Thermometer (a visual analog scale allowing patients to rate their perceived level of distress in the last 7 days) and an evidence-based treatment decision algorithm.

Screening processes were improved through “Plan-Do-Study-Act” cycles, the authors explained. “Cause-effect diagramming suggested that lack of a formalized process for distress assessment contributed to missed diagnoses. Providers were also unfamiliar with mental health resources.” Among specific strategies to improve screening were: including visual prompts on clinic notes for providers to incorporate distress screening into routine care, revising provider note templates to ease the burden of documentation, compiling an antidepressant guideline and list of available mental health resources, and developing a patient-centered poster to educate patients about distress and encourage them to take a more active role in their care.

“After implementing process changes, biweekly distress screening rates rose from 0% to 38% between January and July 2011. Furthermore, with additional [Plan-Do-Study-Act] cycles, these rates increased to 74% between October 2011 and April 2012,” the authors reported.

The screening rate for newly diagnosed patients using the NCCN Distress Thermometer was 84%, “and this screening rate met previously described benchmarks for best performing cancer centers.”

The investigators identified four “keys to success” in designing a head and neck cancer screening program: (1) characterize and address the unique needs of their patients and providers, (2) incorporate screening into established workflow patterns and electronic medical record, (3) track outcomes and share results with key stakeholders, and (4) involve senior leadership in improvement efforts.

Riblet N, et al: J Natl Comp Canc Netw 12:1005–1013, 2014.

MULTIPLE MYELOMA Higher-Dose Carfilzomib Produces ‘Remarkable’ Response Duration in Relapsed/ Refractory Multiple Myeloma Higher-dose carflizomib (Kyprolis) “provided a high overall response rate with a remarkable duration of response in patients with relapsed or refractory multiple myeloma” in a phase II study, Nikoletta Lendvai, MD, PhD, and colleagues from Memorial Sloan Kettering Center, New York, wrote in Blood.

Of 42 patients evaluable for response, 23 (55%) achieved at least a partial response, with 4 requiring dexamethasone, the researchers reported.

Median duration of response was 11.7 months (range, 6.7–14.7). At a median follow-up of 18.4 months (range, 6.5–25.2), median progressionfree survival was 4.1 months (range, 2.5–11.8), and overall survival was 20.3 months. The investigators concluded that the reported data “support future studies of carfilzomib 56 mg/m2 either alone or in combination with dexamethasone to validate its potential use as a standard option in clinical practice.”

Single-agent carfilzomib, a selective inhibitor, has been shown to be safe and effective in a series of phase II studies in advanced multiple myeloma, generally administered as a 2-to 10-minute intravenous infusion twice weekly for 3 weeks of a 4-week cycle at 20 mg/m2 for cycle 1 and then at 27 mg/m2 (20/27 mg/m2).

“Based on these studies, carfilzomib is currently indicated in the United States for patients with relapsed and refractory [multiple myeloma] using the 20/27 mg/m2 dose,” the investigators stated.

As carfilzomib continues to be developed, its use at higher doses is being investigated, and preliminary reports suggest improved activity with manageable adverse events at higher doses, the investigators commented. In the current singlecenter, open-label study, carfilzomib was administered at 20 mg/m2 on days 1 to 2 of cycle 1, and at 56 mg/m2 thereafter (30-minute infusion), with the option of adding dexamethasone at 20 mg for suboptimal response/progression.

Eligibility requirements included measurable symptomatic multiple myeloma that had relapsed or was refractory to at least two prior treatment regimens (median, 5). Prior treatment with bortezomib (Velcade) and immunomodulatory drugs was required, with 77% refractory to bortezomib and 64% to both bortezomib and lenalidomide (Revlimid). The median age of patients was 63, and 43% were male.

Key Results The 23 patients who achieved at least a partial response as their best response included 1 with a complete response and 9 with a very good partial response.

They further noted that 19 patients achieved at least a partial response with single-agent carfilzomib, and 4 of 11 patients who received dexamethasone because of a suboptimal initial response eventually achieved at least a partial response and continued treatment for an additional 4.5 cycles on average.

Six patients who achieved at least a partial response with single-agent carfilzomib had disease progression, and then had dexamethasone added to their regimen. Of these, four achieved at least stable disease and continued treatment for an additional 5.5 cycles on average, the researchers reported. “Treatment was active in bortezomib-refractory subgroups, but these patients tended to have poorer outcomes compared with nonrefractory patients.”

The most frequent grade 3/4 adverse events “possibly related to carfilzomib included lymphopenia (43%), thrombocytopenia (32%), hypertension (25%), pneumonia (18%), and heart failure (11%),” the investigators noted. “It is possible that the increased rates of cardiovascular events reported here, particularly worsening of previously controlled hypertension, are a dose-dependent phenomenon associated with carfilzomib, but we also cannot rule out the potential impact of established cardiovascular risk factors in our study population,” the investigators noted. In addition to hypertension, these included cardiomyopathy and prior exposure to cardiotoxic therapies.

Adding dexamethasone did not have a clinically meaningful impact on the types or rates of adverse events. Grade 3/4 adverse events attributed to dexamethasone included fatigue, gastric ulcer, and hyperglycemia, each affecting one patient. Seven patients (16%) discontinued treatment due to adverse events, and 17 required dose reductions. Two patients died for reasons other than disease progression but considered unrelated to study treatment.

“Moving forward, more efficacy and safety data are needed to better characterize the benefit-to-risk profile of carfilzomib 56 mg/m2 ± dexamethasone in relation to standard doses of single-agent carfilzomib across [multiple myeloma] populations with respect to response, survival outcomes, and safety,” the investigators stated. Two studies are looking at higher-dose carfilzomib in patients with multiple myeloma and another at the drug’s effect on cardiac function.

“Until data from these studies become available, it would appear practical to ensure adequate blood pressure control before initiating carfilzomib 56 mg/m2 and to closely monitor patients with a history of hypertension or other cardiovascular risk factors,” the authors cautioned. “In addition, avoidance of overhydration, especially in patients with cardiac risk factors, and obtaining a baseline echocardiogram prior to initiating therapy may be indicated.” n Lendvai N, et al: Blood. June 24, 2014 (early release online).

Clifford A. Hudis, MD President-Elect

Allen S. Lichter, MD

ASCO MeMber SinCe 1991

ASCO Chief Executive Officer

ASCO MeMber SinCe 1980

Sandra M. Swain, MD ASCO President

ASCO MeMber SinCe 1986

Join AsCo’s leadership development program

shApe your Future & ours If you completed your final subspecialty training between 2004 and 2009 and are interested in becoming a future leader in ASCO, our Leadership Development Program is for you.

Participants in this year-long program will learn valuable leadership skills and gain exposure to the roles and mission of ASCO and the Society’s powerful place in developing the future of cancer care.

This program requires a time commitment for travel and training.

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The ASCO Leadership Development Program strives to teach its participants how to build a team and then lead that team to greatness. As participants in this program, we have been challenged to define a strategic issue and work together to reach a desired outcome. I see this program as a springboard for future leadership opportunities in my clinic and oncology.

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The ASCO Post | AUGUST 15, 2014

PAGE 170

Letters to the Editor

What Do Humans and Laboratory Rats Have in Common?

T

he requirements for sound evidence of a drug’s therapeutic benefit have translated laboratory experience to human testing. In the laboratory, experimental animals give their lives to lethal testing of drugs and scientific analysis. LD50, the terminology denoting an anticipated 50% death rate of laboratory rats in a drug study, reflects standard procedure in this setting.

In human drug studies as well, this translates to preplanned deaths when a drug is tested for treatment of lethal disease. The current concept of overall survival when testing drugs in humans demands a preplanned number of deaths so that the test drug can be shown to be more effective than placebo or a placebo equivalent. Overall survival amounts to nontreatment of lethal or debilitating disease in the study patient. We tend to overlook the human cost of these studies.

Ignoring Drastic Effects A classic double-blind study performed by Rammelkamp and colleagues in the 1950s in the Great Lakes Naval Training facility demonstrated that penicillin, properly administered, completely eradicated beta-hemolytic streptococcic infection in young recruits with pharyngitis and prevented the sequel of rheumatic heart disease.1 No mention is made of the known, lifelong debilitating effect of rheumatic heart disease occurring in 17 of the young sailors in the placebo cohort.

This pattern of focus on the success of a treated group, while ignoring drastic effects on the placebo group continues in today’s studies. In the AFFIRM trial of enzalutamide (Xtandi), there were over 700 preplanned fatalities.2 In the trials of abiraterone ­(Zytiga), > 500 preplanned fatalities were documented.3,4 Is overall survival, a holdover from the animal lab, an ethical determination? Is it the only valid determination of drug effectiveness?

A comparison between early studies of lethal infectious disease—renal tuberculosis and HIV-AIDS—addresses this question. Lattimer demonstrated that triple-drug therapy arrested poten-

tially lethal renal tuberculosis at every stage of the disease. There was no placebo cohort and no deaths, preplanned or otherwise.5 On the other hand, in early trials of zidovudine, the drug was administered to patients with lethal HIV-AIDS in a 1:1 ratio to placebo despite the known outcome of untreated HIV-AIDS.6 One can legitimately ask if anything was accomplished by mortalities in the placebo group.

Further Considerations The insistence on placebo-controlled preplanned deaths in lethal disease has additional ramifications. Enrollment of patients into a study is usually the ratelimiting factor in clinical trials. When death is a planned outcome in 50% of

take years to accumulate patients, and at such financial expense that the price of new drugs reflecting the protracted studies is usually prohibitive.

More Humane Options There are alternatives. If a drug to be tested is known to be superior to its comparator, the concept of “equipoise” suggests that the comparator study need not be done. Extending this concept, if during a study there is clear superiority of one drug to its comparator, “clinical equipoise” suggests that logically and humanely, the effective drug should be available to all participants.

Furthermore, surrogate markers may be used as primary endpoints according to the International Conference on

Although narrow-entry, randomized, placebo-controlled trials based on preplanned deaths and overall survival may be the gold standard in the laboratory today, human beings are not laboratory rats.

Sound scientific research can be done without lethality as a planned endpoint.

—Donald M. Gleason, MD, and Ryan G.N. Seltzer, PhD

study patients, physicians are not anxious to enroll their patients in such studies.

Furthermore, the informed consent process seldom clearly expresses this reality to the volunteer subject, a violation of one of several tenets of the Belmont Report guidelines for ethical treatment of patients. Patients offering their lives and well-being to a study expect “beneficence”—that is, they expect the study will not do them harm. Moreover, patients with lethal disease are a very vulnerable population, willing to take a chance for survival.

Taking advantage of a vulnerable population and ignoring the concept of beneficence are not within the concept of justice according to the Belmont Report, yet are integral parts of the overall survival concept pervading current human research. It is not surprising that human research studies of lethal disease

The ASCO Post

Wants to Hear From You

Harmonisation, “when the surrogate is reasonably likely to predict clinical outcome.” When predictive surrogate markers are available, there is no need for a study to require planned deaths.

Surrogate markers may include imaging studies, biochemical markers, circulating tumor cells, etc.

Yet another approach is to abandon comparator, placebo-controlled trials entirely, in favor of registries. Registries are currently employed in postmarketing surveillance and are responsible for uncovering recondite side effects and drug interactions. Introducing registries in the premarketing space, replacing phase III trials, would facilitate the evaluation of a drug at different stages of disease simultaneously at greatly reduced cost.

Such investigative registries exist for the study of rare diseases (such as Gaucher’s disease), where the luxury of a

population of 1,000 volunteers and 500 deaths are just not available. Diseasespecific registries would feature wide entry criteria, no placebo, and retention of patients who might otherwise leave and bias a study because of placebo concerns. Statistical techniques exist to deal with confounding variables, simulate the benefits of randomized controlled trials, and offer a humane way to meld scientific and humanitarian concerns.

Although narrow-entry, randomized, placebo-controlled trials based on preplanned deaths and overall survival may be the gold standard in the laboratory today, human beings are not laboratory rats. Sound scientific research can be done without lethality as a planned endpoint. n —­­Donald M. Gleason, MD Clinical Professor, Urology (retired) College of Medicine The University of Arizona —Ryan G.N. Seltzer, PhD Mel and Enid Zuckerman College of Public Health The University of Arizona, Tucson Disclosure: Drs. Gleason and Seltzer reported no potential conflicts of interest.

References 1. Denny FW, Wannamaker LW, Rammelkamp CH, et al: Landmark article May 13, 1950: Prevention of rheumatic fever.

Treatment of the preceding streptococcic infection. JAMA 254:534-537, 1985.

2. Scher HI, Saad F, Tapin Me, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367:1187-1197, 2012.

3. de Bono JS, Logothetis CJ, Molina A, et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995-2005, 2011.

4. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2012.

5. Lattimer JK: Renal tuberculosis. N Engl J Med 273:208-211, 1965.

6. Levine C: Has AIDS changed the ethics of human subjects research? Law, Med Health Care 16:167-173, 1988.

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

ASCOPost.com | AUGUST 15, 2014

PAGE 171

Journal Spotlight Survivorship

Childhood Cancer Survivors Hospitalized Frequently Years After Cancer Treatment

S

urvivors of childhood cancers were hospitalized more often and for longer durations because of blood disorders and other problems, many years

ized and their hospital-related costs. n Disclosure: This study was funded by a Huntsman Cancer Institute Cancer Control and Population Sciences Research Award, the Huntsman Cancer Foundation, a Primary

Children’s Medical Foundation Career Development Award, the Utah Cancer Registry, and the National Institutes of Health. Dr. Kirchhoff reported no potential conflicts of interest.

Reserve Your Seat Today at NCCN.org/hem

Register Now!

Scan QR code to go to NCCN.org/hem

Anne C. Kirchhoff, PhD, MPH

after cancer treatment was completed, compared with the general population, according to a study published in Cancer Epidemiology, Biomarkers & Prevention.1 “Our findings demonstrate that childhood cancer survivors face ongoing problems that can lead to hospitalization, even for those who are decades past their original cancer diagnosis. This can negatively impact their quality of life,” said Anne C. Kirchhoff, PhD, MPH, Assistant Professor of Pediatrics at the Huntsman Cancer Institute of the University of Utah in Salt Lake City.

Cancer-Focused Care “Regular cancer-focused health care is important for identifying health problems for survivors throughout their lives,” Dr. Kirchhoff added. “Patients and families who have experienced childhood cancer should obtain a cancer treatment summary and recommendations for follow-up care from their oncologist, and coordinate their follow-up care with their oncology and primary care doctors to ensure their health-care needs are being managed.”

In this study, survivors were 52% more likely to be hospitalized, and their number of admissions was 67% higher, compared with age- and sex-matched individuals who did not have cancer.

Survivors were also 35% more likely to have stayed longer every time they were hospitalized, compared with controls.

Common reasons for hospitalizations for survivors compared with the controls included conditions like blood disorders (such as anemia) and cancer, although it is unclear if this was for their original cancer diagnosis or new cancers. Infections, nervous system problems, and respiratory problems were other leading reasons for hospitalization.

Dr. Kirchhoff and colleagues will conduct further analyses to better understand the reasons survivors are hospital-

Reference 1. Kirchhoff AC, Fluchel MN, Wright J, et al: Risk of hospitalization for survivors of childhood and adolescent cancer. Cancer Epidemiol Biomarkers Prev 23:1280-1289, 2014.

NCCN 9th Annual Congress:

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Join Steven M. Horwitz, MD, and Andrew D. Zelenetz, MD, PhD, Memorial Sloan Kettering Cancer Center, as they lead this engaging, session on the current and evolving standards for the management of patients with indolent non-Hodgkin’s lymphoma.

This program will help you improve your competence in a variety of aspects of clinical management, including: • Accurate diagnosis • Determining stage and anatomic extent of lymphoma • Current standards of care

• Novel therapeutic options (particularly in specific populations) • Current pivotal studies enrolling patients

Pre-registration for this satellite lunch program is not required. This program is available to attendees on a first-come, first-seated basis.

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of NCCN and Clinical Care Options, LLC. NCCN is accredited by the ACCME to provide continuing medical education for physicians.

This activity is be approved for AMA PRA Category 1 Credit(s)™ for physicians and is also be accredited for nurses, pharmacists, case managers, and other health care professionals. Please refer to the complete accreditation details for more information.

This congress is supported by educational grants from CELGENE CORPORATION; Millennium: The Takeda Oncology Company; and Sigma-Tau Pharmaceuticals, Inc.

Sponsorship and exhibit opportunities available!

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The ASCO Post | AUGUST 15, 2014

PAGE 172

Opinion Health-Care Policy

Hagop Kantarjian, MD continued from page 1

with lower premiums (39% paid more but often for much better coverage).3 Moreover, the law is already improving lives. Adolescents and young adults who had care through their parents’ insurance were reported to be doing better.4 That said, some problems were noted. The choices of providers were narrower,5 there were “hidden cliffs” (referring to people who earn slightly more than four times the federal poverty level—$46,000 for an individual, $95,000 for a family of four—and who could not receive tax credit subsidies to reduce insurance premiums),6 insurers exerted pressures to restrict care and pharmacy outlets attempted to restrict drug choices, and insurers raised outof-pocket expenses on particular drugs (eg, antiretroviral drugs for HIV infection) to discourage vulnerable groups (patients with preexisting conditions) from applying to a particular insurance program.7 These can be remedied with additional legislation.

Mostly Good News Thus, so far, most of the Affordable Care Act news is good, and the scary scenarios painted by some experts never happened: low enrollment and

“death spiral” of the Affordable Care Act, high loss rates of existing coverage, insurance rate shocks, soaring healthcare costs, younger people not signing up, people not paying premiums.8 Why is there then still resistance to and bad press about the Affordable Care Act, and even calls to repeal it if Republicans win a majority in the two houses of Congress? Perhaps it is

best is hyped by some media that offer proof with anecdotes of presidents, foreign dignitaries, and wealthy individuals who seek health care in the United States, and of Canadians who wait longer for procedures than Americans. Prominent figures like Republican House Speaker John Boehner add strength to the argument by stating that the Affordable Care Act “is going to de-

The Affordable Care Act is far from being ideal, but it is a good start, and there are many opportunities for improvement. As more Americans get access to insurance at affordable prices, the results for the U.S. health-care system will improve in lockstep.

—Hagop Kantarjian, MD

because some Americans still believe that before the Affordable Care Act, we had “the best health-care system in the world.” This mantra is repeated so often that it is held by many as an unshakable truth. Repetition transforms belief into reality: We believe what we say, which becomes truer by repetition.

The belief that our health care is the

stroy the best health-care delivery system in the world.”

Sadly, almost all objective analyses suggest otherwise. The U.S. health-care system often ranks very low by multiple quantifiable measures.9-12 The most recent Commonwealth Fund 2014 Update titled ranked U.S. health care last among 11 developed nations by several objec-

tive parameters: low patient satisfaction, high rate of medical errors, worse infant mortality, shorter life expectancy, and poor efficiency (see Fig. 1).13

Troubling Findings Critics argue that while the results are bad for the average American, for those with health insurance, the United States is still the best place to receive care. They highlight the data where survival rates for some cancers (cervix, breast, gastrointestinal) are better in the United States than in other developed nations.14 For example, one study showed that patients with cancer live an average of 11.1 years after diagnosis in the United States, but only 9.3 years after diagnosis in Europe.15 However, this may not be because we have better treatments, but because we do more screening procedures (mammograms, colonoscopies, Pap smears) and diagnose more cancers earlier.16 When annual mortality rates are considered (a better measure of treatment efficacy than survival rates), the U.S. results are not better.17 Moreover, some of the findings regarding U.S. health care are quite troubling.11 For example, 37% of Americans do not seek medical help when they become sick, or fail to fill prescriptions

Fig. 1: Overall Ranking of 11 Developed Nations in Various Health-Care Parameters. Reprinted from Davis K, et al,13 with permission from The Commonwealth Fund.

ASCOPost.com | AUGUST 15, 2014

PAGE 173

Opinion

due to high cost (vs only 4%–6% in Britain and Sweden). About 23% of Americans have problems paying bills (vs only 6% or less in Britain and Sweden).

Three-quarters of Americans believe our health-care system should undergo major changes; on the other hand, 50% to 73% of Europeans are happy with their systems. And Americans wait longer than most Europeans to see a doctor, but we do beat the Canadians by a narrow margin.

High Spending These poor results startle many, because the United States already spends more on health care than any other nation: 18% of the gross domestic product, close to $8,500 per capita. The two closest high-spending countries were Norway and Switzerland at about $5,500 each. Most other nations spend between $3,000 and $5,000 per capita.13 If we pay so much for health care in the United States, why do we get so little in return, and where does the money go? It is important to bear in mind that health care in most advanced nations is not for profit, and is a moral if not legal right of citizens. In the United States, health care is considered a “privilege” by some and an “entitlement” by others. It is provided for profit and, indeed, is a very profitable industry. For example, return on investment of drug companies has increased from 10% in the 1970s to 19% in 2010.

While we spent about $2.8 trillion on health care in 2012 (actually $8,900 per capita).18 less than $1 trillion was spent on direct patient care. Most of the dollars dissipate in the form of excessive profits to health-care businesses, including hospitals, drug and medical device companies, and insurance companies.

Hundreds of millions of dollars are also spent on overburdened bureaucracies and wasteful practices aimed at maximizing profits, without any evident benefit in relation to quality or quantity of patient care. For example, about 30% of health-care dollars are for administrative costs (vs less than 10%–15% in other countries).19 In one typical 900bed hospital in the United States, about 400 employees handle insurance and billing paperwork compared with fewer than a dozen in a comparable Canadian hospital.20 We pay two to three times more for patented drugs in the United States compared with Canada or Europe.

An extreme example is the hepatitis C treatment sofosbuvir (Sovaldi), which costs $80,000 to $160,000 for a 3- to 6-month treatment in the United States, but only $900 in Egypt. The average cost for a hip replacement is $80,000 in the United States, but less than $14,000 in Europe.21 An MRI costs, on average, $1,145 in the United States, and only $138 in Switzerland. Giving birth?

Hospital costs can run to $10,000 in the United States, compared with $2,200 in Spain.22 Even within the United States, the prices show an incomprehensible wide range of variations. A colonoscopy in New York cost $740 in one area and $8,500 in another. The cost of treating an ankle sprain in an emergency room ranged from $100 to $24,000.23

Opportunities for Improvement Can we improve things? We already are, through the implementation of the Affordable Care Act. Our results were poor because we marginalized 50 million Americans who did not have insurance, while another 50 million believed they had good insurance, which in fact offered little if any protection when faced with major medical illnesses.

The Affordable Care Act is far from being ideal, but it is a good start, and there are many opportunities for improvement. As more Americans get access to insurance at affordable prices, the results for the U.S. health-care system will improve in lockstep.

The expansion of Medicaid could also save an estimated 90,000 lives every year.24 Unfortunately, for obscure and incomprehensible reasons, 24 states still refuse to implement the Medicaid expansion of the Affordable Care Act,25 which could harm millions and potentially cause the loss of an estimated 19,000 lives a year.24,26 Studies analyzing data from the Affordable Care Act implementation and from the similar Massachusetts universal healthcare program are already showing better outcomes.27 Will the Affordable Care Act or a more universal health-care system increase costs? Not necessarily. By reducing bureaucracy and administrative expenses, eliminating waste, suppressing fraud, negotiating better prices for hospital care, procedures, drugs and devices, and curbing current excessive profits, we will be able to deliver better and more health care to all Americans

at affordable individual prices, and with lower spending per capita.

If this was possible in most advanced countries, why not in the United States? n

Disclosure: Dr. Kantarjian reported no potential conflicts of interest.

References 1. Blumenthal D: Collins S: Health care coverage under the Affordable Care Act—a progress report. N Engl J Med. July 2, 2014 (early release online).

2. Ander S, Newport F: After exchanges close, 5% of Americans are newly insured.

Gallup, June 23, 2014. Available at www. gallup.com. Accessed July 11, 2014.

3. Hamel L, Rao M, Levitt L, et al: Survey of non-group health insurance enrollees. Kaiser Family Foundation, June 19, 2014. Available at kff.org. Accessed July 11, 2014.

4. Chua, KP, Sommers BD: Changes in health and medical spending among young adults under health reform. JAMA 311:2437-2439, 2014.

5. Brill S: Hate Obama, love Obamacare.

Time 3:18, 2014.

6. Brill S: The hidden cliffs in Obamacare. Time 22:18-19, 2014.

7. Novack S: Is Obamacare living up to its preexisting-conditions promise? National Journal, June 23, 2014. Available at www.nationaljournal.com. Accessed July 11, 2014.

8. Krugman P: The conscience of a liberal: Zero for six. New York Times, June 26, 2014. Available at krugman.blogs.nytimes. com. Accessed July 11, 2014.

9. Social Progress Imperative: The Social Progress Index 2014. Available at www. socialprogressimperative.org. Accessed July 11, 2014.

10. Institute of Medicine: U.S. health in international perspective: Shorter lives, poorer health. Report brief, January 2013.

Available at www.iom.edu. Accessed July 11, 2014.

11. Commonwealth Fund: U.S. ranks last among seven countries on health system performance based on measures of quality, efficiency, access, equity, and healthy lives. News release, June 23, 2010.

Available at www.commonwealthfund.org.

Accessed July 11, 2014.

12. Nolte E, McKee M: Variations in amenable mortality—trends in 16 highincome nations. Health Policy 103:47-52, 2011.

13. Davis K, Stremikis K, Squires D, et al: Mirror, mirror on the wall, 2014 update: How the U.S. health care system compares internationally. Commonwealth Fund, June 16, 2014. Available at www.commonwealthfund.org. Accessed July 11, 2014.

14. Hussey PS, Anderson GF, Osborn R, et al: How does the quality of care compare in five countries? Health Aff (Millwood) 23:89-99, 2004.

15. Philipson T, Eber M, Lakdawalla D, et al: An analysis of whether higher health care spending in the United States versus Europe is ‘worth it’ in the case of cancer.

Health Aff (Millwood) 31:667-675, 2012.

16. Klein E: Is America better at treating cancer than Europe? Vox, June 24, 2014.

Available at www.vox.com. Accessed July 11, 2014.

17. Carroll A: Survival rates are not the same as mortality rates. Incidental Economist, August 31, 2010. Available at theincidentaleconomist.com. Accessed July 11, 2014.

18. Centers for Medicare & Medicaid Services: National Health Expenditures 2012 Highlights. Available at www.cms.gov.

2012. Accessed July 11, 2014.

19. Woolhandler S, Campbell T, Himmelstein D: Cost of health care administration in the United States and Canada. N Engl J Med 349:768-775, 2003.

20. Solman P: Why does health care cost so much in America? Ask Harvard’s David Cutler. PBS Newshour, November 19, 2013. Available at www.pbs.org. Accessed July 11, 2014.

21. Rosenthal E: In need of a new hip, but priced out of the U.S. New York Times, August 3, 2013. Available at www.nytimes. com. Accessed July 11, 2013.

22. Freedman J: Pay more, get less. How American socio-economic policy is falling short. New America Foundation. April 30, 2014. Available at newamerica.net. Accessed July 11, 2014.

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April 23, 2014. Available at www.cms.gov.

Accessed July 11, 2014.

24. Price CC, Eibner C: For states that opt out of Medicaid expansion: 3.6 million fewer insured and $8.4 billion less in federal payments. Health Aff (Millwood) 32:10301036, 2013.

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27. Sommers B, Long S, Baicker K: Changes in mortality after Massachusetts health care reform: A quasi-experimental study. Ann Intern Med 160:585-593, 2014.

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The ASCO Post | AUGUST 15, 2014

News

National Ovarian Cancer Coalition Featured in New York’s Rockefeller Center Window During August Effort to Raise Awareness and Promote Education about Ovarian Cancer

T

hroughout August, the National Ovarian Cancer Coalition (NOCC) is being featured in the highly coveted 10 Rockefeller Plaza showcase window in New York. The space is being donated by EHE International, a historic preventive health-care company, dedicated to proactive health-care management. The eye-catching window display, designed in partnership with Stephen Pannone of designojo, presents colorful flip-flops symbolizing women’s footsteps, in a ratio that denotes the alarmingly low ovarian cancer survival rate beyond 5 years.

“The 5-year survival rate for women diagnosed with the disease is only 44%.

The associated impacts on families and communities make ovarian cancer More Than a Woman’s Disease®. We thank EHE International for affording NOCC the opportunity to increase awareness, which is essential to saving lives,” comments David Barley, Chief Executive Officer of

the National Ovarian Cancer Coalition.

“EHE International is proud to support the National Ovarian Cancer Coalition’s efforts to raise awareness about ovarian cancer,” said Deborah McKeever, President of EHE International. “Together, we hope to spread awareness and promote education about this insidious disease, and help save lives.”

Ovarian cancer continues to be the deadliest of all gynecologic cancers, affecting 1 in 72 women in their lifetime.

There is no screening test for the disease, and it is undetected by a Pap test.

The symptoms can be vague, and mimic those of unrelated conditions. As a result, most cases are diagnosed in later stages of the disease when the prognosis is poor.

Helping to raise awareness about these signs and symptoms is integral to the mission of the NOCC. For more information, please visit www.ovarian.org. n

S:9.5" S:9.5"

(bevacizumab) AVASTIN AVASTIN®® (bevacizumab) Solution Solution for for intravenous intravenous infusion infusion Initial Initial U.S. U.S.Approval: Approval: 2004 2004 This This is is aa brief brief summary summary of of information information about about AVASTIN. AVASTIN. Before Before prescribing, prescribing, please please see see full full Prescribing Prescribing Information.

Information.

WARNING: WARNING: GASTROINTESTINAL GASTROINTESTINAL PERFORATIONS, PERFORATIONS, SURGERY SURGERY AND AND WOUND WOUND HEALING HEALING COMPLICATIONS, COMPLICATIONS, and and HEMORRHAGE HEMORRHAGE Gastrointestinal Gastrointestinal Perforations Perforations The The incidence incidence of of gastrointestinal gastrointestinal perforation, perforation, some some fatal, fatal, in in Avastin‑treated Avastin‑treatedpatients patientsranges rangesfrom from0.3 0.3to to2.4%.

2.4%.Discontinue Discontinue Avastin Avastin in in patients patients with with gastrointestinal gastrointestinal perforation. perforation. [See [See Dosage Dosage and and Administration Administration (2.4), (2.4), Warnings Warnings and and Precautions Precautions (5.1).]

(5.1).]

Surgery Surgery and and Wound Wound Healing Healing Complications Complications The The incidence incidence of of wound wound healing healing and and surgical surgical complications, complications, including including serious serious and and fatal fatal complications, complications, is is increased increased in in Avastin‑treated Avastin‑treated patients. patients. Discontinue Discontinue Avastin Avastin in in patients patients with with wound wound dehiscence. dehiscence. The The appropriate appropriate interval interval between between termination termination of of Avastin Avastin and and subsequent subsequent elective elective surgery surgery required requiredto toreduce reducethe therisks risksof ofimpaired impairedwound woundhealing/wound healing/wound dehiscence dehiscence has has not not been been determined. determined. Discontinue Discontinue at at least least 28 28 days days prior prior to to elective elective surgery. surgery. Do Do not not initiate initiate Avastin Avastin for for at at least least 28 28 days days after after surgery surgery and and until until the the surgical surgical wound wound is is fully fully healed. healed. [See [See Dosage Dosage and and Administration Administration (2.4), (2.4), Warnings Warnings and and Precautions Precautions (5.2), (5.2), Adverse Adverse Reactions Reactions (6.1).]

(6.1).]

Hemorrhage Hemorrhage Severe Severe or or fatal fatal hemorrhage, hemorrhage, including including hemoptysis, hemoptysis, gastrointestinal gastrointestinal bleeding, bleeding, central central nervous nervous systems systems (CNS) (CNS) hemorrhage, hemorrhage, epistaxis, epistaxis, and and vaginal vaginal bleeding bleeding occurred occurred up up to to five‑fold five‑fold more more frequently frequently in in patients patients receiving receiving Avastin.

Avastin. Do Do not not administer administer Avastin Avastin to to patients patients with with serious serious hemorrhage hemorrhage or or recent recent hemoptysis. hemoptysis. [See [See Dosage Dosage and and Administration Administration (2.4), (2.4), Warnings Warnings and and Precautions Precautions (5.3), (5.3), Adverse Adverse Reactions Reactions (6.1).]

(6.1).]

11 INDICATIONS INDICATIONS AND AND USAGE USAGE 1.1 1.1 Metastatic Metastatic Colorectal Colorectal Cancer Cancer (mCRC) (mCRC) Avastin Avastin isis indicated indicated for for the the first‑ first‑ or or second‑line second‑line treatment treatment of of patients patients with with metastatic metastatic carcinoma carcinoma of of the the colon colon or or rectum rectum in in combination combination with with intravenous intravenous 5‑fluorouracil–based 5‑fluorouracil–based chemotherapy. chemotherapy.

Avastin, Avastin,in incombination combinationwith withfluoropyrimidine‑irinotecan‑ fluoropyrimidine‑irinotecan‑or orfluoropyrimidine‑ fluoropyrimidine‑ oxaliplatin‑based oxaliplatin‑based chemotherapy, chemotherapy,isis indicated indicated for for the the second‑line second‑line treatment treatment of of patients patientswith withmetastatic metastaticcolorectal colorectalcancer cancerwho whohave haveprogressed progressedon onaafirst‑line first‑line Avastin‑containing Avastin‑containing regimen. regimen.

Limitation Limitation of of Use: Use:Avastin Avastin isis not not indicated indicated for for adjuvant adjuvant treatment treatment of of colon colon cancer. cancer. [See [See Clinical Clinical Studies Studies (14.2).]

(14.2).]

1.2 1.2 Non‑Squamous Non‑Squamous Non–Small Non–Small Cell Cell Lung Lung Cancer Cancer (NSCLC) (NSCLC) Avastin Avastin isis indicated indicated for for the the first‑line first‑line treatment treatment of of unresectable, unresectable, locally locally advanced, advanced, recurrent recurrent or or metastatic metastatic non–squamous non–squamous non–small non–small cell cell lung lung cancer cancer in in combination combination with with carboplatin carboplatin and and paclitaxel. paclitaxel.

1.3 1.3 Glioblastoma Glioblastoma Avastin Avastin isis indicated indicated for for the the treatment treatment of of glioblastoma glioblastoma with with progressive progressive disease disease in in adult adult patients patients following following prior prior therapy therapy as as aa single single agent. agent.

The The effectiveness effectiveness of ofAvastin Avastin in in glioblastoma glioblastoma isis based based on on an an improvement improvement in in objective objective response response rate. rate.There There are are no no data data demonstrating demonstrating an an improvement improvement in indisease‑related disease‑relatedsymptoms symptomsor orincreased increasedsurvival survivalwith withAvastin.

Avastin.[See [SeeClinical Clinical Studies Studies (14.4).]

(14.4).]

1.4 1.4 Metastatic Metastatic Renal Renal Cell Cell Carcinoma Carcinoma (mRCC) (mRCC) Avastin Avastin isis indicated indicated for for the the treatment treatment of of metastatic metastatic renal renal cell cell carcinoma carcinoma in in combination combination with with interferon interferon alfa. alfa.

44 CONTRAINDICATIONS CONTRAINDICATIONS None.

None.

55 WARNINGS WARNINGS AND AND PRECAUTIONS PRECAUTIONS 5.1 5.1 Gastrointestinal Gastrointestinal Perforations Perforations Serious Serious and and sometimes sometimes fatal fatal gastrointestinal gastrointestinal perforation perforation occurs occurs at at aa higher higher incidence incidence in in Avastin Avastin treated treated patients patients compared compared to to controls. controls. The The incidence incidence of of gastrointestinal gastrointestinal perforation perforation ranged ranged from from 0.3 0.3 to to 2.4% 2.4% across across clinical clinical studies. studies. [See [SeeAdverse Adverse Reactions Reactions (6.1).]

(6.1).]

The The typical typical presentation presentation may may include include abdominal abdominal pain, pain, nausea, nausea, emesis, emesis, constipation, constipation,and andfever. fever.Perforation Perforationcan canbe becomplicated complicatedby byintra‑abdominal intra‑abdominal abscess abscess and and fistula fistula formation. formation. The The majority majority of of cases cases occurred occurred within within the the first first 50 50 days days of of initiation initiation of ofAvastin.

Avastin.

Discontinue Discontinue Avastin Avastin in in patients patients with with gastrointestinal gastrointestinal perforation. perforation. [See [See Boxed BoxedWarning, Warning, Dosage Dosage and andAdministration Administration (2.4).]

(2.4).]

The National Ovarian Cancer Coalition is being featured in the 10 Rockefeller Plaza showcase window in New York throughout August to raise awareness about ovarian cancer. September is Ovarian Cancer Awareness Month.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

AVASTIN AVASTIN®® (bevacizumab) (bevacizumab) 5.4 5.4 Non‑Gastrointestinal Non‑Gastrointestinal Fistula Fistula Formation Formation Serious Serious and and sometimes sometimes fatal fatal non‑gastrointestinal non‑gastrointestinal fistula fistula formation formation involving involving tracheo‑esophageal, tracheo‑esophageal, bronchopleural, bronchopleural, biliary, biliary, vaginal, vaginal, renal renal and and bladder bladder sites sites occurs occurs at at aa higher higher incidence incidence in in Avastin‑treated Avastin‑treated patients patients compared compared to to controls. controls. The The incidence incidence of of non‑gastrointestinal non‑gastrointestinal perforation perforation was was ≤≤ 0.3% 0.3% in in clinical clinical studies. studies. Most Most events events occurred occurred within within the the first first 66 months months of ofAvastin Avastin therapy. therapy.

Discontinue Discontinue Avastin Avastin in in patients patients with with fistula fistula formation formation involving involving an an internal internal organ. organ. [See [See Dosage Dosage and andAdministration Administration (2.4).]

(2.4).]

5.5 5.5 Arterial Arterial Thromboembolic Thromboembolic Events Events Serious, Serious, sometimes sometimes fatal, fatal, arterial arterial thromboembolic thromboembolic events events (ATE) (ATE) including including cerebral cerebral infarction, infarction, transient transient ischemic ischemic attacks, attacks, myocardial myocardial infarction, infarction, angina, angina,and andaavariety varietyof ofother otherATE ATEoccurred occurredat ataahigher higherincidence incidencein inpatients patients receiving receivingAvastin Avastin compared compared to to those those in in the the control control arm. arm.Across Across indications, indications, the the incidence incidence of of Grade Grade ≥≥ 33 ATE ATE in in the the Avastin Avastin containing containing arms arms was was 2.6% 2.6% compared compared to to 0.8% 0.8% in in the the control control arms. arms.Among Among patients patients receiving receivingAvastin Avastin in in combination combination with with chemotherapy, chemotherapy,the the risk risk of of developing developingATE ATE during during therapy therapy was was increased increased in in patients patients with with aa history history of of arterial arterial thromboembolism, thromboembolism, diabetes, diabetes,or orage agegreater greaterthan than65 65years. years.[See [SeeUse Usein inSpecific SpecificPopulations Populations(8.5).]

(8.5).]

The The safety safety of of resumption resumption of ofAvastin Avastin therapy therapy after after resolution resolution of of an anATE ATE has has not notbeen beenstudied. studied.Discontinue DiscontinueAvastin Avastinin inpatients patientswho whoexperience experienceaasevere severe ATE. ATE. [See [See Dosage Dosage and andAdministration Administration (2.4).]

(2.4).]

5.6 5.6 Hypertension Hypertension The The incidence incidence of of severe severe hypertension hypertension isis increased increased in in patients patients receiving receiving Avastin Avastin as as compared compared to to controls. controls. Across Across clinical clinical studies studies the the incidence incidence of of Grade Grade 33 or or 44 hypertension hypertension ranged ranged from from 5‑18%.

5‑18%.

Monitor Monitor blood blood pressure pressure every every two two to to three weeks three weeks during during treatment treatment with with Avastin.

Avastin. Treat Treat with with appropriate appropriate anti‑hypertensive anti‑hypertensive therapy therapy and and monitor monitor blood blood pressure pressure regularly. regularly. Continue Continue to to monitor monitor blood blood pressure pressure at at regular regular intervals intervals in in patients patients with with Avastin‑induced Avastin‑induced or or ‑exacerbated ‑exacerbated hypertension hypertension after after discontinuation discontinuation of ofAvastin.

Avastin.

Temporarily Temporarily suspend suspend Avastin Avastin in in patients patients with with severe severe hypertension hypertension that that isis not not controlled controlled with with medical medical management. management.Discontinue DiscontinueAvastin Avastin in in patients patients with with hypertensive hypertensive crisis crisis or or hypertensive hypertensive encephalopathy. encephalopathy.[See [See Dosage Dosage and and Administration Administration (2.4).]

(2.4).]

5.7 5.7 Reversible Reversible Posterior Posterior Leukoencephalopathy Leukoencephalopathy Syndrome Syndrome (RPLS) (RPLS) RPLS RPLS has has been been reported reported with with an an incidence incidence of of << 0.1% 0.1% in in clinical clinical studies. studies.

The The onset onset of of symptoms symptoms occurred occurred from from 16 16 hours hours to to 11 year year after after initiation initiation of of Avastin.

Avastin.RPLS RPLS isis aa neurological neurological disorder disorder which which can can present present with with headache, headache, seizure, seizure, lethargy, lethargy, confusion, confusion, blindness blindness and and other other visual visual and and neurologic neurologic disturbances. disturbances. Mild Mild to to severe severe hypertension hypertension may may be be present. present. Magnetic Magnetic resonance resonance imaging imaging (MRI) (MRI) isis necessary necessary to to confirm confirm the the diagnosis diagnosis of of RPLS. RPLS. Discontinue Discontinue Avastin Avastin in in patients patients developing developing RPLS. RPLS. Symptoms Symptoms usually usually resolve resolve or or improve improve within within days, days,although although some some patients patients have have experienced experienced ongoing ongoing neurologic neurologic sequelae. sequelae.The The safety safety of of reinitiating reinitiatingAvastin Avastin therapy therapy in in patients patients previously previously experiencing experiencing RPLS RPLS isis not not known. known. [See [See Dosage Dosage and and Administration Administration (2.4).]

(2.4).]

5.8 5.8 Proteinuria Proteinuria The The incidence incidence and and severity severity of of proteinuria proteinuria isis increased increased in in patients patients receiving receiving Avastin Avastin as as compared compared to to controls. controls.Nephrotic Nephrotic syndrome syndrome occurred occurred in in << 1% 1% of of patients patients receiving receiving Avastin Avastin in in clinical clinical trials, trials, in in some some instances instances with with fatal fatal outcome. outcome.[See [SeeAdverse Adverse Reactions Reactions (6.1).]

(6.1).] In In aa published published case case series, series,kidney kidney biopsy biopsy of of six six patients patients with with proteinuria proteinuria showed showed findings findings consistent consistent with with thrombotic thrombotic microangiopathy. microangiopathy.

Monitor Monitor proteinuria proteinuria by by dipstick dipstick urine urine analysis analysis for for the the development development or or worsening worsening of of proteinuria proteinuria with with serial serial urinalyses urinalyses during during Avastin Avastin therapy. therapy.

Patients Patients with with aa 22 ++ or or greater greater urine urine dipstick dipstick reading reading should should undergo undergo further further assessment assessment with with aa 24‑hour 24‑hour urine urine collection. collection.

Suspend Suspend Avastin Avastin administration administration for for ≥≥22 grams grams of of proteinuria/24 proteinuria/24 hours hours and and resume resume when when proteinuria proteinuria isis << 22 gm/24 gm/24 hours. hours. Discontinue Discontinue Avastin Avastin in in patients patients with with nephrotic nephrotic syndrome. syndrome.[See [See Dosage Dosage and andAdministration Administration (2.4).]

(2.4).]

Data Data from from aa postmarketing postmarketing safety safety study study showed showed poor poor correlation correlation between between UPCR UPCR (Urine (Urine Protein/Creatinine Protein/Creatinine Ratio) Ratio) and and 24 24 hour hour urine urine protein protein (Pearson (Pearson Correlation Correlation 0.39 0.39 (95% (95% CI CI 0.17, 0.17, 0.57).

0.57). [See [See Use Use in in Specific Specific Populations Populations (8.5).]

(8.5).]

5.9 5.9 Infusion Infusion Reactions Reactions Infusion Infusion reactions reactions reported reported in in the the clinical clinical trials trials and and post‑marketing post‑marketing experience experience include include hypertension, hypertension, hypertensive hypertensive crises crises associated associated with with neurologic neurologic signs signs and and symptoms, symptoms, wheezing, wheezing, oxygen oxygen desaturation, desaturation, Grade Grade 33 hypersensitivity, hypersensitivity, chest chest pain, pain, headaches, headaches, rigors, rigors, and and diaphoresis. diaphoresis. In In clinical clinical studies, studies, infusion infusion reactions reactions with with the the first first dose dose of of Avastin Avastin were were uncommon uncommon (< (<3%) 3%) and and severe severe reactions reactions occurred occurred in in 0.2% 0.2% of of patients. patients.

Stop Stop infusion infusion ifif aa severe severe infusion infusion reaction reaction occurs occurs and and administer administer appropriate appropriate medical medical therapy. therapy. [See [See Dosage Dosage and andAdministration Administration (2.4).]

(2.4).]

5.10 5.10 Ovarian Ovarian Failure Failure The The incidence incidence of of ovarian ovarian failure failure was was higher higher (34% (34% vs. vs. 2%) 2%) in in premenopausal premenopausal women women receiving receiving Avastin Avastin in in combination combination with with mFOLFOX mFOLFOX chemotherapy chemotherapy as as compared compared to to those those receiving receiving mFOLFOX mFOLFOX chemotherapy chemotherapy alone alone for for adjuvant adjuvant treatment treatment for for colorectal colorectal cancer, cancer, aa use use for for which which Avastin Avastin isis not not 5.2 5.2 Surgery Surgery and and Wound Wound Healing Healing Complications Complications approved. approved.

Inform Inform females females of of reproductive reproductive potential potential of of the the risk risk of of ovarian ovarian Avastin Avastin impairs impairs wound wound healing healing in in animal animal models. models. [See [See Nonclinical Nonclinical failure prior prior to to starting starting treatment treatment with with Avastin.

Avastin. [See [See Adverse Adverse Reactions Reactions Toxicology Toxicology (13.2).]

(13.2).] In In clinical clinical trials, trials, administration administration of of Avastin Avastin was was not not failure (6.1),Use Usein inSpecific SpecificPopulations Populations(8.6).]

(8.6).] allowed allowed until until at at least least 28 28 days days after after surgery. surgery. In In aa controlled controlled clinical clinical trial, trial, (6.1), the the incidence incidence of of wound wound healing healing complications, complications,including including serious serious and and fatal fatal 66 ADVERSE ADVERSE REACTIONS REACTIONS complications, complications, in in patients patients with with mCRC mCRC who who underwent underwent surgery surgery during during the the The The following following serious serious adverse adverse reactions reactions are are discussed discussed in in greater greater detail detail in in course course of ofAvastin Avastin treatment treatment was was 15% 15% and and in in patients patients who who did did not not receive receive other other sections sections of of the the label: label: Avastin, Avastin, was was 4%.

4%. [See [SeeAdverse Adverse Reactions Reactions (6.1).]

(6.1).]

•• Gastrointestinal Gastrointestinal Perforations Perforations [See [See Boxed Boxed Warning, Warning, Dosage Dosage and and Avastin Avastin should should not not be be initiated initiated for for at at least least 28 28 days days following following surgery surgery and and Administration Administration (2.4), (2.4),Warnings Warnings and and Precautions Precautions (5.1).]

(5.1).] until until the the surgical surgical wound wound isis fully fully healed. healed. Discontinue Discontinue Avastin Avastin in in patients patients •• Surgery Surgeryand andWound WoundHealing HealingComplications Complications[See [SeeBoxed BoxedWarning, Warning,Dosage Dosage with with wound wound healing healing complications complications requiring requiring medical medical intervention. intervention. and andAdministration Administration (2.4), (2.4),Warnings Warnings and and Precautions Precautions (5.2).]

(5.2).]

The The appropriate appropriate interval interval between between the the last last dose dose of of Avastin Avastin and and elective elective •• Hemorrhage Hemorrhage [See [See Boxed Boxed Warning, Warning, Dosage Dosage and and Administration Administration (2.4), (2.4), surgery surgery isis unknown; unknown; however, however, the the half‑life half‑life of of Avastin Avastin isis estimated estimated to to be be Warnings Warnings and and Precautions Precautions (5.3).]

(5.3).]

20 days.

20 days. Suspend SuspendAvastin Avastin for for at at least least 28 28 days days prior prior to to elective elective surgery. surgery. Do Do •• Non‑Gastrointestinal Non‑Gastrointestinal Fistula Fistula Formation Formation [See [See Dosage Dosage and andAdministration Administration not not administer administer Avastin Avastin until until the the wound wound isis fully fully healed. healed. [See [See Boxed Boxed (2.4), (2.4),Warnings Warnings and and Precautions Precautions (5.4).]

(5.4).]

Warning, Warning, Dosage Dosage and andAdministration Administration (2.4).]

(2.4).]

••Arterial Arterial Thromboembolic Thromboembolic Events Events [See [See Dosage Dosage and and Administration Administration (2.4), (2.4), Necrotizing Necrotizing fasciitis fasciitis including including fatal fatal cases, cases, has has been been reported reported in in patients patients Warnings Warnings and and Precautions Precautions (5.5).]

(5.5).] treated treated with with Avastin; Avastin; usually usually secondary secondary to to wound wound healing healing complications, complications, • • Hypertensive Hypertensive Crisis Crisis [See [See Dosage Dosage and and Administration Administration (2.4), (2.4), Warnings Warnings and and gastrointestinal gastrointestinal perforation perforation or or fistula fistula formation. formation. Discontinue Discontinue Avastin Avastin Precautions Precautions (5.6).]

(5.6).] therapy therapy in in patients patients who who develop develop necrotizing necrotizing fasciitis. fasciitis. [See [See Adverse Adverse •• Reversible Reversible Posterior Posterior Leukoencephalopathy Leukoencephalopathy Syndrome Syndrome [See [See Dosage Dosage and and Reactions Reactions (6.3).]

(6.3).]

Administration Administration (2.4), (2.4),Warnings Warnings and and Precautions Precautions (5.7).]

(5.7).]

5.3 5.3 Hemorrhage Hemorrhage •• Proteinuria Proteinuria [See [See Dosage Dosage and and Administration Administration (2.4), (2.4), Warnings Warnings and and Avastin Avastin can can result result in in two two distinct distinct patterns patterns of of bleeding: bleeding: minor minor hemorrhage, hemorrhage, Precautions Precautions (5.8).]

(5.8).] most most commonly commonly Grade Grade 11 epistaxis; epistaxis; and and serious, serious, and and in in some some cases cases fatal, fatal, • • Ovarian Ovarian Failure Failure [See [See Warnings Warnings and and Precautions Precautions (5.10), (5.10), Use Use in in Specific Specific hemorrhagic hemorrhagic events. events. Severe Severe or or fatal fatal hemorrhage, hemorrhage, including including hemoptysis, hemoptysis, Populations Populations (8.6).]

(8.6).] gastrointestinal gastrointestinal bleeding, bleeding, hematemesis, hematemesis, CNS CNS hemorrhage, hemorrhage, epistaxis, epistaxis, and and The most most common common adverse adverse reactions reactions observed observed in inAvastin Avastin patients patients at at aa rate rate vaginal vaginal bleeding bleeding occurred occurred up up to to five‑fold five‑fold more more frequently frequently The 10% and and at at least least twice twice the the control control arm arm rate, rate, are are epistaxis, epistaxis, headache, headache, in in patients patients receiving receiving Avastin Avastin compared compared to to patients patients receiving receiving only only >>10% hypertension, rhinitis, rhinitis, proteinuria, proteinuria, taste taste alteration, alteration, dry dry skin, skin, rectal rectal chemotherapy. chemotherapy.Across Across indications, indications, the the incidence incidence of of Grade Grade ≥≥ 33 hemorrhagic hemorrhagic hypertension, hemorrhage,lacrimation lacrimation disorder, disorder,back back pain pain and and exfoliative exfoliative dermatitis. dermatitis. events events among among patients patients receiving receiving Avastin Avastin ranged ranged from from 1.2 1.2 to to 4.6%.

4.6%. [See [See hemorrhage, Adverse Adverse Reactions Reactions (6.1).]

(6.1).]

Across Across all all studies, studies, Avastin Avastin was was discontinued discontinued in in 8.4 8.4 to to 21% 21% of of patients patients because of of adverse adverse reactions. reactions.

Serious Serious or or fatal fatal pulmonary pulmonary hemorrhage hemorrhage occurred occurred in in four four of of 13 13 (31%) (31%) because patients patients with with squamous squamous cell cell histology histology and and two two of of 53 (4%) 53 (4%) patients patients with with 6.1 6.1 Clinical Clinical Trial Trial Experience Experience non‑squamous non‑squamous non‑small non‑small cell cell lung lung cancer cancer receiving receiving Avastin Avastin and and Because Because clinical clinical trials trials are are conducted conducted under under widely widely varying varying conditions, conditions, chemotherapy chemotherapy compared compared to to none none of of the the 32 32 (0%) (0%) patients patients receiving receiving adverse adverse reaction reaction rates rates observed observed in in the the clinical clinical trials trials of of aa drug drug cannot cannot be be chemotherapy chemotherapy alone. alone. directly directly compared compared to to rates rates in in the the clinical clinical trials trials of of another another drug drug and and may may In In clinical clinical studies studies in in non–small non–small cell cell lung lung cancer cancer where where patients patients with with CNS CNS not not reflect reflect the the rates rates observed observed in in practice. practice. metastases metastases who who completed completed radiation radiation and and surgery surgery more more than than 4 4 weeks weeks The The data data below below reflect reflect exposure exposure to to Avastin Avastin in in 4599 4599 patients patients with with CRC, CRC, prior prior to to the the start start of of Avastin Avastin were were evaluated evaluated with with serial serial CNS CNS imaging, imaging, non‑squamous non‑squamous NSCLC, NSCLC, glioblastoma, glioblastoma, or or mRCC mRCC trials trials including including controlled controlled symptomatic symptomatic Grade Grade 22 CNS CNS hemorrhage hemorrhage was was documented documented in in one one of of 83 83 (Studies 1, (Studies 1, 2, 2, 4, 4, 55 and and 8) 8) or or uncontrolled, uncontrolled, single single arm arm (Study 6) (Study 6) treated treated at at the the Avastin‑treated Avastin‑treated patients patients (rate (rate 1.2%, 1.2%, 95% 95% CI CI 0.06%–5.93%).

0.06%–5.93%). recommended recommended dose dose and and schedule schedule for for aa median median of of 88 to to 23 doses 23 doses of of Avastin.

Avastin.

Intracranial Intracranial hemorrhage hemorrhage occurred occurred in in 88 of of 163 163 patients patients with with previously previously [See [See Clinical Clinical Studies Studies (14).]

(14).]The The population population was was aged aged 18‑89 years 18‑89 years (median 60 (median 60 treated treated glioblastoma; glioblastoma; two two patients patients had had Grade Grade 3–4 3–4 hemorrhage. hemorrhage. years), years), 45.4% 45.4% male male and and 85.8% 85.8% (3729/4345) (3729/4345) White.

White. The The population population included included 2184 first‑and andsecond‑line second‑linemCRC mCRCpatients patientswho whoreceived receivedaamedian medianof of10 doses 10 doses Do Do not not administer administerAvastin Avastin to to patients patients with with recent recent history history of of hemoptysis hemoptysis of of 2184 first‑ ofAvastin, Avastin,480 first‑line 480 first‑line metastatic metastatic NSCLC NSCLC patients patients who who received received aa median median of of ≥≥ 1/2 1/2 teaspoon teaspoon of of red red blood. blood. Discontinue Discontinue Avastin Avastin in in patients patients with with of 8 8 doses doses of of Avastin, Avastin, 163 163 glioblastoma glioblastoma patients patients who who received received aa median median of of hemorrhage. hemorrhage. [See [See Boxed BoxedWarning, Warning, Dosage Dosage and andAdministration Administration (2.4).]

(2.4).]

T:10.25" T:10.25" S:9.5" S:9.5"

(bevacizumab) AVASTIN AVASTIN®® (bevacizumab) 9 doses 9 dosesof ofAvastin, Avastin,and and337 mRCC 337 mRCCpatients patientswho whoreceived receivedaamedian medianof of16 doses 16 doses of of Avastin.

Avastin. These These data data also also reflect reflect exposure exposure to to Avastin Avastin in in 363 patients 363 patients with with metastatic metastaticbreast breastcancer cancer(MBC) (MBC)who whoreceived receivedaamedian medianof of9.5 doses 9.5 dosesof ofAvastin, Avastin, 669 669 female female adjuvant adjuvant CRC CRC patients patients who who received received aa median median of of 23 23 doses doses of of Avastin Avastin and and exposure exposure to to Avastin Avastin in in 403 403 previously previously untreated untreated patients patients with with diffuse diffuse large large B‑cell B‑cell lymphoma lymphoma (DLBCL) (DLBCL) who who received received aa median median of of 88 doses doses of of Avastin.

Avastin.Avastin Avastin isis not not approved approved for for use use in in MBC, MBC, adjuvant adjuvant CRC, CRC, or or DLBCL. DLBCL. Surgery Surgery and andWound Wound Healing Healing Complications Complications The The incidence incidence of of post‑operative post‑operative wound wound healing healing and/or and/or bleeding bleeding complications complications was was increased increased in in patients patients with with mCRC mCRC receiving receiving Avastin Avastin as as compared compared to to patients patients receiving receiving only only chemotherapy. chemotherapy. Among Among patients patients requiring requiring surgery surgery on on or or within within 60 60 days days of of receiving receiving study study treatment, treatment, wound wound healing healing and/or and/or bleeding bleeding complications complications occurred occurred in in 15% 15% (6/39) (6/39) of of patients patients receiving receiving bolus‑IFL bolus‑IFL plus plus Avastin Avastin as as compared compared to to 4% 4% (1/25) (1/25) of of patients patients who who received received bolus‑IFL bolus‑IFL alone. alone.

In In Study Study 6, 6, events events of of post‑operative post‑operative wound wound healing healing complications complications (craniotomy (craniotomy site site wound wound dehiscence dehiscence and and cerebrospinal cerebrospinal fluid fluid leak) leak) occurred occurred in in patients patients with with previously previously treated treated glioblastoma: glioblastoma: 3/84 3/84 patients patients in in the the Avastin Avastin alone alone arm arm and and 1/79 1/79 patients patients in in the theAvastin Avastin plus plus irinotecan irinotecan arm. arm. [See [See Boxed Boxed Warning, Warning,Dosage Dosage and andAdministration Administration (2.4), (2.4),Warnings Warnings and and Precautions Precautions (5.2).]

(5.2).]

Hemorrhage Hemorrhage The The incidence incidence of of epistaxis epistaxis was was higher higher (35% (35% vs. vs. 10%) 10%) in in patients patients with with mCRC mCRC receiving receiving bolus‑IFL bolus‑IFL plus plus Avastin Avastin compared compared with with patients patients receiving receiving bolus‑IFL bolus‑IFL plus plus placebo. placebo.All All but but one one of of these these events events were were Grade Grade 11 in in severity severity and and resolved resolved without without medical medical intervention. intervention. Grade Grade 11 or or 22 hemorrhagic hemorrhagic events events were were more more frequent frequent in in patients patients receiving receiving bolus‑IFL bolus‑IFL plus plus Avastin Avastin when when compared compared to to those those receiving receiving bolus‑IFL bolus‑IFL plus plus placebo placebo and and included included gastrointestinal gastrointestinalhemorrhage hemorrhage(24% (24%vs. vs.6%), 6%),minor minorgum gumbleeding bleeding(2% (2%vs. vs.0), 0), and and vaginal vaginal hemorrhage hemorrhage (4% (4% vs. vs. 2%).

2%). [See [See Boxed Boxed Warning, Warning, Dosage Dosage and and Administration Administration (2.4), (2.4),Warnings Warnings and and Precautions Precautions (5.3).]

(5.3).]

Venous VenousThromboembolic Thromboembolic Events Events The The overall overall incidence incidence of of Grade Grade 3–4 3–4 venous venous thromboembolic thromboembolic events events in in Study Study 11 was was 15.1% 15.1% in in patients patients receiving receiving bolus‑IFL bolus‑IFL plus plusAvastin Avastin and and 13.6% 13.6% in in patients patients receiving receiving bolus‑IFL bolus‑IFL plus plus placebo. placebo. In In Study Study 1, 1, more more patients patients in in the the Avastin Avastin containing containing arm arm experienced experienced deep deep venous venous thrombosis thrombosis (34 (34 vs. vs.

19 19 patients patients )) and and intra‑abdominal intra‑abdominal venous venous thrombosis thrombosis (10 (10 vs. vs. 55 patients). patients).

The Therisk riskof ofdeveloping developingaasecond secondthromboembolic thromboembolicevent eventwhile whileon onAvastin Avastinand and oral oralanticoagulants anticoagulantswas wasevaluated evaluatedin intwo tworandomized randomizedstudies. studies.In InStudy Study1, 1,53 53 patients patients (14%) (14%) on on the the bolus‑IFL bolus‑IFL plus plus Avastin Avastin arm arm and and 30 30 patients patients (8%) (8%) on on the the bolus‑IFL bolus‑IFL plus plus placebo placebo arm arm received received full full dose dose warfarin warfarin following following aa venous venous thromboembolic thromboembolic event event (VTE). Among (VTE). Among these these patients, patients, an an additional additional thromboembolic thromboembolic event event occurred occurred in in 21% 21% (11/53) (11/53) of of patients patients receiving receiving bolus‑IFL bolus‑IFL plus plusAvastin Avastin and and 3% 3% (1/30) (1/30) of of patients patients receiving receiving bolus‑IFL bolus‑IFL alone. alone.

In In aa second, second, randomized, randomized, 4‑arm 4‑arm study study in in 1401 1401 patients patients with with mCRC, mCRC, prospectively prospectively evaluating evaluating the the incidence incidence of of VTE VTE (all (all grades), grades), the the overall overall incidence incidence of of first first VTE VTE was was higher higher in in the the Avastin Avastin containing containing arms arms (13.5%) (13.5%) than than the the chemotherapy chemotherapy alone alone arms arms (9.6%).

(9.6%). Among Among the the 116 116 patients patients treated treated with with anticoagulants anticoagulants following following an an initial initial VTE VTE event event (73 (73 in in the the Avastin Avastin plus plus chemotherapy chemotherapy arms arms and and 43 43 in in the the chemotherapy chemotherapy alone alone arms), arms), the the overall overall incidence incidence of of subsequent subsequent VTEs VTEs was was also also higher higher among among the the Avastin Avastin treated treated patients patients (31.5% (31.5% vs. vs. 25.6%).

25.6%). In In this this subgroup subgroup of of patients patients treated treated with with anticoagulants, anticoagulants, the the overall overall incidence incidence of of bleeding, bleeding, the the majority majority of of which which were were Grade Grade 1, 1, was was higher higher in in the the Avastin Avastin treated treated arms arms than than the the chemotherapy chemotherapy arms arms (27.4% (27.4% vs. vs. 20.9%).

20.9%). [See [See Dosage Dosage and and Administration Administration (2.4).]

(2.4).]

Ovarian Ovarian Failure Failure The The incidence incidence of of new new cases cases of of ovarian ovarian failure failure (defined (defined as as amenorrhoea amenorrhoea lasting lasting 33 or or more more months, months, FSH FSH level level ≥≥ 30 30 mIU/mL mIU/mL and and aa negative negative serum serum β‑HCG β‑HCG pregnancy pregnancy test) test) was was prospectively prospectively evaluated evaluated in in aa subset subset of of 179 179 women women receiving receiving mFOLFOX mFOLFOX chemotherapy chemotherapy alone alone (n (n == 84) 84) or or with withAvastin Avastin (n (n == 95).

95). New New cases cases of of ovarian ovarian failure failure were were identified identified in in 34% 34% (32/95) (32/95) of of women women receiving receiving Avastin Avastin in in combination combination with with chemotherapy chemotherapy compared compared with with 2% 2% (2/84) (2/84) of of women women receiving receiving chemotherapy chemotherapy alone alone [relative [relative risk risk of of

Unresectable Unresectable Non‑Squamous Non‑Squamous Non‑Small Non‑Small Cell Cell Lung Lung Cancer Cancer (NSCLC) (NSCLC) Only Only Grade Grade 3‑5 3‑5 non‑hematologic non‑hematologic and and Grade Grade 4‑5 4‑5 hematologic hematologic adverse adverse events events were were collected collected in in Study Study 5.

5. Grade Grade 3–5 3–5 non‑hematologic non‑hematologic and and Grade Grade 4–5 4–5hematologic hematologicadverse adverseevents events(occurring (occurringat ataahigher higherincidence incidence(≥2%) (≥2%)in in 427 427 patients patients receiving receiving PC PC plus plus Avastin Avastin compared compared with with 441 441 patients patients receiving receiving PC PC alone alone were were neutropenia neutropenia (27% (27% vs. vs. 17%), 17%), fatigue fatigue (16% (16% vs. vs.

13%), 13%),hypertension hypertension (8% (8% vs. vs.0.7%), 0.7%),infection infection without without neutropenia neutropenia (7% (7% vs. vs.

3%), 3%),venous venous thrombus/embolism thrombus/embolism (5% (5% vs. vs.3%), 3%),febrile febrile neutropenia neutropenia (5% (5% vs. vs.

2%), 2%),pneumonitis/pulmonary pneumonitis/pulmonary infiltrates infiltrates (5% (5% vs. vs.3%), 3%),infection infection with with Grade Grade 33 or or 44 neutropenia neutropenia (4% (4% vs. vs. 2%), 2%), hyponatremia hyponatremia (4% (4% vs. vs. 1%), 1%), headache headache (3% (3% vs. vs. 1%) 1%) and and proteinuria proteinuria (3% (3% vs. vs. 0%).

0%).

Glioblastoma Glioblastoma All All adverse adverse events events were were collected collected in in 163 163 patients patients enrolled enrolled in in Study Study 66 who who either either received received Avastin Avastin alone alone or or Avastin Avastin plus plus irinotecan. irinotecan. All All patients patients received received prior prior radiotherapy radiotherapy and and temozolomide. temozolomide.Avastin Avastin was was administered administered at at 10 10 mg/kg mg/kg every every 22 weeks weeks alone alone or or in in combination combination with with irinotecan. irinotecan.

Avastin Avastin was was discontinued discontinued due due to to adverse adverse events events in in 4.8% 4.8% of of patients patients treated treated with withAvastin Avastin alone. alone.

AA drug drug interaction interaction study study was was performed performed in in which which irinotecan irinotecan was was administered administered as as part part of of the the FOLFIRI FOLFIRI regimen regimen with with or or without withoutAvastin.

Avastin.The The results results demonstrated demonstrated no no significant significant effect effect of of bevacizumab bevacizumab on on the the pharmacokinetics pharmacokinetics of of irinotecan irinotecan or or its its active active metabolite metabolite SN38.

SN38.

In Inaarandomized randomizedstudy studyin in99 99patients patientswith withNSCLC, NSCLC,based basedon onlimited limiteddata, data,there there did didnot notappear appearto tobe beaadifference differencein inthe themean meanexposure exposureof ofeither eithercarboplatin carboplatinor or paclitaxel paclitaxel when when each each was was administered administered alone alone or or in in combination combination with withAvastin.

Avastin.

However, However,33 of of the the 8 patients 8 patients receiving receivingAvastin Avastin plus plus paclitaxel/carboplatin paclitaxel/carboplatin had had substantially substantially lower lower paclitaxel paclitaxel exposure exposure after after four four cycles cycles of of treatment treatment (at (at Day 63) Day 63) than than those those at at Day 0, Day 0, while while patients patients receiving receiving paclitaxel/carboplatin paclitaxel/carboplatin without withoutAvastin Avastinhad hadaagreater greaterpaclitaxel paclitaxelexposure exposureat atDay 63 Day 63than thanat atDay 0.

Day 0.

In InStudy Study8, 8,there therewas wasno nodifference differencein inthe themean meanexposure exposureof ofinterferon interferonalfa alfa administered administered in in combination combination with with Avastin Avastin when when compared compared to to interferon interferon alfa alfa alone. alone.

AVASTIN AVASTIN®® (bevacizumab) (bevacizumab) 88 USE USE IN IN SPECIFIC SPECIFIC POPULATIONS POPULATIONS 8.1 8.1 Pregnancy Pregnancy Pregnancy Pregnancy Category Category CC There There are are no no adequate adequate or or well well controlled controlled studies studies of of bevacizumab bevacizumab in in pregnant pregnant women. women. While While itit isis not not known known ifif bevacizumab bevacizumab crosses crosses the the placenta, placenta,human human IgG IgG isis known known to to cross cross the the placenta placenta Reproduction Reproduction studies studies in in rabbits rabbits treated treated with with approximately approximately 11 to to 12 12 times times the the recommended recommended human human dose dose of of bevacizumab bevacizumab demonstrated demonstrated teratogenicity, teratogenicity, including including an an increased increased incidence incidence of of specific specific gross gross and and skeletal skeletal fetal fetal alterations. alterations.

Adverse Adverse fetal fetal outcomes outcomes were were observed observed at at all all doses doses tested. tested.Other Other observed observed effects effects included included decreases decreases in in maternal maternal and and fetal fetal body body weights weights and and an an increased increased number number of of fetal fetal resorptions. resorptions.[See [See Nonclinical NonclinicalToxicology Toxicology (13.3).]

(13.3).]

Because Because of of the the observed observed teratogenic teratogenic effects effects of of bevacizumab bevacizumab in in animals animals and and of of other other inhibitors inhibitors of of angiogenesis angiogenesis in in humans, humans, bevacizumab bevacizumab should should be be used used during during pregnancy pregnancy only only ifif the the potential potential benefit benefit to to the the pregnant pregnant woman woman justifies justifies the the potential potential risk risk to to the the fetus. fetus.

8.3 8.3 Nursing Nursing Mothers Mothers ItIt isis not not known known whether whetherAvastin Avastin isis secreted secreted in in human human milk. milk. Human Human IgG IgG isis excreted excreted in in human human milk, milk, but but published published data data suggest suggest that that breast breast milk milk antibodies antibodies do do not not enter enter the the neonatal neonatal and and infant infant circulation circulation in in substantial substantial amounts. amounts.Because Because many many drugs drugs are are secreted secreted in in human human milk milk and and because because of of the the potential potential for for serious serious adverse adverse reactions reactions in in nursing nursing infants infants from from bevacizumab, bevacizumab, aa decision decision should should be be made made whether whether to to discontinue discontinue nursing nursing or or discontinue discontinue drug, drug, taking taking into into account account the the half‑life half‑life of of the the bevacizumab bevacizumab (approximately (approximately 20 days 20 days [range [range 11–50 11–50 days]) days]) and and the the importance importance of of the the drug drug to to the the mother. mother. [See [See Clinical Clinical Pharmacology Pharmacology (12.3).]

(12.3).]

8.4 8.4 Pediatric Pediatric Use Use The The safety, safety, effectiveness effectiveness and and pharmacokinetic pharmacokinetic profile profile of of Avastin Avastin in in pediatric pediatric patients patients have have not not been been established. established.

Antitumor Antitumor activity activity was was not not observed observed among among eight eight children children with with relapsed relapsed glioblastoma glioblastoma treated treated with with bevacizumab bevacizumab and and irinotecan. irinotecan. There There isis insufficient insufficient information information to to determine determine the the safety safety and and efficacy efficacy of ofAvastin Avastin in in children children with with glioblastoma. glioblastoma.

Juvenile Juvenile cynomolgus cynomolgus monkeys monkeys with with open open growth growth plates plates exhibited exhibited physeal physeal dysplasia dysplasia following following 44 to to 26 26 weeks weeks exposure exposure at at 0.4 0.4 to to 20 20 times times the the recommended recommended human human dose dose (based (based on on mg/kg mg/kg and and exposure). exposure).The The incidence incidence and and severity severity of of physeal physeal dysplasia dysplasia were were dose‑related dose‑related and and were were partially partially reversible reversible upon upon cessation cessation of of treatment. treatment.

8.5 8.5 Geriatric Geriatric Use Use In In Study Study 1, 1, severe severe adverse adverse events events that that occurred occurred at at aa higher higher incidence incidence (≥ (≥2%) 2%) in in patients patients aged aged ≥≥65 65 years years as as compared compared to to younger younger patients patients were were asthenia, asthenia, sepsis, sepsis, deep deep thrombophlebitis, thrombophlebitis, hypertension, hypertension, hypotension, hypotension, myocardial myocardial infarction, infarction, congestive congestive heart heart failure, failure, diarrhea, diarrhea, constipation, constipation, anorexia, anorexia, leukopenia, leukopenia, anemia, anemia, dehydration, dehydration, hypokalemia, hypokalemia, and and hyponatremia. hyponatremia. The The effect effect of of Avastin Avastin on on overall overall survival survival was was similar similar in in elderly elderly patients patients as as compared compared to to younger younger patients. patients.

In In Study Study 2, 2, patients patients aged ≥ aged ≥65 65 years years receiving receiving Avastin Avastin plus plus FOLFOX4 FOLFOX4 had had aa greater greater relative relative risk risk as as compared compared to to younger younger patients patients for for the the following following adverse adverse events: events: nausea, nausea, emesis, emesis, ileus, ileus, and and fatigue. fatigue.

In In Study Study 5, 5, patients patients aged aged ≥65 ≥65 years years receiving receiving carboplatin, carboplatin, paclitaxel, paclitaxel, and and Avastin Avastin had had aa greater greater relative relative risk risk for for proteinuria proteinuria as as compared compared to to younger younger patients. patients. [See [SeeWarnings Warnings and and Precautions Precautions (5.8).]

(5.8).]

Of Of the the 742 patients 742 patients enrolled enrolled in in Genentech‑sponsored Genentech‑sponsored clinical clinical studies studies in in which which all all adverse adverse events events were were captured, captured, 212 212 (29%) (29%) were were age age 65 65 or or older older and and 43 43 (6%) (6%) were were age age 75 75 or or older. older. Adverse Adverse events events of of any any severity severity that that occurred occurred at at aa higher higher incidence incidence in in the the elderly elderly as as compared compared to to younger younger patients, patients, in in addition addition to to those those described described above, above, were were dyspepsia, dyspepsia, gastrointestinal gastrointestinal hemorrhage, hemorrhage, edema, edema, epistaxis, epistaxis, increased increased cough, cough, and and voice voice alteration. alteration.

In In an an exploratory, exploratory, pooled pooled analysis analysis of of 1745 1745 patients patients treated treated in in five five randomized, randomized, controlled controlled studies, studies, there there were were 618 618 (35%) (35%) patients patients aged aged ≥≥65 65 years years and and 1127 1127 patients patients <<65 65 years years of of age. age. The The overall overall incidence incidence of of arterial arterial thromboembolic thromboembolic events events was was increased increased in in all all patients patients receiving receiving Avastin Avastin with with chemotherapy chemotherapy as as compared compared to to those those receiving receiving chemotherapy chemotherapy alone, alone, regardless regardless of of age. age. However, However, the the increase increase in in arterial arterial thromboembolic thromboembolic events events incidence incidence was was greater greater in in patients patients aged ≥ aged ≥65 65 years years (8.5% (8.5% vs. vs. 2.9%) 2.9%) as as compared compared to to those those <<65 65 years years (2.1% (2.1% vs. vs. 1.4%).

1.4%). [See [See Warnings Warnings and and Precautions Precautions (5.5).]

(5.5).]

8.6 8.6 Females Females of of Reproductive Reproductive Potential Potential Avastin Avastin increases increases the the risk risk of of ovarian ovarian failure failure and and may may impair impair fertility. fertility.

Inform Inform females females of of reproductive reproductive potential potential of of the the risk risk of of ovarian ovarian failure failure prior prior to to starting starting treatment treatment with withAvastin.

Avastin. Long Long term term effects effects of ofAvastin Avastin exposure exposure on on fertility fertility are are unknown. unknown.

In In aa prospectively prospectively designed designed substudy substudy of of 179 179 premenopausal premenopausal women women randomized randomized to to receive receive chemotherapy chemotherapy with with or or without without Avastin, Avastin, the the incidence incidence of of ovarian ovarian failure failure was was higher higher in in the the Avastin Avastin arm arm (34%) (34%) compared compared to to the the control control arm arm (2%).

(2%). After After discontinuation discontinuation of of Avastin Avastin and and chemotherapy, chemotherapy, recovery recovery of of ovarian ovarian function function occurred occurred in in 22% 22% (7/32) (7/32) of of these these Avastin‑treated Avastin‑treated patients. patients. [See [See Warnings Warnings and and Precautions Precautions (5.10), (5.10), Adverse Adverse Reactions Reactions (6.1).]

(6.1).]

10 10 OVERDOSAGE OVERDOSAGE The The highest highest dose dose tested tested in in humans humans (20 (20 mg/kg mg/kg IV) IV) was was associated associated with with headache headache in in nine nine of of 16 16 patients patients and and with with severe severe headache headache in in three three of of 16 patients.

16 patients.

17 17 PATIENT PATIENT COUNSELING COUNSELING INFORMATION INFORMATION Advise Advise patients: patients: ••To To undergo undergo routine routine blood blood pressure pressure monitoring monitoring and and to to contact contact their their health health care care provider provider ifif blood blood pressure pressure isis elevated. elevated.

••To To immediately immediately contact contact their their health health care care provider provider for for unusual unusual bleeding, bleeding, high high fever, fever, rigors, rigors, sudden sudden onset onset of of worsening worsening neurological neurological function, function, or or persistent persistent or or severe severe abdominal abdominal pain, pain, severe severe constipation, constipation, or or vomiting. vomiting.

•• Of Of increased increased risk risk of of wound wound healing healing complications complications during during and and following followingAvastin.

Avastin.

•• Of Of increased increased risk risk of of an an arterial arterial thromboembolic thromboembolic event. event.

•• Of Of the the potential potential risk risk to to the the fetus fetus during during and and following following Avastin Avastin and and the the need need to to continue continue adequate adequate contraception contraception for for at at least least 66 months months following following last last dose dose of ofAvastin.

Avastin.

•• Of Of the the increased increased risk risk for for ovarian ovarian failure failure following followingAvastin Avastin treatment. treatment.

Avastin Avastin®®(bevacizumab) (bevacizumab) Manufactured Manufactured by: by: Genentech, Genentech, Inc. Inc. AA Member Member of of the the Roche Roche Group Group 11 DNA DNAWay Way South South San San Francisco, Francisco, CA CA 94080‑4990 94080‑4990

03/14 03/14AVA0000765907 AVA0000765907 Initial Initial U.S. U.S.Approval: Approval: February 2004 February 2004 Code Code Revision Revision Date: Date:March March 2014 2014 registered trademark trademark Avastin Avastin®®isis aa registered of of Genentech, Genentech, Inc. Inc. © © 2014 2014 Genentech, Genentech, Inc. Inc.

S:12.5"

Congestive Congestive Heart Heart Failure Failure (CHF) (CHF) The The incidence incidence of of Grade Grade ≥ ≥ 33 left left ventricular ventricular dysfunction dysfunction was was 1.0% 1.0% in in patients patients receiving receiving Avastin Avastin compared compared to to 0.6% 0.6% in in the the control control arm arm across across indications. indications.In In patients patients with with metastatic metastatic breast breast cancer cancer (MBC), (MBC),an an indication indication for for which which Avastin Avastin isis not not approved, approved, the the incidence incidence of of Grade 3–4 Grade 3–4 CHF CHF was was increased increased in in patients patients in in the the Avastin Avastin plus plus paclitaxel paclitaxel arm arm (2.2%) (2.2%) as as compared compared to to the the control control arm arm (0.3%).

(0.3%). Among Among patients patients receiving receiving prior prior anthracyclines anthracyclines for for MBC, MBC, the the rate rate of of CHF CHF was was 3.8% 3.8% for for patients patients receiving receiving Avastin Avastin as as compared compared to to 0.6% 0.6% for for patients patients receiving receiving paclitaxel paclitaxel alone. alone.

The The safety safety of of continuation continuation or or resumption resumption of of Avastin Avastin in in patients patients with with cardiac cardiac dysfunction dysfunction has has not not been been studied. studied.

In In previously previously untreated untreated patients patients with with diffuse diffuse large large B‑cell B‑cell lymphoma lymphoma (DLBCL), (DLBCL), an an indication indication for for which which Avastin Avastin isis not not approved, approved, the the incidence incidence of of CHF CHF and and decline decline in in left‑ventricular left‑ventricular ejection ejection fraction fraction (LVEF) (LVEF) were were significantly significantly increased increased in in the the Avastin Avastin plus plus R‑CHOP R‑CHOP (rituximab, (rituximab, cyclophosphamide, cyclophosphamide,doxorubicin, doxorubicin,vincristine, vincristine,and and prednisone) prednisone) arm arm (n=403) (n=403) compared compared to to the the placebo placebo plus plus R‑CHOP R‑CHOP arm arm (n=379); (n=379); both both regimens regimens were were given given for for 66 to to 88 cycles. cycles. At At the the completion completion of of R‑CHOP R‑CHOP therapy, therapy, the the incidence incidence of of CHF CHF was was 10.9% 10.9% in in the the Avastin Avastin plus plus R‑CHOP R‑CHOP arm arm compared compared to to 5.0% 5.0% in in the the R‑CHOP R‑CHOP alone alone arm arm [relative [relative risk risk (95% (95% CI) CI) of of 2.2 2.2 (1.3, (1.3, 3.7)].

3.7)]. The The incidence incidence of of aa LVEF LVEF event, event, defined defined as as aa decline decline from from baseline baseline of of 20% 20% or or more more in in LVEF LVEF or or aa decline decline from from baseline baseline of of 10% 10% or or more more to to aa LVEF LVEF value value of of less less than than 50%, 50%, was was also also increased increased in in the theAvastin Avastin plus plus R‑CHOP R‑CHOP arm arm (10.4%) (10.4%) compared compared to to the the R‑CHOP R‑CHOP alone alone arm arm (5.0%).

(5.0%).

Time Time to to onset onset of of left‑ventricular left‑ventricular dysfunction dysfunction or or CHF CHF was was 1‑6 1‑6 months months after after initiation initiation of of therapy therapy in in at at least least 85% 85% of of the the patients patients and and was was resolved resolved in in 62% 62% of of the the patients patients experiencing experiencing CHF CHF in in the the Avastin Avastin arm arm compared compared to to 82% 82% in in the the control control arm. arm.

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Proteinuria Proteinuria Grade 3–4 Grade 3–4 proteinuria proteinuria ranged ranged from from 0.7 0.7 to to 7.4% 7.4% in in Studies Studies 1, 1, 2, 2, 4, 4, 55 and and 8.

8.

The The overall overall incidence incidence of of proteinuria proteinuria (all (all grades) grades) was was only only adequately adequately assessed assessed in in Study Study 8, 8, in in which which the the incidence incidence was was 20%.

20%. Median Median onset onset of of proteinuria proteinuria was was 5.6 5.6 months months (range (range 15 15 days days to to 37 37 months) months) after after initiation initiation of of Avastin.

Avastin. Median Median time time to to resolution resolution was was 6.1 6.1 months months (95% (95% CI CI 2.8 2.8 months, months, 11.3 11.3 months). months). Proteinuria Proteinuria did did not not resolve resolve in in 40% 40% of of patients patients after after median median follow follow up up of of 11.2 11.2 months months and and required required permanent permanent discontinuation discontinuation of of Avastin Avastin in in 30% 30% of of the the patients patients who who developed developed proteinuria proteinuria (Study (Study 8).

8).

In Inan anexploratory, exploratory,pooled pooledanalysis analysisof of8,273 8,273patients patientstreated treatedin in77randomized randomized clinical clinical trials, trials, 5.4% 5.4% (271 (271 of of 5037) 5037) of of patients patients receiving receiving Avastin Avastin in in combination combination with with chemotherapy chemotherapy experienced experienced Grade Grade ≥≥ 22 proteinuria. proteinuria. The The Grade Grade ≥≥ 22 proteinuria proteinuria resolved resolved in in 74.2% 74.2% (201 (201 of of 271) 271) of of patients. patients.Avastin Avastin was was re‑initiated re‑initiated in in 41.7% 41.7% (113 (113 of of 271) 271) of of patients. patients.Of Of the the 113 113 patients patients who who re‑initiated re‑initiated Avastin, Avastin, 47.8% 47.8% (54 (54 of of 113) 113) experienced experienced aa second second episode episode of of Grade Grade ≥≥ 22 proteinuria. proteinuria.[See [See Warnings Warnings and and Precautions Precautions (5.8).]

(5.8).]

AVASTIN AVASTIN®® (bevacizumab) (bevacizumab) In patients patients receiving receivingAvastin Avastin alone alone (N (N == 84), 84),the the most most frequently frequently reported reported In adverse events events of of any any grade grade were were infection infection (55%), (55%), fatigue fatigue (45%), (45%), adverse headache (37%), (37%), hypertension hypertension (30%), (30%), epistaxis epistaxis (19%) (19%) and and diarrhea diarrhea headache (21%). Of Of these, these, the the incidence incidence of of Grade Grade ≥≥33 adverse adverse events events was was infection infection (21%).

(10%), fatigue fatigue (4%), (4%), headache headache (4%), (4%), hypertension hypertension (8%) (8%) and and diarrhea diarrhea (10%), (1%). Two Two deaths deaths on on study study were were possibly possibly related related to to Avastin: Avastin: one one (1%). retroperitoneal hemorrhage and one neutropenic infection. retroperitoneal hemorrhage and one neutropenic infection.

In patients patients receiving receiving Avastin Avastin alone alone or or Avastin Avastin plus plus irinotecan irinotecan (N (N == 163), 163), the the In incidence of of Avastin‑related Avastin‑related adverse adverse events events (Grade (Grade 1–4) 1–4) were were bleeding/ bleeding/ incidence Metastatic Metastatic Colorectal Colorectal Cancer Cancer (mCRC) (mCRC) hemorrhage (40%), (40%), epistaxis epistaxis (26%), (26%), CNS CNS hemorrhage hemorrhage (5%), (5%), hypertension hypertension The The data data in in Table Table 11 and and Table Table 22 were were obtained obtained in in Study Study 1, 1, aa randomized, randomized, hemorrhage (32%), venous venous thromboembolic thromboembolic event event (8%), (8%), arterial arterial thromboembolic thromboembolic event event double‑blind, double‑blind, controlled controlled trial trial comparing comparing chemotherapy chemotherapy plus plus Avastin Avastin with with (32%), (6%), wound‑healing wound‑healing complications complications (6%), (6%), proteinuria proteinuria (4%), (4%), gastrointestinal gastrointestinal chemotherapy chemotherapy plus plus placebo. placebo. Avastin Avastin was was administered administered at at 55 mg/kg mg/kg (6%), perforation (2%), and RPLS (1%).

The incidence of Grade 3–5 events in these perforation (2%), and RPLS (1%).

The incidence of Grade 3–5 events in these every every 22 weeks. weeks.

163 patients patients were were bleeding/hemorrhage bleeding/hemorrhage (2%), (2%), CNS CNS hemorrhage hemorrhage (1%), (1%), 163 All All Grade Grade 3–4 3–4 adverse adverse events events and and selected selected Grade Grade 1–2 1–2 adverse adverse events events hypertension (5%), (5%), venous venous thromboembolic thromboembolic event event (7%), (7%), arterial arterial hypertension (hypertension, (hypertension, proteinuria, proteinuria, thromboembolic thromboembolic events) events) were were collected collected in in the the thromboembolic event event (3%), (3%),wound‑healing wound‑healing complications complications (3%), (3%),proteinuria proteinuria thromboembolic entire entire study study population. population. Severe Severe and and life‑threatening life‑threatening (Grade 3–4) (Grade 3–4) adverse adverse (1%),and and gastrointestinal gastrointestinal perforation perforation (2%).

(2%).

(1%), events, events,which which occurred occurred at at aa higher higher incidence incidence (( ≥ 2%) ≥ 2%) in in patients patients receiving receiving Metastatic Renal Renal Cell Cell Carcinoma Carcinoma (mRCC) (mRCC) bolus‑IFL bolus‑IFL plus plus Avastin Avastin as as compared compared to to bolus‑IFL bolus‑IFL plus plus placebo, placebo, are are Metastatic All grade grade adverse adverse events events were were collected collected in in Study Study 8.

8. Grade Grade 3–5 3–5 adverse adverse presented All presented in inTable 1.

Table 1. events occurring occurring at at aa higher higher incidence incidence (( ≥≥ 2%) 2%) in in 337 337 patients patients receiving receiving events Table Table 11 interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving NCI‑CTC NCI‑CTC Grade Grade 3−4 3−4 Adverse Adverse Events Events in in Study Study 11 IFN‑α plus plus placebo placebo arm arm were were fatigue fatigue (13% (13% vs. vs.8%), 8%),asthenia asthenia (10% (10% vs. vs.7%), 7%), IFN‑α (Occurring (Occurring at at Higher Higher Incidence Incidence [[ ≥≥ 22 %] %] Avastin Avastin vs. vs. Control) Control) proteinuria (7% (7% vs. vs. 0%), 0%), hypertension hypertension (6% (6% vs. vs. 1%; 1%; including including hypertension hypertension proteinuria Arm Arm Arm11 Arm22 and hypertensive hypertensive crisis), crisis),and and hemorrhage hemorrhage (3% (3% vs. vs.0.3%; 0.3%;including including epistaxis, epistaxis, and IFL+ IFL+ IFL+++Placebo Placebo IFL+++Avastin Avastin small intestinal intestinal hemorrhage, hemorrhage, aneurysm aneurysm ruptured, ruptured, gastric gastric ulcer ulcer hemorrhage, hemorrhage, small (n (n (n==396) 396) (n==392) 392) gingival bleeding, bleeding, haemoptysis, haemoptysis, hemorrhage hemorrhage intracranial, intracranial, large large intestinal intestinal gingival hemorrhage,respiratory respiratory tract tract hemorrhage, hemorrhage,and and traumatic traumatic hematoma). hematoma). hemorrhage, NCI‑CTC 74% 87% NCI‑CTC Grade Grade 3‑4 3‑4 Events Events 74% 87% Body Body as as aa Whole Whole Grade 1–5 1–5 adverse adverse events events occurring occurring at at aa higher higher incidence incidence (( ≥≥ 5%) 5%) in in Grade Asthenia 7% 10% Asthenia 7% 10% patients receiving receiving IFN‑α IFN‑α plus plusAvastin Avastin compared compared to to the the IFN‑α IFN‑α plus plus placebo placebo patients Abdominal 5% 8% Abdominal Pain Pain 5% 8% arm are are presented presented in inTable Table 3.

3. arm Pain 5% 8% Pain 5% 8% Table 33 Table Cardiovascular Cardiovascular NCI‑CTC Grades Grades 1−5 1−5 Adverse Adverse Events Events in in Study Study 88 NCI‑CTC Hypertension 2% 12% Hypertension 2% 12% (Occurringat atHigher HigherIncidence Incidence[≥ [≥5%] 5%]ininIFN‑α IFN‑α++Avastin Avastinvs. vs.IFN‑α IFN‑α++Placebo) Placebo) (Occurring Deep 5% 9% Deep Vein Vein Thrombosis Thrombosis 5% 9% System Organ Organ Class/ Class/ IFN‑α++Placebo Placebo IFN‑α IFN‑α++Avastin Avastin System IFN‑α Intra‑Abdominal 1% 3% Intra‑Abdominal Thrombosis Thrombosis 1% 3% aa Preferred term term Preferred (n (n==304) 304) (n (n==337) 337) Syncope 1% 3% Syncope 1% 3% Digestive Digestive Gastrointestinal Gastrointestinal disorders disorders Diarrhea 25% 34% Diarrhea 25% 34% Diarrhea Diarrhea 16% 16% 21% 21% Constipation 2% 4% Constipation 2% 4% General Generaldisorders disordersand andadministration administration Hemic/Lymphatic Hemic/Lymphatic site site conditions conditions Leukopenia 31% 37% Leukopenia 31% 37% Fatigue Fatigue 27% 27% 33% 33% Neutropenia 14% 14% 21% 21% Neutropeniaaa Investigations Investigations aa Weight Weight decreased decreased 15% 15% 20% 20% Central Central laboratories laboratories were were collected collected on on Days 1 Days 1 and and 21 21 of of each each cycle. cycle.

Neutrophil Neutrophil counts counts are are available available in in 303 patients 303 patients in in Arm 1 Arm 1 and and 276 276 in in Arm 2.

Arm 2.

Metabolism Metabolism and and nutrition nutrition disorders disorders Anorexia Anorexia 31% 31% 36% 36% Grade Grade 1–4 1–4 adverse adverse events events which which occurred occurred at at aa higher higher incidence incidence ((≥≥5%) 5%) in in Musculoskeletal Musculoskeletal and and connective connective patients patients receiving receiving bolus‑IFL bolus‑IFL plus plus Avastin Avastin as as compared compared to to the the bolus‑IFL bolus‑IFL tissue tissue disorders disorders plus plusplacebo placeboarm armare arepresented presentedin inTable 2.

Table 2.Grade Grade1–4 1–4adverse adverseevents eventswere were Myalgia Myalgia 14% 14% 19% 19% collected collected for for the the first first approximately approximately 100 100 patients patients in in each each of of the the three three Back Back pain pain 6% 6% 12% 12% treatment treatment arms arms who who were were enrolled enrolled until until enrollment enrollment in in Arm Arm 33 (5‑FU/LV (5‑FU/LV ++ Nervous Nervous system system disorders disorders Avastin) Avastin) was was discontinued. discontinued.

Headache Headache 16% 16% 24% 24% Table Table 22 Renal Renal and and urinary urinary disorders disorders NCI‑CTC NCI‑CTC Grade 1‑4 Grade 1‑4 Adverse Adverse Events Events in in Study 1 Study 1 Proteinuria Proteinuria 3% 3% 20% 20% (Occurring (Occurring at at Higher Higher Incidence Incidence [≥ [≥5%] 5%] in in IFL IFL ++ Avastin Avastin vs. vs. IFL) IFL) Respiratory, Respiratory, thoracic thoracic and and Arm 1 Arm 1 Arm 2 Arm 2 Arm 3 Arm 3 mediastinal mediastinal disorders disorders IFL + Placebo IFL + Placebo IFL + Avastin IFL + Avastin 5‑FU/LV + Avastin 5‑FU/LV + Avastin Epistaxis Epistaxis 4% 4% 27% 27% (n = 98) (n = 98) (n = 102) (n = 102) (n = 109) (n = 109) Dysphonia Dysphonia 0% 0% 5% 5% Vascular Vascular disorders disorders Body Body as as aa Whole Whole Hypertension Hypertension 9% 9% 28% 28% Pain Pain 55% 55% 61% 61% 62% 62% aa Adverse Adverse events events were were encoded encoded using using MedDRA, MedDRA,Version 10.1.

Version 10.1.

Abdominal Abdominal Pain Pain 55% 55% 61% 61% 50% 50% Headache Headache 19% 19% 26% 26% 26% 26% The The following following adverse adverse events events were were reported reported at at aa 5‑fold 5‑fold greater greater incidence incidence Cardiovascular Cardiovascular in in the the IFN‑α IFN‑α plus plus Avastin Avastin arm arm compared compared to to IFN‑α IFN‑α alone alone and and not not Hypertension Hypertension 14% 14% 23% 23% 34% 34% represented represented in in Table Table 3: 3: gingival gingival bleeding bleeding (13 (13 patients patients vs. vs. 11 patient); patient); Hypotension Hypotension 7% 7% 15% 15% 7% 7% rhinitis rhinitis (9 (9 vs.0 vs.0 );); blurred blurred vision vision (8 (8 vs. vs. 0); 0); gingivitis gingivitis (8 (8 vs. vs. 1); 1); Deep Deep Vein Vein Thrombosis Thrombosis 3% 3% 9% 9% 6% 6% gastroesophageal gastroesophageal reflux reflux disease disease (8 (8 vs.1 vs.1 );); tinnitus tinnitus (7 (7 vs. vs. 1); 1); tooth tooth abscess abscess Digestive Digestive (7 (7 vs.0); vs.0); mouth mouth ulceration ulceration (6 (6 vs. vs. 0); 0); acne acne (5 (5 vs. vs. 0); 0); deafness deafness (5 (5 vs. vs. 0); 0); Vomiting 47% 52% 47% Vomiting 47% 52% 47% gastritis gastritis (5 (5 vs. vs.0); 0);gingival gingival pain pain (5 (5 vs. vs.0) 0) and and pulmonary pulmonary embolism embolism (5 (5 vs. vs.1).

1).

Anorexia 30% 43% 35% Anorexia 30% 43% 35% 6.2 6.2 Immunogenicity Immunogenicity Constipation 29% 40% 29% Constipation 29% 40% 29% As As with with all all therapeutic therapeutic proteins, proteins, there there isis aa potential potential for for an an immune immune response response Stomatitis 18% 32% 30% Stomatitis 18% 32% 30% to toAvastin.

Avastin. In In clinical clinical trials trials of of adjuvant adjuvant colon colon carcinoma, carcinoma, 14 14 of of 2233 evaluable 2233 evaluable Dyspepsia 15% 24% 17% Dyspepsia 15% 24% 17% patients patients (0.63%) (0.63%) tested tested positive positive for for treatment‑emergent treatment‑emergent anti‑bevacizumab anti‑bevacizumab GI Hemorrhage Hemorrhage 6% 24% 19% GI 6% 24% 19% antibodies antibodies detected detected by by an an electrochemiluminescent electrochemiluminescent (ECL) (ECL) based based assay. assay.Among Among Weight Loss Loss 10% 15% 16% Weight 10% 15% 16% these these 14 14 patients, patients, three three tested tested positive positive for for neutralizing neutralizing antibodies antibodies against against Dry Mouth Mouth 2% 7% 4% Dry 2% 7% 4% bevacizumab bevacizumab using using an an enzyme‑linked enzyme‑linked immunosorbent immunosorbent assay assay (ELISA).

(ELISA).

The The Colitis 1% 6% 1% Colitis 1% 6% 1% clinical clinical significance significance of of these these anti‑product anti‑product antibody antibody responses responses to to bevacizumab bevacizumab Hemic/Lymphatic Hemic/Lymphatic isisunknown. unknown.

Thrombocytopenia 0% 5% 5% Thrombocytopenia 0% 5% 5% Immunogenicity Immunogenicity assay assay results results are are highly highly dependent dependent on on the the sensitivity sensitivity Nervous Nervous and specificity and specificity of of the the test test method method and and may may be be influenced influenced by by several several Dizziness 20% 26% 19% Dizziness 20% 26% 19% factors, factors, including including sample sample handling, handling, timing timing of of sample sample collection, collection, concomitant concomitant Respiratory Respiratory medications, medications, and and underlying underlying disease. disease. For For these these reasons, reasons, comparison comparison of of the the UpperRespiratory RespiratoryInfection Infection 39% 39% 47% 40% Upper 47% 40% incidence incidence of of antibodies antibodies to to Avastin Avastin with with the the incidence incidence of of antibodies antibodies to to other other Epistaxis 10% 35% 32% Epistaxis 10% 35% 32% products may be misleading. products may be misleading.

Dyspnea 15% 26% 25% Dyspnea 15% 26% 25% Voice Alteration Alteration 2% 9% 6% Voice 2% 9% 6% 6.3 6.3 Postmarketing Postmarketing Experience Experience Skin/Appendages Skin/Appendages The Thefollowing followingadverse adversereactions reactionshave havebeen beenidentified identifiedduring duringpost‑approval post‑approval Alopecia 26% 32% 6% Alopecia 26% 32% 6% use use of of Avastin.

Avastin. Because Because these these reactions reactions are are reported reported voluntarily voluntarily from from aa Skin Ulcer Ulcer 1% 6% 6% Skin 1% 6% 6% population population of of uncertain uncertain size, size, itit isis not not always always possible possible to to reliably reliably estimate estimate Special Senses Senses Special their their frequency frequency or or establish establish aa causal causal relationship relationship to to drug drug exposure. exposure.

Taste Disorder Disorder 9% 14% 21% Taste 9% 14% 21% Body Body as as aaWhole: Whole: Polyserositis Polyserositis Urogenital Urogenital Cardiovascular: Cardiovascular: Pulmonary Pulmonary hypertension, hypertension,RPLS, RPLS,Mesenteric Mesenteric venous venous occlusion occlusion Proteinuria 24% 36% 36% Proteinuria 24% 36% 36% Eye Eye disorders disorders (from (from unapproved unapproved intravitreal intravitreal use use for for treatment treatment of of various various Avastin in in Combination Combination with with FOLFOX4 FOLFOX4 in in Second‑line Second‑line mCRC mCRC Avastin ocular ocular disorders): disorders): Permanent Permanent loss loss of of vision; vision; Endophthalmitis Endophthalmitis (infectious (infectious and and OnlyGrade Grade3‑5 3‑5non‑hematologic non‑hematologicand andGrade Grade4–5 4–5hematologic hematologicadverse adverseevents events sterile); Only sterile); Intraocular Intraocular inflammation; inflammation; Retinal Retinal detachment; detachment; Increased Increased intraocular intraocular related to to treatment treatment were were collected collected in in Study Study 2.

2. The The most most frequent frequent adverse adverse pressure; related pressure; Hemorrhage Hemorrhage including including conjunctival, conjunctival, vitreous vitreous hemorrhage hemorrhage or or retinal retinal events (selected (selected Grade Grade 3–5 3–5 non‑hematologic non‑hematologic and and Grade Grade 4–5 4–5 hematologic hematologic hemorrhage; events hemorrhage;Vitreous Vitreous floaters; floaters;Ocular Ocular hyperemia; hyperemia;Ocular Ocular pain pain or or discomfort discomfort adverse events) events) occurring occurring at at aa higher higher incidence incidence (≥2%) (≥2%) in in 287 287 patients patients Gastrointestinal: adverse Gastrointestinal: Gastrointestinal Gastrointestinal ulcer, ulcer, Intestinal Intestinal necrosis, necrosis, Anastomotic Anastomotic receivingFOLFOX4 FOLFOX4plus plusAvastin Avastincompared comparedto to285 285patients patientsreceiving receivingFOLFOX4 FOLFOX4 ulceration receiving ulceration alone were were fatigue fatigue (19% (19% vs. vs. 13%), 13%), diarrhea diarrhea (18% (18% vs. vs. 13%), 13%), sensory sensory alone Hemic and and lymphatic: lymphatic: Pancytopenia Pancytopenia neuropathy (17% (17% vs. vs. 9%), 9%), nausea nausea (12% (12% vs. vs. 5%), 5%), vomiting vomiting (11% (11% vs. vs. 4%), 4%), Hemic neuropathy Hepatobiliary disorders: disorders: Gallbladder Gallbladder perforation perforation dehydration(10% (10%vs. vs.5%), 5%),hypertension hypertension(9% (9%vs. vs.2%), 2%),abdominal abdominalpain pain(8% (8%vs. vs. Hepatobiliary dehydration 5%),hemorrhage hemorrhage (5% (5% vs. vs.1%), 1%),other other neurological neurological (5% (5% vs. vs.3%), 3%),ileus ileus (4% (4% vs. vs. Infections 5%), Infections and and infestations: infestations: Necrotizing Necrotizing fasciitis, fasciitis, usually usually secondary secondary to to wound wound 1%) and and headache headache (3% (3% vs. vs. 0%).

0%).These These data data are are likely likely to to under‑estimate under‑estimate the the healing 1%) healing complications, complications, gastrointestinal gastrointestinal perforation perforation or or fistula fistula formation formation true adverse adverse event event rates rates due due to to the the reporting reporting mechanisms mechanisms used used in in Study 2.

Study 2. true Musculoskeletal: Musculoskeletal: Osteonecrosis Osteonecrosis of of the the jaw jaw Avastinin inCombination Combinationwith withFluoropyrimidine‑Irinotecan Fluoropyrimidine‑Irinotecanor orFluoropyrimidine‑ Fluoropyrimidine‑ Renal: Avastin Renal: Renal Renal thrombotic thrombotic microangiopathy microangiopathy (manifested (manifested as as severe severe proteinuria) proteinuria) Oxaliplatin Based Based Chemotherapy Chemotherapy in in Second‑line Second‑line mCRC mCRC Patients Patients who who have have Oxaliplatin Respiratory: Respiratory: Nasal Nasal septum septum perforation, perforation, dysphonia dysphonia Progressed Progressed on on an anAvastin AvastinContaining Containing Regimen Regimen in in First‑line First‑line mCRC: mCRC: Systemic Events Events (from (from unapproved unapproved intravitreal intravitreal use use for for treatment treatment of of No No new new safety safety signals signals were were observed observed in in Study Study 44 when when Avastin Avastin was was Systemic various ocular ocular disorders): disorders): Arterial Arterial thromboembolic thromboembolic events, events, Hypertension, Hypertension, administered administered in in second second line line mCRC mCRC patients patients who who progressed progressed on on an anAvastin Avastin various Gastrointestinal perforation, perforation, Hemorrhage Hemorrhage containing containing regimen regimen in in first first line line mCRC. mCRC. The The safety safety data data was was consistent consistent Gastrointestinal with with the the known known safety safety profile profile established established in in first first and and second second line line mCRC. mCRC. 77 DRUG DRUG INTERACTIONS INTERACTIONS

S:12.5"

Neutropenia Neutropenia and and Infection Infection The The incidences incidences of of neutropenia neutropenia and and febrile febrile neutropenia neutropenia are are increased increased in in patients patients receiving receiving Avastin Avastin plus plus chemotherapy chemotherapy compared compared to to chemotherapy chemotherapy alone. alone. In In Study Study 1, 1, the the incidence incidence of of Grade Grade 33 or or 44 neutropenia neutropenia was was increased increased in in mCRC mCRC patients patients receiving receiving IFL IFL plus plus Avastin Avastin (21%) (21%) compared compared to to patients patients receiving receiving IFL IFL alone alone (14%).

(14%).In In Study Study 5, 5,the the incidence incidence of of Grade Grade 44 neutropenia neutropenia was was increased increased in in NSCLC NSCLC patients patients receiving receiving paclitaxel/carboplatin paclitaxel/carboplatin (PC) (PC) plus plus Avastin Avastin (26.2%) (26.2%) compared compared with with patients patients receiving receiving PC PC alone alone (17.2%).

(17.2%).

Febrile Febrile neutropenia neutropenia was was also also increased increased (5.4% (5.4% for for PC PC plus plusAvastin Avastin vs. vs. 1.8% 1.8% for forPC PCalone). alone).There Therewere were19 19(4.5%) (4.5%)infections infectionswith withGrade 3 Grade 3or or44neutropenia neutropenia in in the the PC PC plus plus Avastin Avastin arm arm of of which which 33 were were fatal fatal compared compared to to 99 (2%) (2%) neutropenic neutropenic infections infections in in patients patients receiving receiving PC PC alone, alone, of of which which none none were were fatal. fatal. During During the the first first 66 cycles cycles of of treatment, treatment, the the incidence incidence of of serious serious infections infectionsincluding includingpneumonia, pneumonia,febrile febrileneutropenia, neutropenia,catheter catheterinfections infectionsand and wound wound infections infections was was increased increased in in the the PC PC plus plus Avastin Avastin arm arm [58 [58 patients patients (13.6%)] (13.6%)] compared compared to to the the PC PC alone alone arm arm [29 patients [29 patients (6.6%)].

(6.6%)].

In In Study Study 6, 6, one one fatal fatal event event of of neutropenic neutropenic infection infection occurred occurred in in aa patient patient with with previously previously treated treated glioblastoma glioblastoma receiving receiving Avastin Avastin alone. alone. The The incidence incidence of of any any grade grade of of infection infection in in patients patients receiving receivingAvastin Avastin alone alone was was 55% 55% and and the the incidence incidence of of Grade Grade 3–5 3–5 infection infection was was 10%.

10%.

AVASTIN AVASTIN®® (bevacizumab) (bevacizumab) 14 14 (95% (95% CI CI 4, 4,53)].

53)].After After discontinuation discontinuation of ofAvastin Avastin treatment, treatment,recovery recovery of of ovarian ovarian function function at at all all time time points points during during the the post‑treatment post‑treatment period period was was demonstrated demonstrated in in 22% 22% (7/32) (7/32) of of the the Avastin‑treated Avastin‑treated women. women. Recovery Recovery of of ovarian ovarian function function isis defined defined as as resumption resumption of of menses, menses, aa positive positive serum serum β‑HCG β‑HCG pregnancy pregnancy test, test, or or aa FSH FSH level level <<30 30 mIU/mL mIU/mL during during the the post‑ post‑ treatment treatment period. period. Long Long term term effects effects of of Avastin Avastin exposure exposure on on fertility fertility are are unknown. unknown. [See [See Warnings Warnings and and Precautions Precautions (5.10), (5.10), Use Use in in Specific Specific Populations Populations (8.6).]

(8.6).]

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Confronting a common threat across approved indications Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Rhinitis — Dry skin — Back pain — Headache — Proteinuria — Rectal hemorrhage — Exfoliative dermatitis — Hypertension — Taste alteration — Lacrimation disorder Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

©2013 Genentech USA, Inc.

All rights reserved.

AVA0000488404

Printed in USA.

(12/13)

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%).

Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,* the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC *Avastin is not approved for use in combination with irinotecan or any other combination regimens.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Reference: 1. Avastin Prescribing Information.

Genentech, Inc. March 2013.

www.avastin-hcp.com