TAP Vol 4 Issue 13

CT Screening for Lung Cancer

7, 36

| Ibrutinib in Leukemia, Lymphoma 24, 26 | Future of Pediatric Oncology

VOLUME 4, ISSUE 13

70

AUGUST 15, 2013

Editor-in-Chief, James O. Armitage, MD

ASCO Annual Meeting

Maintenance Treatment Delays Progression in Metastatic Colorectal Cancer

ASCOPost.com

Molecular Tests and Precision Medicine: Not So Fast Now!

By Caroline Helwick

By William T. McGivney, PhD

F

or patients with unresectable metastatic colorectal cancer, maintenance treatment with capecitabine (Xeloda) and bevacizumab (Avastin) significantly delayed disease progression and improved overall survival in the phase III CAIRO3 study by the Dutch Colorectal Cancer Group. Miriam Koopman, MD, PhD, of University Medical Center Utrecht in The Netherlands, presented the findings at the 2013 ASCO Annual Meeting.1

Study Rationale “The optimal duration of chemotherapy and bevacizumab in metastatic colorectal cancer is not well established, and the value of chemotherapy-free intervals tested in several studies is still a matter of debate.

What we do know is that drug holidays are preferred by many patients,” Dr. Koopman said.

“Given this, the CAIRO3 study was designed to investigate the efficacy of observation vs maintenance treatment with capecitabine plus bevacizumab after induction treatment with six cycles of capecitabine/oxaliplatin plus bevacizumab Miriam Koopman, MD, PhD (CAPOX-B) in patients not progressing during induction,” she said.

The study included patients with previously untreated, unresectable metastatic colorectal cancer who had stable disease or better after six cycles of standard CAPOX-B. Patients were randomly assigned between observation or maintenance with capecitabine at 625 mg/m2 twice daily and bevacicontinued on page 16

Issues in Oncology

continued on page 132

Oncologists Speak Out Against the High Cost of Cancer Drugs

Dr. McGivney is Principal, McGivney Global Advisors.

By Jo Cavallo

MORE IN THIS ISSUE

T

hat the United States spends twice as much on health care than other industrialized countries—about $2.8 trillion in 2012—without reaping appreciably better outcomes1 is not news. The topic has been dissected on the front pages of leading newspapers for years and was the subject of the entire feature section of an issue of Time2 magazine in March. What is different about the debate making news now is the number of oncologists speaking out

Peter B. Bach, MD

T

he era of the application of genomic, proteomic, and a host of other “omic” analyses to guide decision-making in the therapeutic selection of drugs and biologics is now a key part of cancer care. Medical practice is working to keep up with the scientific advances, evaluate them, and add a variety of biomarker tests to the guidelines and pathways that drive decisions about patient management.

While medical practice is challenged, the regulatory and coverage/reimbursement worlds are struggling to determine how this emerging, critically important area of oncology should be managed. The depth of the struggle and potential negative implications for integrating molecular testing into everyday practice are well illustrated by a declaration in February 2013 issued by the Medicare contractor Palmetto.

Leonard B. Saltz, MD

Send your comments to editor@ASCOPost.com

against the high cost of cancer drugs and its impact on patient care.

Last October, three physicians from Memorial Sloan-Kettering Cancer Center in New York—Peter B. Bach, MD, Director of the Center for Health Policy and Outcomes; Leonard B. Saltz, MD, Chief, Gastrointestinal Oncology Service and Chairman of the Pharmacy and Therapeutics Committee; and Robert E. Wittes, MD, former Physician-in-Chief—led the way with an Op-Ed piece in The New York Times.3 They wrote the editorial to explain their decision not to give ziv-afilbercept (Zaltrap), a new “phenomenally expensive” cancer drug, to their patients with advanced colorectal cancer. They noted that the new agent provided no advantage over bevacizumab Robert E. Wittes, MD

ASCO Annual Meeting Breast Cancer ������������������������������������������ 3 Ovarian Cancer ��������������������������������� 4, 6 Lung Cancer����������������������������������������� 15 Lymphoma ������������������������������������������� 18 Issues in Oncology������������������������������� 44 ALK Inhibition in NSCLC ������������� 14, 30 Women in Oncology: Diane E. Meier, MD �������������������������������� 40 Afatinib in Lung Cancer����������������� 50, 56 New Genomic Resource for Cancer Research�������������������������������� 62 Direct from ASCO �������������������������� 75–78

continued on page 130

A Harborside Press® Publication

The ASCO Post | AUGUST 15, 2013

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ASCOPost.com | AUGUST 15, 2013

PAGE 3

ASCO Annual Meeting Breast Cancer

GeparSixto Study Finds Benefit for Neoadjvuant Carboplatin in Triple-negative Breast Cancer

By Caroline Helwick

I

n patients with triple-negative breast cancer, the addition of carboplatin significantly improved the rate of pathologic complete response after neoadjuvant chemotherapy in a study by the German Breast Group (GBG)/Gynecologic Oncology Working Group–Breast (AGO-B) reported at the 2013 ASCO Annual Meeting.1 “An absolute increase of more than 20% was observed in patients with triple-negative breast cancer, but the HER2-positive subgroup did not benefit,” reported Gunter von Minckwitz, MD, PhD, Chairman of the German Breast Group and Professor of Gynecology at the University of Frankfurt.

Several neoadjuvant studies have suggested that triple-negative patients are sensitive to cisplatin and carboplatin, especially those with BRCA muta-

Gunter von Minckwitz, MD, PhD

tions. However, randomized trials incorporating platinums have produced mixed results.

“The role of carboplatin in breast cancer is not yet fully understood, and its efficacy has not been determined,” he said.

GeparSixto Design The GeparSixto study evaluated the benefit of adding carboplatin to paclitaxel plus pegylated liposomal doxorubicin given as a weekly regimen for 18 weeks to 595 patients. Added to this backbone were three targeted agents corresponding to tumor subtype: trastuzumab (Herceptin) and lapatinib (Tykerb) for HER2-positive patients and bevacizumab (Avastin) for triple-negative patients. Halfway into the study, the carboplatin dose was reduced from AUC 2 to AUC 1.5 because of toxicity concerns at the interim safety analysis.

EXPERT POINT OF VIEW with BRCA1 mutations received six cycles of cisplatin at 75 mg/m2 and 80% responded, with complete responses seen in 45%.2 However, in the phase II BALI-1 study reported

by Baselga et al, also in the metastatic setting, only 10% of patients unselected for BRCA status with triple-negative disease responded to cisplatin alone.3 Judy Garber, MD, MPH

J

Unanswered Questions

udy Garber, MD, MPH, Professor of Medicine at Harvard Medical School and Director of the Cancer Risk and Prevention Center at Dana-Farber Cancer Institute, Boston, was the formal discussant of the GeparSixto paper.

The rationale for studying platinum in triple-negative breast cancer is clear: The drugs are active in ovarian cancer, which has molecular similarities to basal-like breast cancer; BRCA-associated breast cancer is basal-like on microarrays; and response to platinum is associated with germline BRCA mutations, low BRCA expression or inactivation of BRCA by methylation, suggestive of a DNA repair theme, she said.

Clinically, however, the benefit of platinum is less clear. In a small ongoing neoadjuvant study of 38 patients with BRCA1 mutations, Polish investigators observed a pathologic complete response in 60.5% of patients receiving four cycles of cisplatin.1 In their phase II study in the metastatic setting, 20 patients

“Certainly, there is interest and concern about platinum agents, and therefore it is particularly important that the German Breast Group has taken on the evaluation of carboplatin in this setting, building upon their prior work,” Dr. Garber said.

“They showed very impressive results in the triple-negative group,” she noted, “but this came with significant adverse effects, and one wonders what simplifications might have made the regimen more tolerable.”

Dr. Garber would like to see further evaluation of various predictors of response, including germline BRCA mutation status. Follow-up for clinical outcomes beyond pathologic complete response will also be critical, she said. While data from collaborative trials show that risk of recurrence is reduced when patients achieve pathologic complete responses, “this is not the same as cure,” she noted, “and we need to ask whether [pathologic complete re-

Investigators compared the rates of pathologic complete response (ypT0, ypN0, ie, invasive and no in situ residual disease) between paclitaxel/doxorubicin and paclitaxel/ doxorubicin/carboplatin. The level of statistical significance was set at P < .2.

Of the 588 patients who started treatment, 31% of the control arm and 38% of the carboplatin arm discontinued due to adverse events. Six cycles were completed by 61% and 52%, respectively.

Forty percent of patients experienced at least one serious adverse event. The control arm had more pneumonia (17 vs 2 patients), but more hematologic toxicity was seen with carboplatin (49 vs 10 patients), and diarrhea was most likely in patients receiving lapatinib (15 vs 0–3 patients in other arms).

Key Data The addition of carboplatin significantly increased the pathologic complete response rate, which was

sponse] is enough to make decisions going forward.”

“We must figure out for whom the platinums work before we give them indiscriminately. They clearly have activity but also toxicity,” she concluded, adding that the optimal, least toxic platinum-containing regimen still remains unclear.

“Physicians who don’t like to change therapy based on a single study may want to wait for the results of the Alliance 40603 trial, the results of which are anticipated in December 2013,” she said. n Disclosure: Dr. Garber has been a consultant or advisor to Novartis, Pfizer, and Tesaro, and has received research funding from AstraZeneca, Myriad Genetics, Novartis, and Pfizer.

References 1. Byrski T, Gronwald J, Huzarski T, et al: Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Hered Cancer Clin Pract 9(suppl 2):A4, 2011.

2. Byrski T, Dent R, Blecharz P, et al: Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res 14:R110, 2012.

3. Baselga J, Gomez P, Greil R, et al: Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol 31:25862592, 2013.

37.2% in the control arm and 46.7% in the carboplatin arm (P < .2). Using other, more liberal definitions of pathologic complete response, the same pattern was observed, with absolute differences of 8% to 10%, Dr. von Minckwitz reported.

The difference, however, was driven by the drug’s effect in the triple-negative subgroup, in which pathologic complete response was achieved by 37.9% of the control arm and 58.7% of the carboplatin continued on page 4

The ASCO Post | AUGUST 15, 2013

PAGE 4

ASCO Annual Meeting Gynecologic Oncology

Weekly Carboplatin/Paclitaxel Improves Quality of Life, Toxicity vs Every-3-week Regimen in Advanced Ovarian Cancer

By Alice Goodman

P

atients with advanced ovarian cancer have similar survival outcomes thus far with a weekly regimen of carboplatin/paclitaxel vs the standard every-3-week regimen, but

cally significant, but all quality-oflife measures significantly favored weekly treatment,” said presenting author Sandro Pignata, MD, PhD, National Cancer Institute, Naples, Italy. “These results support a weekly regimen as first-line treatment for advanced ovarian cancer.”

Study Details

Sandro Pignata, MD, PhD

the weekly regimen is much better tolerated with improved quality of life, according to final results of the Multicenter Italian Trials in Ovarian Cancer (MITO)-7 randomized, controlled, phase III study.1 “Progression-free survival was only 2 months longer with the weekly regimen, which was not statisti-

MITO-7 was based on a previous trial by Japanese investigators showing significantly longer p rog re s s i o n - f ree and overall survival with weekly paclitaxel combined with every-3-week carboplatin vs standard carboplatin/paclitaxel given every 3 weeks.2 The study randomly assigned 822 patients with stage IC through IV ovarian cancer to receive carboplatin/paclitaxel (carboplatin AUC6 plus paclitaxel 175 mg/m2 on day 1) every 3 weeks for six cycles vs weekly carboplatin/paclitaxel (carboplatin

Optimizing Chemotherapy for Ovarian Cancer ■ Every-3-week carboplatin/paclitaxel is considered standard of care for advanced ovarian cancer.

■ A large randomized controlled trial found that weekly carboplatin/

paclitaxel achieved comparable survival but was much better tolerated with improved quality of life compared with the every-3-week regimen.

GeparSixto Study continued from page 3

arm (P < .05). “You can see there is a tremendous 20% difference between the arms in these patients,” he noted.

In HER2-positive patients, on the other hand, pathologic complete responses were achieved by 36.3% and

33.1%, respectively.

Clinical complete responses were consistent with the overall result, achieved by 36.9% of patients on the control arm and 43.1% of those on the carboplatin arm. Breast-conserving therapy rates, however, were no different between the two arms— 76.7% and 72.4%, respectively, show-

Neoadjuvant Carboplatin in Early Breast Cancer ■ In the phase II GeparSixto trial, carboplatin added to chemotherapy plus a targeted agent significantly increased pathologic complete response rates.

■ The benefit was observed only in patients with triple-negative disease, not HER2-positive patients.

■ In triple-negative patients, pathologic complete response rates were

37.9% in the control arm and 58.7% in the carboplatin arm, for an absolute benefit of 20%.

EXPERT POINT OF VIEW

W

eekly vs every-3-week therapy is a somewhat controversial area in ovarian cancer, said formal discussant of the MITO-7 trial, Jonathan S. Berek, MD, Director of the Stanford Women’s Cancer Center, Palo Alto, California. “[ Japan Clinical Oncology Group ( JCOG)]-16 showed a survival advantage for both progression-free and overall survival for dose-dense chemotherapy, and another study—[Gynecologic Oncology Group (GOG)] 262—is looking at this question along with bevacizumab [Avastin].

MITO-7 seems to trend toward improved survival with the weekly schedule, but a fairly high proportion of patients with low-stage disease were included in this trial, and dose-dense chemotherapy may be more relevant for more advanced-stage patients,” Dr. Berek told listeners.

Better Therapeutic Index Quality of life was significantly better in the weekly arm (P < .0001) in MITO-7. “This shows the importance of giving therapy at the right time, because the toxicity was lower and [quality of life] was better, leading to a better therapeutic index. The results support the weekly schedule as part of practice,” Dr. Berek stated.

“We await data from other trials. Several studies are maturing within 1 to 5 years, and will help us answer the question,” he said.

Dr. Berek applauded the quality-of-life analysis of MITO-7. “It is critical to continue to analyze [quality of life] in all these trials. The choice of therapy may come down to what patients can tolerate better,” he commented.n Disclosure: Dr. Berek reported no potential conflicts of interest.

AUC2 plus paclitaxel 60 mg/m2) for 18 consecutive administrations.

The final analysis was conducted March 2013 at a median follow-up of 20 months and included 808 pa-

tients. Both treatment arms were well balanced for baseline characteristics. Median age was 60 years, 75% were Eastern Cooperative Oncology

ing “very high efficacy for both arms,” he said.

greatest benefit from carboplatin. The investigators are also analyzing the results according to BRCA mutation status.

“Finally, the results have to be set in context with the upcoming [Cancer and Leukemia Group B]/Alliance 40603 phase II study, which is adding bevacizumab and/or carboplatin to weekly paclitaxel followed by dose-dense anthracycline/cyclophosphamide,” he said. n

Results in Context Dr. von Minckwitz concluded that while the carboplatin-containing regimen increased pathologic complete response, “the observed high efficacy of this regimen has to be weighed against a high rate of treatment discontinuations,” which occurred for 39% of patients treated with chemotherapy plus a targeted agent and 48% of those receiving the same plus carboplatin.

“We have to further analyze the adverse events for the different regimens, to find out which of the components is most responsible,” he suggested.

A biomarker program aims to identify subgroups of patients with triple-negative breast cancer who may obtain the

continued on page 6

Disclosure: Dr. Von Minckwitz has received honoraria from Roche and Sanofi and research funds from Roche, GlaxoSmithKline, and Teva.

Reference 1. Von Minckwitz G, Schneeweiss A, Salat C, et al: A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). 2013 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2012.

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The ASCO Post | AUGUST 15, 2013

PAGE 6

ASCO Annual Meeting Gynecologic Oncology

Neoadjuvant Chemotherapy and Interval Debulking May Be Appropriate for Some Patients With Poor Performance Status Advanced Ovarian Cancer

By Alice Goodman

P

atients with newly diagnosed advanced ovarian cancer—especially patients with poor performance status—appear to derive benefits from neoadjuvant chemotherapy followed by surgery vs primary surgery followed by chemotherapy, according to results of the Medical Research Council (MRC) CHORUS trial. In the study, neoad-

Study Background Ovarian cancer is the most frequent cause of death from gynecological cancers. Symptoms are nonspecific, and over 60% of patients present with advanced disease. Only about 40% of patients are alive at 5 years, and better treatments are needed, he told listeners.

The MRC CHORUS trial enrolled

This is the second randomized controlled noninferiority trial to indicate that neoadjuvant chemotherapy is an alternative to primary surgery.

—Sean Kehoe, MD

juvant chemotherapy improved operative debulking rates and operative morbidity and mortality compared with primary surgery, but median survival remained low in all patients.

“This is the second randomized controlled noninferiority trial to indicate that neoadjuvant chemotherapy is an alternative to primary surgery,” said principal investigator Sean Kehoe, MD, Lawson Tait Professor of Gynecological Cancer, University of Birmingham, UK. The first was the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial.

552 patients with stage III/IV ovarian cancer between March 2004 and August 2010. Of these, 276 were randomly assigned to primary debulking surgery followed by six cycles of platinum-based chemotherapy and 274 were randomly assigned to three cycles of neoadjuvant platinum-based chemotherapy followed by surgery and then another three cycles of chemotherapy.

Both arms had similar demographic and disease characteristics. Median age was 65.5 years, median tumor size was 8 cm, and 25% had stage IV disease. About 20% of patients in both

EXPERT POINT OF VIEW

T

he CHORUS trial had similar results to the previous European Organisation for Research and Treatment of Cancer (EORTC) 55971 study, showing noninferiority for primary debulking surgery followed by chemotherapy vs neoadjuvant chemotherapy followed by surgery and additional chemotherapy, said formal discussant Jonathan S. Berek, MD, Director of the Stanford Women’s Cancer Center, Palo Alto, California. Both studies showed an optimal debulking rate of about 41% for Jonathan S. Berek, MD primary surgery vs 75% to 80% in the neoadjuvant chemotherapy arms. Dr. Berek emphasized, however, that the two trials had slightly different patient populations, with more poor-prognosis and older patients in CHORUS. “Both trials included a sicker group of patients. One needs to consider these factors in selecting patients for neoadjuvant therapy vs cytoreduction,” he said.

He noted that an ongoing Japan Clinical Oncology Group ( JCOG) trial is comparing eight cycles of chemotherapy following surgery vs four cycles of neoadjuvant chemotherapy, surgery, and four more chemotherapy cycles, but results of that trial won’t be available until 5 years from now.

Impact of Where Surgery Is Done The extent of debulking is controversial and depends on the country where the study was conducted, he continued. Also, the high postoperative mortality rate in the primary surgery arm of CHORUS is of concern, and was probably related to the center where surgery was performed.

“In the EORTC trial, optimal debulking rates and hazard ratios varied considerably by country. The extent and quality of resection may impact outcome,” he said.

“In the future, patient selection [for neoadjuvant chemotherapy vs primary debulking surgery] will be critical. We will need to develop tools to predict which patients will do poorly with primary surgery. These findings are not generalizable to all patients with stage III ovarian cancer. My belief is that goodprognosis patients should be treated with primary surgery followed by chemotherapy,” he stated. n Disclosure: Dr. Berek reported no potential conflicts of interest.

continued on page 7

Weekly vs Every-3-week Regimen continued from page 4

Group (ECOG) performance status 0, 85% were stage III or IV, and compliance was good in both arms.

Progression-free survival was slightly—but not significantly—longer with the weekly regimen (18.8 vs 16.5 months). The main prognostic factors associated with progressionfree survival were disease stage and residual disease. No interaction was observed between treatment arm and main prognostic factors, including age, stage, and size of institution. Overall survival data are not yet mature.

Quality-of-life Analysis Quality of life was assessed for the first three cycles of chemotherapy using the Functional Assessment of Cancer Therapy (FACT)-Ovarian scale and the FACT/Gynecologic Oncology Group (GOG)-Neurotoxicity (Ntx) subscale. For all scales, quality of life significantly favored the weekly arm (P < .0001). For patients randomized to the every-3-week regimen, quality of life worsened 1 week after each course, but quality of life remained stable throughout treatment in the weekly arm after a slight dip following week 1.

The weekly arm had significantly

less severe neutropenia, febrile neutropenia, thrombocytopenia, renal toxicity, and neuropathy. Significantly less hair loss, neuropathy, and vomiting were also reported in the weekly arm.

An audience member questioned whether platinum and paclitaxel were underdosed in the weekly arm, but Dr. Pignata said there was no evidence for that. “The Japanese trial was designed to be dose-dense. But if we look at the number of patients that completed six cycles in MITO7, this was much higher than in the Japanese trial,” he noted. n

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

References 1. Pignata S, Scambia G, Lauria R, et al: A randomized multicenter phase III study comparing weekly versus every 3 weeks carboplatin plus paclitaxel in patients with advanced ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO)7—European Network of Gynaecological Trial Groups (ENGOT-ov-10) and Gynaecologic Cancer Intergroup (GCIG) trial.

2013 ASCO Annual Meeting. Abstract LBA5501. Presented June 1, 2013.

2. Katsumata N, Yasuda M, Takahashi F, et al: Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: A phase 3, open-label, randomised controlled trial. Lancet 374:1331-1338, 2009.

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News Prevention

U.S. Preventive Services Task Force Recommends CT Screening for Lung Cancer in High-risk Individuals

T

he U.S. Preventive Services Task Force recently posted its final evidence report and draft recommendation statement on screening for lung cancer.

The Task Force is providing an opportunity for public comment on this draft recommendation statement until

Michael LeFevre, MD, MSPH

August 26. All public comments will be considered as the Task Force develops its final recommendation.

Based on the available evidence, the Task Force recommends screening people who are at high risk for lung cancer with annual low-dose CT

scans, which can prevent a substantial number of lung cancer-related deaths.

This is a grade B draft recommendation.

Biggest Risk Factor Smoking is the biggest risk factor for developing lung cancer, resulting in about 85% of lung cancers in the United States. The risk for developing lung cancer also increases with age, with most lung cancers occurring in people age 55 or older.

“The more you smoke over time, the more at risk you are for lung cancer. When deciding who should be screened, clinicians will need to assess the person’s age, overall health, how much the person has smoked, and whether the person is still smoking or how many years it has been since the person quit,” says Task Force Co-Vice Chair Michael LeFevre, MD, MSPH. “This evaluation will help clinicians decide whether it may be beneficial to screen a given person,” Dr. LeFevre said. continued on page 12

USPSTF Recommends CT Screening for Lung Cancer ■ The U.S. Preventive Services Task Force recommends screening people who are at high risk for lung cancer with annual low-dose CT scans.

■ This is a grade B draft recommendation. The USPSTF defines grade B

as high certainty that net benefit of the service is moderate, or there is moderate certainty that net benefit of the service is moderate to substantial, and the service should be offered or provided to patients meeting the criteria.

Neoadjuvant Chemotherapy continued from page 6

arms had poor performance status (World Health Organization [WHO] performance status 2 or 3). About 79% of those in the primary surgery arm and 68% of those in the neoadjuvant arm had high-grade serous carcinoma.

Key Findings Optimal debulking was possible in 16% of the primary surgery arm vs 40% of the neoadjuvant chemotherapy arm. Toxicity was greater in the primary surgery arm. Grade 3 or higher toxicity occurred in 48% vs 40%, respectively. Postoperative complications were higher as well, with

grade 3 or 4 complications occurring in 24% vs 14%, respectively.

Hospital stay was shorter with neoadjuvant chemotherapy; 74% in the primary surgery arm were discharged

‘Major Milestone in War on Cancer’

By James L. Mulshine, MD

T

he recommendation by the U.S. Preventative Services Task Force (USPSTF) for the use of low-dose, computed tomography (CT) to detect early lung cancer in high-risk individuals is a major milestone in the war on cancer.

Lung cancer is the leading cause of cancer death across the world. Despite intensive efforts over the past decades, no measure has been found to significantly reduce lung cancer mortality in individuals with heavy smoking exposure. From the pilot observations of the Early Lung Cancer Action Project, to the work of the National Lung Screening Trial, to the many groups that have refined the screening process, this has been an extensive international collaboration to responsibly advance this screening process.

Now, with the new recommendation from the USPSTF, we move into an equally challenging phase. How do we safely, economically, and effecJames L. Mulshine, MD tively implement this new screening service across the nation? Further, lung cancer is a disease that is largely caused by tobacco exposure and it is clear that there are major disparities in the use of those products in our society. How do we implement a

Federal reimbursement is an essential component to the fair and equitable access to this new service. lung cancer screening system with effective tobacco cessation provisions so that those in our society with the greatest risk have access to these life-saving screening and cessation services? Federal reimbursement is an essential component to the fair and equitable access to this new service, and the USPSTF deserves great credit for its thoughtful recommendation. n Disclosure: Dr. Mulshine reported no potential conflicts of interest.

Dr. Mulshine is Professor, Internal Medicine, and Vice President of Research at Rush Medical College, Rush University, Chicago.

within 14 days, compared with 92% treated with neoadjuvant chemotherapy arm. Fewer deaths within 28 days were reported with neoadjuvant chemotherapy: 14 (5.6%) in the primary

Neoadjuvant Chemotherapy for Advanced Ovarian Cancer

surgery arm vs 1 (0.5%) in the neoadjuvant chemotherapy arm.

No significant difference in median progression-free survival was observed between the two arms (10.3 months for primary surgery vs 11.7 months for neoadjuvant chemotherapy). Median survival was 22.8 vs 24.5 months, respectively. n

■ A large randomized, controlled, trial found that neoadjuvant

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

■ Progression-free survival and overall survival were similar in both arms.

Reference 1. Kehoe S, Hook J, Nankivell M, et al: Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial.

2013 ASCO Annual Meeting. Abstract 5500. Presented June 1, 2013.

chemotherapy was noninferior to primary surgery in patients with advanced ovarian cancer.

However, more patients in the neoadjuvant chemotherapy arm were able to have optimal debulking surgery, and this arm also had fewer postoperative complications and deaths compared with the primary surgery arm.

■ These results were obtained in older, sicker patients, suggesting that this subpopulation gains the most benefit from the neoadjuvant approach.

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News

CT Screening for Lung Cancer continued from page 7

Reasonable Balance of Benefits and Harms After reviewing the evidence, the Task Force determined that you can reach a reasonable balance of benefits and harms by screening people who

are 55 to 80 years old and have a 30 pack-year or greater history of smoking, who are either current smokers or have quit in the past 15 years.

A “pack-year” means that someone has smoked an average of one pack of cigarettes per day for a year. For example, a person reaches 30 pack-years of smoking history by smoking a pack a

day for 30 years or two packs a day for 15 years.

“Lung cancer is the leading cause of cancer death in the United States and a devastating diagnosis for more than 200,000 people each year,” says Task Force Chair Virginia Moyer, MD, MPH. “Sadly, nearly 90% of people who develop lung cancer die from the

disease, in part because it often is not found until it is at an advanced stage.

Earlier Detection By screening those at high risk, we can find lung cancer at earlier stages when it is more likely to be treatable.”Dr. LeFevre also cautions, “It’s important to remember that help-

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PAGE 13

News

ing smokers stop smoking and protecting nonsmokers from exposure to tobacco smoke are the most effective ways to decrease the sickness and death associated with lung cancer. In addition, people who quit smoking will continue to see their risk go down over time. Screening for lung cancer is beneficial, but it is not an alternative

to quitting smoking.”

The Task Force’s draft recommendation statement has been posted for public comment on the Task Force website at www.uspreventiveservicestaskforce.org.

Comments can be submitted from July 30 to August 26 at www.uspreventiveservicestaskforce.org/tfcomment. htm. n

More on Lung Cancer For more on lung cancer is this issue of The ASCO Post, see the following: • Acquired resistance to crizotinib, see page 14 • Crizotinib improves progression-free survival vs pemetrexed or docetaxel in advanced ALK-positive NSCLC, see page 30 • Low-dose CT screening for lung cancer, see page 36 • First-line carboplatin/pemetrexed improves survival vs pemetrexed alone, see page 83

The ASCO Post | AUGUST 15, 2013

PAGE 14

Journal Spotlight Thoracic Oncology

Acquired Resistance to Crizotinib from ROS1 G2032R Mutation

By Matthew Stenger

T

he ALK inhibitor crizotinib (Xalkori) has also shown activity in lung cancers with ROS1 translocations. As recently reported by Mark M. Awad, MD, PhD, of Mas-

sachusetts General Hospital, Boston, and colleagues in The New England Journal of Medicine, a mutation conferring resistance to crizotinib was found to emerge during treatment in

a patient with metastatic lung adenocarcinoma with a CD74-ROS1 rearrangement who had initially shown dramatic response to crizotinib.1 The patient, who had no mutations in

KRAS or EGFR and no ALK translocation on initial evaluation, had fared poorly on first-line pemetrexed (Alimta) and carboplatin. Further testing identified a ROS1 rearrangement, and the patient was enrolled in a trial evaluating crizotinib in cancers with ROS1 rearrangements.

Progression after Response Within 1 week of starting crizotinib, the patient had substantial reductions in dyspnea and fatigue and a substantial increase in appetite. A CT scan at 2 months showed dramatic response to treatment, but a month later, the patient’s respiratory symptoms worsened and imaging showed disease progression.

Subsequent biopsy of a resistant tumor and genetic analysis identified a mutation consisting of a glycine-to-arginine substitution at codon 2032 (G2032R) in the ROS1 kinase domain. This mutation had not been detected in the malignant cells assessed prior to crizotinib therapy.

On autopsy, all sites of disease examined had the G2032R mutation, indicating that its occurrence was an early event in the clonal expansion of crizotinib-resistant tumor cells.

Not a Gatekeeper Mutation Molecular analysis showed that the mutation confers resistance to ROS1 kinase inhibition through steric interference with drug binding. In contrast to the gatekeeper residue mutations for drug resistance found in ABL, EGFR, and ALK, the G2032R ROS1 mutation is located in the solvent front of the kinase domain and is analogous to the G1202R ALK mutation found in crizotinib-resistant ALK-rearranged lung cancers.

The investigators stated, “Whereas the L1196M ALK gatekeeper mutant may still be sensitive to newer ALK inhibitors, such as CH5424802, we previously found that G1202R ALK confers high-level resistance to crizotinib and to all the next-generation ALK inhibitors that were examined. In light of these observations, it may be necessary to identify novel compounds that specifically target the G1202R ALK or G2032R ROS1 mutant, to overcome the development of crizotinib resistance….” n

Disclosure: The study was funded by Pfizer and others. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Awad MM, et al: N Engl J Med 368:2395-2401, 2013.

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PAGE 15

ASCO Annual Meeting Thoracic Oncology

Tecemotide Vaccine Warrants Further Study in Unresectable Stage III Non–Small Cell Lung Cancer

By Alice Goodman

R

esults of the START trial suggest that maintenance therapy with the investigational immunotherapy tecemotide (formerly known as LBLP25) may have a role in the treatment of patients with unresectable stage III non–small cell lung cancer (NSCLC). Although there was no significant overall survival advantage for tecemotide in the main modified intent-to-treat analysis of the trial, a prespecified subgroup analysis showed a 10-month survival edge for maintenance therapy with tecemotide vs placebo in patients treated with concurrent chemoradiotherapy.

Large Subgroup “Patients receiving concurrent [chemoradiotherapy] followed by maintenance immunotherapy represent a very large subgroup of 806 patients. We haven’t seen this type of clinically meaningful survival benefit with any other investigational therapies [in unresectable stage III NSCLC]. Nothing else has been as exciting,” said lead author Charles A. Butts, MD, a medical oncologist at Cross Cancer Institute, Edmonton, Canada. Dr. Butts believes that further study of tecemotide should go forward.

Tecemotide is an antigen-specific injectable peptide vaccine that targets MUC1, a mucinous glycoprotein that is overexpressed in lung cancer. Preliminary studies have established the safety of this therapy and shown promise in extending survival in patients with NSCLC, Dr. Butts said.

Study Design START (Stimulated Targeted Antigenic Responses To NSCLC) is a multicenter, randomized, double-blind, placebo-controlled, phase III study of patients with unresectable stage III NSCLC who have responded or had stable disease after at least two cycles of platinum-based chemotherapy plus

radiation and had good performance status. (Drugs used with platinum were not prespecified.) Patients were stratified for stage IIIA IIIA and IIIB, complete response/partial response vs stable disease on chemoradiotherapy, concurrent vs sequential chemoradiotherapy, and geographic region.

Following chemoradiotherapy, eligible patients (ie, responding or with stable disease) were randomized to maintenance therapy with tecemotide vs placebo. Both groups received weekly injections for 8 consecutive weeks, followed by maintenance injections every 6 weeks until disease progression.

After the trial was initiated, with a planned enrollment of 1,322 patients, it was halted temporarily, triggered by a single case of fatal encephalitis in a phase II study of tecemotide in a patient with multiple myeloma. At the time of the clinical hold, 531 patients

EXPERT POINT OF VIEW

F

ormal discussant Johan F. Vansteenkiste, MD, PhD, Professor of Internal Medicine at University Hospital KU, Leuven, Belgium, was also enthusiastic about the findings in the concurrent chemoradiotherapy arm, and believes that a confirmatory trial should be done.

“Does the promise of immunotherapy meet reality? It starts to in START. The study delivers clinically relevant results,” Dr. Vansteenkiste said.

A confirmatory trial should be designed to adJohan F. Vansteenkiste, dress the potential issues in START, he said. Such a MD, PhD trial would include patient registration at the start of treatment so they can be followed, homogeneous contemporary concurrent stage III treatment, extensive biomarker research, and translational research on radiotherapy-immunotherapy links, he continued. n Disclosure: Dr. Vansteenkiste has been a consultant or advisor for GlaxoSmithKline, Lilly, and Merck Serono.

most likely to be impacted by interruption of their treatment,” said Dr. Butts.

“The 6 months represents the eight weekly injections and two subsequent 6-weekly injections of tecemotide. It was felt that this duration was likely necessary to induce the immune response.”

“This was the largest trial ever reported in stage III NSCLC,” Dr. Butts told listeners.

Key Data Charles A. Butts, MD

had received treatment and had treatment suspended for a median of 4 months. After additional safety monitoring, treatment was restarted.

The final sample size—excluding patients randomized within 6 months of the clinical hold—was 1,239 patients who were included in a modified intent-to-treat analysis. The safety population included 1,501 patients who received at least one dose of the study therapy.

“Patients within 6 months of randomization at the time of the clinical hold were thought to be the patients

Immunotherapy for Lung Cancer ■ The START trial showed that immunotherapy maintenance with tecemotide was safe, with no new safety signals reported.

■ Although the study failed to meet the primary endpoint of overall survival, survival was prolonged in a large subgroup of patients who received concurrent chemoradiotherapy, but not sequential chemoradiotherapy.

Both arms were well balanced for demographic and disease characteristics. The largest group of patients received concurrent chemoradiotherapy (65%) as initial therapy; 35% received sequential chemoradiotherapy.

At a median follow-up of about 39 months, the study failed to meet the primary endpoint of overall survival.

In a modified intent-to-treat analysis, median overall survival was 25.6 months for immunotherapy vs 22.3 months for placebo, demonstrating a nonsignificant trend favoring tecemotide. Time to disease progression (median, 10 vs 8.4 months for tecemotide and placebo, respectively) and time to symptomatic progression (median, 14.2 vs 11.4 months) were also not significantly different.

“When patients who were excluded from the primary analysis due to the clinical hold were analyzed, there was no treatment effect, suggesting that uninterrupted therapy is critical for efficacy,” Dr. Butts emphasized.

Subgroup Analysis Prespecified subgroup analysis favored tecemotide, and this finding was most robust for concurrent vs sequential chemoradiotherapy, he continued. In the concurrent chemoradiotherapy patients (n = 806), median overall survival was 30.8 months for tecemotide recipients vs 20.6 months for placebo recipients (P = .016). No difference was seen between the two treatment arms in the group of patients treated with sequential chemoradiotherapy.

No safety signals emerged in this trial. No difference between the two treatment arms was found in frequent adverse events, grades 3 and 4 adverse events, or adverse events leading to death.

Dr. Butts speculated on the “million dollar question”: Why were results so much better in the concurrent chemoradiotherapy arm? “It may be explained by patient selection. Probably patients selected for sequential therapy are not treated with a curative intent,” he noted. n

Disclosure: Dr. Butts has been a consultant or advisor for and has received honoraria from Merck KGaA and Merck Serono.

Reference 1. Butts CA, Socinski MA, Mitchell P, et al: START: A phase III study of LBLP25 (tecemotide) cancer immunotherapy for unresectable stage III on-small cell lung cancer. 2013 ASCO Annual Meeting.

Abstract 7500. Presented June 4, 2013.

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ASCO Annual Meeting Gastrointestinal Oncology

Metastatic Colorectal Cancer continued from page 1

zumab at 7.5 mg/kg every 3 weeks.

Upon the first episode of disease progression, patients in both arms were treated with CAPOX-B until second progression, which was the study’s primary endpoint. For patients not able to receive CAPOX-B upon first progression, the second episode of disease progression was considered equal to first progression, per protocol.

Secondary endpoints were overall survival and time to second progression, which was defined as the time to progression or death on any treatment (including CAPOX-B) following the first episode of disease progression.

All endpoints were calculated from the time of randomization, which occurred after induction therapy.

A total of 558 patients from 74 Dutch centers were randomized and followed for a median of 40 months.

Progression Delayed in Maintenance Arm “Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B was feasible, and it significantly prolonged [time to first and second episodes of disease progression],” Dr. Koopman reported.

The median first episode of progression in the observation arm occurred at 4.1 months, compared to 8.5 months in the maintenance arm, for an adjusted hazard ratio (HR) of 0.41 (P < .001), Dr. Koopman reported.

In the observation arm, 76% were reintroduced to CAPOX-B. In the maintenance arm, 47% were reintroduced to CAPOX-B. Patients were followed until their second disease progression, and the median time to second progression at that time was 10.5 months with observation and 11.8 months with maintenance, a 23% reduction in risk of second progression (adjusted HR = .77, P = .007), the primary endpoint.

The median time to second progression—ie, time from randomization to disease progression on any treatment given after first progression—was 15 months for observation and 19.8 for maintenance (adjusted HR = .63, P < .001).

Overall Survival Also Improved Maintenance also afforded an overall survival benefit in CAIRO3.

Although the difference was not statistically significant in the unadjusted analysis, it reached significance when adjusted for covariates, including disease stage, interval between diagnosis and randomization, and other factors.

In the adjusted analysis, median overall survival was 18.2 months with observation and 21.7 months with maintenance (adjusted HR = .80, P = .035). Dr. Koopman emphasized that this overall survival time does not include the 4 months of induction treatment.

Almost 50% of each arm received four effective agents during the course of their metastatic disease, and about 11% received five. “The percentage of patients receiving four to five drugs during their metastatic disease is comparable between the arms; therefore, time on treatment appears to be an additional relevant factor for overall survival in this study,” she suggested.

Grade 3/4 toxicity was manageable. Differences between the arms included hand-foot syndrome (0% with observation vs 22% with maintenance) and neurotoxicity (5% vs 10%, respectively).

Dr. Koopman acknowledged the need to weigh the modest, though statistically significant, benefit with the potential for lesser quality of life due to continued chemotherapy. Quality-oflife data from the study are currently being analyzed.

“The primary endpoint, [second progression-free survival rate], and also time to second progression [on any

Maintenance in Metastatic Colorectal Cancer ■ In the phase III CAIRO3 study, maintenance treatment with capecitabine

plus bevacizumab significantly delayed disease progression and improved overall survival in metastatic colorectal cancer patients with unresectable disease

■ The first progression occurred at a median time of 4.1 months in the

observation arm and 8.5 months in the maintenance arm; second progression, the primary endpoint, occurred at 10.5 months and 11.8 months, respectively—both differences were statistically significant.

■ In the adjusted analysis, overall survival was significantly improved by approximately 3.5 months in the maintenance arm.

EXPERT POINT OF VIEW

M

aintenance treatment with capecitabine plus bevacizumab can be considered in clinical practice, according to Tim Maughan, MD, Professor of Clinical Oncology at Oxford University in the United Kingdom, who discussed CAIRO3 at the session.

He said that approximately 60% of patients with metastatic colorectal cancer will have their disease controlled, but not cured, by first-line chemotherapy. The best approach to preventing recurrence is Tim Maughan, MD still being determined, he commented.

“It is important to include our patients in this conversation,” he emphasized. “They are thinking not only about survival but also about time free of cancer symptoms, treatment side effects, visits to the doctor, financial pressure, and worry—time to live life normally.”

Robust Series of Endpoints “I was impressed by the robustness of the series of primary and secondary endpoints in the study.… Among all the trial of chemotherapy-free intervals vs maintenance, CAIRO3 shows the most benefit in interval progression-free survival,” he noted. “Overall survival, however, remains the key endpoint for registration, for our patients, and for changing practice. In CAIRO3, this was about 3.5 months—modest, but statistically significant,” he noted.

That said, is the benefit due to the combination of the two drugs or to one or the other alone? “The lack of benefit from bevacizumab monotherapy shown in the [Swiss Group for Clinical Cancer Research (SAKK)] 41/06 study1 and the benefit of fluoropyrimidine maintenance in the [Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR)] OPTIMOX2 study2 suggest that the fluoropyrimidine component certainly makes a major—and possibly the dominant—contribution,” he told The ASCO Post. “Further, it is not clear which patients benefit from maintenance therapy, and it is likely that this is a subset of patients. Further work is required to address this question,” he said.

“While some questions remain, and the combination is expensive, bevacizumab plus capecitabine shows a clinical benefit over no maintenance and can be considered for routine use,” Dr. Maughan said. n

Disclosure: Dr. Maughan has been a consultant or advisor for Sanofi and has received research funding from Merck Serono.

References 1. Koeberle D, Betticher DC, Von Moos R, et al: Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06). 2013 ASCO Annual Meeting. Abstract 3503. Presented June 1, 2013.

2. Chibaudel B, Maindrault-Goebel F, Lledo G, et al: Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 27:5727-5733, 2009.

treatment given after first progression], were highly significantly different between the arms. I think the time where the patients were not on treatment in the observation arm accounts for these differences. For patients who have stable disease or better after six cycles of chemotherapy, I believe maintenance is the treatment to choose,” she said.

Relevant Endpoint In conclusion, Dr. Koopman maintained, “Our data support the use of bevacizumab plus capecitabine until progression or unacceptable toxicity.… When any treatment after [first disease progression] was con-

sidered, maintenance therapy also significantly prolonged the time to second progression, and this is probably the endpoint that is most relevant for clinical practice.” n Disclosure: Dr. Koopman reported no potential conflicts of interest.

Reference 1. Koopman M, Simkens LH, Ten Tije AJ et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer: The phase III CAIRO3 study of the Dutch Colorectal Cancer Group. 2013 ASCO Annual Meeting. Abstract 3502. Presented June 1, 2013.

What if we could harness the potential of the immune system to fight cancer?

With immuno-oncology, it may be possible.

Immuno-oncology is a rapidly evolving field of research that focuses on working directly on the immune system to fight cancer.1 At Bristol-Myers Squibb, we are committed to researching and developing innovative treatments that harness the potential of the immune system to help patients fight cancer.

Bristol-Myers Squibb is leading the way in immuno-oncology.

To find out more about our cutting-edge immuno-oncology research, visit BMSImmunoOncology.com.

For information on investigational studies, including study sites, visit BMSStudyConnect.com.

References: 1. Borghaei H, Smith MR, Campbell KS. Immunotherapy of cancer. Eur J Pharmacol. 2009; 625(1-3): 41â&#x20AC;&#x201C;54.

Leading the way Š2013 Bristol-Myers Squibb Company.

ONCUS13UB01312-01-01

07/13

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ASCO Annual Meeting Hematologic Oncology

B-cell Receptor Signaling Inhibitors Moving Forward in Lymphoma

By Caroline Helwick

T

hough still in early-phase studies, novel B-cell receptor signaling inhibitors look very promising for the treatment of lymphoma, according to reports from the 2013 ASCO Annual Meeting.

Idelalisib in Non-Hodgkin Lymphoma In non-Hodgkin lymphoma (NHL), idelalisib looked impressive as both a single agent and when given in combination with standard therapy. The drug is a first-in-class selective oral inhibitor of PI3K-delta, a pathway that is critical for the

A

t the 2013 ASCO Annual Meeting, Ranjana Advani, MD, the Saul A. Rosenberg, MD, Professor of Lymphoma at Stanford University Medical Center, Palo Alto, California, discussed the promise of the B-cell signaling inhibitors idelalisib and ibrutinib in lymphoma.

Biggest Question Given the single-agent activity of idelalisib in earlier studies, testing the drug in combination, as Leonard et al did, “is a logical step forward,” Dr. Advani said. “Activity was seen in patients exposed to rituximab [Rituxan] and bendamustine [Treanda]—overall, a 78% response rate—and some responses appeared durable,” she said.

But the study was small, the population was heterogeneous, and few patients (about 30%) continued on long-term treatment with idelalisib, she noted. “The biggest question is whether responses are greater with the combination than they would be with single agents,” she suggested. For example, in the study by Benson et al, single-agent activity reached 67% among those optimally dosed. The potential superiority of a regimen containing idelalisib may depend on the backbone, she noted.

With rituximab, McLaughlin et al1 reported a 48% response rate, compared with 72% in the current study of idelalisib/rituximab, in which more than 90% of subjects had prior rituximab. “The combination, therefore, is

John Leonard, MD

activation, proliferation, and survival of B cells. PI3K-delta signaling also plays a role in homing and retention in lymphoid tissues and is hyperactive in many B-cell malignancies.

In a phase I study of 79 previously treated patients with indolent NHL, patients who received idelalisib plus standard therapy achieved a response rate of 78%, including complete responses in 26%, according to John Leonard, MD, of Weill Cornell Medical College, New York.1 Dr. Leonard called idelalisib “an exciting new drug in various lymphoid malignancies,” and noted, “This particular PI3K inhibitor is relatively deltaspecific, which may be important in terms of its activity and tolerability profile. Idelalisib in combination regimens could improve the efficacy

of the standard of care in NHL.” At the discretion of the treating physician, patients in the study received idelalisib in combination with rituximab (Rituxan), bendamustine (Treanda), or rituximab plus bendamustine. Patients were treated for six cycles, and responders could continue idelalisib for a total of 48 weeks.

Median duration of treatment was 11 months.

Response rates were 72% for idelalisib/rituximab, 85% for idelalisib/ bendamustine, and 71% for idelalisib/bendamustine/rituximab (which continued on page 19

EXPERT POINT OF VIEW much more effective than rituximab alone,” she concluded.

With bendamustine alone, a 76% response rate has been reported,2,3 whereas in the current study, bendamustine plus idelalisib yielded an 85% response rate; in this study, 100% had received prior rituximab and 21% prior bendamustine. The combination of

Ranjana Advani, MD

bendamustine plus rituximab yielded a 90% response rate in the landmark study by Rummel et al.4 With idelalisib paired with bendamustine, the response rate was 71%; in the study population, 90% had prior rituximab and 30% prior bendamustine. Regarding this comparison, therefore, Dr. Advani concluded, “Bendamustine/ rituximab in a refractory population already yields very high response rates, and it’s hard to say whether the combination with idelalisib is significantly better or not.”

Uncertain Superiority For mantle cell lymphoma, idelalisib also seems promising, but the

study population was small and heterogeneous. In the bendamustine/ rituximab arm, the 100% response rate (50% complete responses) was impressive, but the patients had not received prior bendamustine or bortezomib (Velcade), ie, this was not a refractory population, she emphasized.

In mantle cell lymphoma as well, the potential superiority of adding idelalisib to standard therapies is not yet certain, she said. This is especially true for bendamustine/rituximab, which has been shown to elicit responses in 75% to 92% of patients. The activity of the triplet of idelalisib/bendamustine/ rituximab appears similar to what can be achieved with bendamustine/rituximab alone, she suggested.

Enhanced Activity Commenting on ibrutinib, Dr. Advani noted that the drug has shown activity across multiple subtypes of relapsed/refractory nonHodgkin lymphoma. In the phase I study reported at the ASCO Annual Meeting by Younes et al, combining ibrutinib with R-CHOP as frontline therapy in a variety of B-cell lymphomas, the 100% response rate was “impressive,” she commented, though the study was small, followup was short, and disease-specific details were lacking.

“From the safety data we have, these studies show that the new agents can be safely combined without significant additive toxicity,” Dr. Advani

continued. “The major issue with the studies is the very small numbers and the relatively short follow-up, but they do set the stage for testing these agents in the front-line setting. Future challenges will be to determine whether to use these drugs as single agents or in combination—it’s not clear if all the combinations tested are better than the single agent—and the optimal sequence for their use.” n

Disclosure: Dr. Advani has been a consultant or advisor for Celgene, Genentech, Pharmacyclics, and has received research funding from Abbott Laboratories, Genentech, Pharmacyclics, Rigel, and Seattle Genetics.

References 1. McLaughlin P, Grillo-López AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998.

2. Friedberg JW, Cohen P, Chen L, et al: Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: Results from a phase II multicenter, single-agent study. J Clin Oncol 26:204-210, 2008.

3. Kahl BS, Bartlett NL, Leonard JP, et al: Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: Results from a multicenter study. Cancer 116:106114, 2010.

4. Rummel MJ, Al-Batran SE, Kim SZ, et al: Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and lowgrade non-Hodgkin’s lymphoma. J Clin Oncol 23:3383-3389, 2005.

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ASCO Annual Meeting B-cell Receptor Inhibitors continued from page 18

achieved the highest rate of complete responses, 43%).

“The vast majority had at least a partial response, whether we treated with two drugs or three,” he said.

Single-agent activity for idelalisib was also confirmed in another phase I study of 64 patients conducted by Don M. Benson, MD, PhD, of Ohio State University Comprehensive Cancer Center, and colleagues.2 The response rate in this trial was 48%,

B-cell Receptor Signaling Inhibitors in Lymphoma

Anas Younes, MD

■ Idelalisib, an oral inhibitor of the PI3K-delta signaling pathway, when

combined with standard treatment, produced responses in 78% of patients with previously treated indolent non-Hodgkin lymphoma.

■ In mantle cell lymphoma, idelalisib plus everolimus, bortezomib, or

rituximab/bendamustine was associated with a 49% response rate overall and a 100% response rate when paired with rituximab/bendamustine in patients with minimal prior therapy.

■ The Bruton’s tyrosine kinase inhibitor ibrutinib, paired with R-CHOP, in a

small phase I/II study of 33 previously untreated NHL patients, produced responses in 100% of patients, including complete responses in 67%.

“The data suggest idelalisib produces high response rates combined with either ributiximab, bendamustine, or both, and we are pleased to see that they are durable.”

Median progression-free survival

Don M. Benson, MD, PhD

for the trial has not been reached. At 24 months, 62.5% of patients remained in remission, Dr. Leonard reported.

tients.4 The combination produced responses in 100% of patients, including complete responses in 67%, reported Anas Younes, MD, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues. n

rising to 67% among optimally dosed patients (> 100 100 mg twice daily). Median progression-free survival was 7.6 months but rose to almost 17 months among the optimally dosed cohort.

Idelalisib in Mantle Cell Lymphoma In mantle cell lymphoma, singleagent idelalisib showed activity in phase I trials but was most beneficial when combined with other agents. In a phase I study of 33 patients reported by Nina D. Wagner-Johnston, MD, of Washington University, St. Louis, the combination of idelalisib and everolimus (Afinitor), bortezomib (Velcade), or bendamustine/ rituximab yielded a 49% response rate, with 12% complete responses.3 In the bendamustine/rituximab

arm, 100% of patients responded, however, unlike the other two arms this population had not been heavily pretreated. Median progression-free survival was 8 months.

The addition of idelalisib does not appear to increase the toxicity of treatment for lymphoma with current agents, the investigators noted in their presentations. “The toxicity profile is consistent with what we see for single agents. We did not see excess toxicity, at least within the limitations of the size of these studies,” Dr. Leonard observed. Liver enzyme elevation is a unique characteristic of idelalisib, but this is manageable with dose reductions. Phase III III trials of the PI3K inhibitor are underway.

Ibrutinib in Non-Hodgkin Lymphoma The Bruton’s tyrosine kinase inhibitor ibrutinib, which has received Breakthrough Therapy status from the U.S. Food and Drug Administration, was evaluated in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in a small phase I/ II study of 33 previously untreated CD20-positive B-cell NHL pa-

Disclosure: Dr. Leonard has been a consultant or advisor for Gilead Sciences.

Dr. Benson has received research funding from Gilead Sciences. Dr. Wagner-Johnston receives research funding from Celgene. Dr. Younes has been a consultant or advisor for Pharmacyclics, has received honoraria from Pharmacyclics, and has received research funding from Janssen and Pharmacyclics.

References 1. Leonard J, Wagner-Johnston ND, Coutre SE, et al: Tolerability and activity of combinations of the PI3K-delta inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma: Updated results from a phase 1 study. 2013 ASCO Annual Meeting. Abstract 8500. Presented June 1, 2013.

2. Benson DM, Kahl BS, Furman RR, et al: Final results of a phase 1 study of idelalisib, a selective inhibitor of PI3K. 2013 ASCO Annual Meeting. Abstract 8526.

Presented June 3, 2013.

3. Wagner-Johnston ND, De Vos S, Leonard J, et al: Preliminary results of PI3K-delta inhibitor idelalisib (GS-1101) treatment in combination with everolimus, bortezomib, or bendamustine/rituximab in patients with previously treated mantle cell lymphoma. 2013 ASCO Annual Meeting. Abstract 8501. Presented June 1, 2013.

4. Younes A, Flinn I, Berdeja JG, et al: Phase 1b study combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with CD20-positive B-cell non-Hodgkin lymphoma. 2013 ASCO Annual Meeting.

Abstract 8502. Presented June 1, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Armando Sardi, MD, FACS, and Rachel Joseph, MPH, on Barriers to Early Cancer Care in Colombia see page 64

Carey K. Anders, MD, on HER2positive Breast Cancer see page 60

Michael P. Link, MD, on The Future of Pediatric Oncology see page 70

Alan Astrow, MD, on Living and Working with Cancer see page 112

Visit The ASCO Post online at ASCOPost.com

Susan M. Swetter, MD, on Survival Outcomes for Young White Men with Melanoma see page 134

The ASCO Post | AUGUST 15, 2013

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FDA Update

FDA Invites Public Input on Menthol in Cigarettes

T

he U.S. Food and Drug Administration (FDA) has issued an Advance Notice of Proposed Rulemaking (ANPRM) seeking additional information to help the agency make informed decisions about menthol in cigarettes.

Despite decades of work to reduce tobacco use in the United States, it continues to be the leading cause of preventable death and disease. In the United States, about 30% of all adult smokers and more than 40% of all youth smokers report smoking menthol cigarettes.

“Menthol cigarettes raise critical public health questions,” said FDA Commissioner Margaret A. Hamburg, MD. “The FDA is com-

mitted to a science-based approach that addresses the public health issues raised by menthol cigarettes, and public input will help us make more informed decisions about how best to tackle this important issue moving forward.”

Agency Exploring Potential Regulatory Options The agency is issuing the ANPRM to obtain additional information related to potential regulatory options it might consider, such as establishing tobacco product standards, among others.

The ANPRM will be available for public comment for 60 days. The FDA will consider all comments, data, research, and other information submitted to the docket to determine what, if any, regulatory action with respect to menthol in cigarettes is appropriate. If the FDA decides to issue a rule,

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication.

the first step in that process would be a Notice of Proposed Rulemaking, which would give the public an opportunity to weigh in on the specifics of the proposed rule.

“FDA’s actions … on menthol reflect our commitment to explore all potential options, S:6.75” including the establishment of product standards. In the meantime, we will conduct new

research to further inform our decision-making,” said Mitch Zeller, JD, Director of the FDA’s Center for Tobacco Products.

The agency is also making available

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

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

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: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 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.

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.

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.

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 (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). 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: 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.

© 2013 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/13 [03-13-00091-A]

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FDA Update

New Research on Menthol Cigarettes In addition, the FDA plans to support new research on the differences between menthol and nonmenthol cigarettes as they relate to menthol’s likely impact S:6.75” on smoking cessation and attempts to quit, as well as assessing the levels of menthol in cigarette

brands and sub-brands.

The FDA is funding three mentholrelated studies: one to look at whether genetic differences in taste perceptions explain why certain racial and ethnic populations are more likely to use menthol cigarettes; the second to compare exposure to smoke-related toxins and carcinogens from menthol

and nonmenthol cigarettes; and a third to examine the effects of menthol and nonmenthol compounds in various tobacco products on both tobacco addiction and toxicants of tobacco smoke.

Finally, the FDA is developing a youth education campaign focused on preventing and reducing tobacco use, including menthol cigarettes. n

PROD

for public comment relevant scientific information, including the FDA’s independent Preliminary Scientific Evaluation of the Possible Public Health Effects of Menthol Versus Nonmenthol Cigarettes, which addresses the association between menthol cigarettes and various outcomes, including initiation, addiction, and cessation.

COMETRIQ™ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.*

median

median

months

months

11.2

ED AE/AS AD

4.0

CW

COMETRIQ™ (n=219)

CD

Progression-free survival (PFS)

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, 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 ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

TC QC PG

Adverse Reactions: 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, 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.

Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value).

In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

B:11.25”

S:9.75”

COMETRIQ.com

DATE

Please see brief summary of full Prescribing Information on next page.

Disk release

SIGNOFF

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

PharmaGraphics

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 (≥ 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.

Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, 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 (<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.

T:10.25”

*Results of the international, multicenter, randomized, double-blind EXAM study in patients (N=330) with progressive, metastatic MTC. Primary endpoint: PFS; secondary endpoints: objective response rate and overall survival (OS). OS data are not yet mature.

S&H

7.5”

15”

ASCOPost.com | AUGUST 15, 2013

The ASCO Post | AUGUST 15, 2013

PAGE 22

News

CDC Report Shows Stagnated HPV Vaccination Rate for Girls

By Jo Cavallo

F

or the first time since the human papillomavirus (HPV) vaccine became available for adolescent girls in 2006, the vaccination rate for teenagers has stalled, according to data

published in the Centers for Disease Control and Prevention’s (CDC’s) Morbidity and Mortality Weekly Report.

The data stems from the 2012 National Immunization Survey-Teen (NIS-Teen),

which the CDC uses to track vaccination coverage among teenagers.

While vaccination coverage with at least a single dose of the HPV vaccine increased from 25.1% in 2007 to

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; 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 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% in 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%) of 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 medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity 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

53.0% in 2011, coverage rates among girls aged 13 to 17 remained virtually unchanged from 2011 to 2012, with 53.8% receiving one dose of the vaccine and only 33.4% receiving all three

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

ASCOPost.com | AUGUST 15, 2013

PAGE 23

News

of the recommended doses.

“We’re used to seeing coverage increases of 10% per year when a new vaccine hits the market. HPV vaccine coverage hasn’t kept pace with other vaccines recommended for preteens and teens,” said Thomas R. Frieden, MD, Director of the CDC. Since mid-2006, the Advisory

Committee on Immunization Practices (ACIP) has recommended routine vaccination of adolescent girls at ages 11 or 12 with three doses of the HPV vaccine. The same guidance was issued for boys in 2011. According to the CDC, about 79 million Americans are infected with HPV and approximately 14 million become newly infected each

year. HPV has been linked to cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers. Each year, more than 20,000 HPV-associated cancers occur in women, with cervical cancer the most common; and about 12,000 HPV-associated cancers occur in men, with oropharyngeal cancers the most common, according to the CDC. Thomas R. Frieden, MD

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 All Grade Grades 3-4 Grades 3-4 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 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.

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 1

2

Table 3.

Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg Pre-hypertension: Systolic 34 54 ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg 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 1

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 singledose 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 singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, 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.

Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

Improving the HPV Vaccination Rate The report highlighted three areas that need to be addressed to improve HPV vaccination coverage, including: • Parent education. According to the NIS-Teen survey, three of the five main reasons parents gave for not vaccinating their daughters were that the vaccine was not needed, lack of knowledge, and that their daughter was not sexually active. They also cited safety concerns.

• Health-care providers must increase the strength of HPV vaccination recommendations. “Studies have documented that, especially when counseling younger adolescents or their parents, providers give weaker recommendations for HPV vaccination compared with other vaccinations recommended for adolescents,” said the report. Because provider recommendations greatly influence parental acceptance, the CDC developed a tip sheet to help providers answer parents’ questions about the vaccine.

• Missed vaccination opportunities need to be reduced. “If HPV vaccine had been administered during healthcare visits when another vaccine was administered, vaccination coverage for one dose could have reached 92.6%,” according to the report. n

HPV Vaccination Trends ■ Coverage with at least a single

dose of the HPV vaccine increased from 25.1% in 2007 to 53.0% in 2011, but coverage rates in girls aged 13–17 did not change from 2011– 2012.

■ Over 20,000 HPV-associated

cancers occur in women annually (most commonly, cervical), and about 12,000 occur in men (most commonly, oropharyngeal).

■ Health-care providers need to increase the consistency and strength of HPV vaccination recommendations.

The ASCO Post | AUGUST 15, 2013

PAGE 24

Journal Spotlight Hematology

High Rate of Durable Remissions with Ibrutinib in Patients with Relapsed Chronic Lymphocytic Leukemia

By Matthew Stenger

D

urable remissions are uncommon with current treatments for relapsed chronic lymphocytic leukemia (CLL). Bruton’s tyrosine kinase is an essential component of B cell– receptor signaling that mediates interactions with the tumor microenvironment and promotes survival and proliferation of CLL cells. Ibrutinib is a first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase designed for treatment of B-cell cancers. As reported in The New England Journal of Medicine, John C. Byrd, MD, of Ohio State University, and colleagues found that ibrutinib treatment produced high rates of durable responses in patients with relapsed or refractory CLL or small lymphocytic lymphoma.1

sisted of 17p13.1 deletion in 33% and 11q22.3 deletion in 36%.

High Response Rate and Survival Response occurred in 36 (71%) of 51 patients in the 420-mg group (2 complete responses and 34 partial responses) and 24 (71%) of 34 in the 840-mg group (24 partial responses).

In addition, 10 patients (20%) in the 420-mg group and 5 (15%) in the 840-mg group had a partial response with persistent lymphocytosis. Re-

Ibrutinib has a favorable therapeutic index, which may facilitate its use in combination with other agents for the treatment of CLL. However, the durable remissions obtained thus far suggest that many patients may be treated successfully with monotherapy.

Study Details In a phase Ib/II multicenter study, 85 patients with relapsed or refractory CLL (n = 82) = 82) 82) or small lymphocytic lymphoma received oral ibrutinib once daily at 420 mg (n = 51) or 840 mg (n = 34) continuously until disease progression or unacceptable toxicity. Patients had a median age of 66 years, 76% were male, the median number of prior therapies was 4, and the median time since last treatment was 3 months (range, 1–98 months).

The most common prior treatments were rituximab (Rituxan, 98%), nucleoside analogs (95%), and alkylators (89%).

Most patients (65%) had high-risk disease (Rai stage III or IV) and unmutated immunoglobulin variableregion heavy-chain genes (81%).

Bulky nodes of ≥ 5 mm and ≥ 10 mm in diameter were present in 52% and 15% of patients, respectively. Interphase cytogenetic abnormalities con-

treatment. Reasons for treatment discontinuation included disease progression in 13% of patients, patient or investigator decision in 15% (with 5 of these 13 patients subsequently undergoing stem cell transplantation), and adverse events in 7 patients (8%), including 3 with pneumonia, 2 with sepsis, 1 with staphylococcal bacteremia without signs of sepsis, and 1 with gastrointestinal hemorrhage.

Disease progression occurred in 11 patients (13%) during follow-up, with 7 having progression by biolog-

—John C. Byrd, MD, and colleagues

sponse was independent of clinical and genomic risk factors present before treatment, including advancedstage disease, number of previous therapies, and the 17p13.1 deletion.

At 26 months, the estimated progression-free survival rate was 75% and the overall survival rate was 83%. Among patients with 17p13.1deletion, estimated 26-month progression-free survival was 57% and overall survival was 70%.

At a median follow-up of 20.9 months (range, 0.7–26.7 months), 64% of patients were still receiving

Ibrutinib in Relapsed CLL ■ Ibrutinib treatment was associated with an overall response rate of 71%

and estimated 26-month progression-free survival of 75% and overall survival of 83%. Response was independent of clinical and genomic risk factors.

■ Adverse events were predominantly grade 1 or 2, with patients being able to receive extended treatment with minimal hematologic toxic effects.

ic transformation. The median time from diagnosis to transformation was 98 months (range, 24–143 months).

Among these 11 patients, 10 had a 17p13.1 or 11q22.3 deletion and 1 had no high-risk cytogenetic abnormalities.

Rising blood lymphocytosis was observed by day 7 in 78% of the patients, peaked at a median of 4 weeks, and then slowly declined. In 50 (79%) of 63 evaluated patients, the lymphocyte count normalized or was reduced by 50% from the baseline level.

Increasing lymphocytosis developed in similar proportions of patients with unmutated vs mutated immunoglobulin variable-region heavy-chain genes (77% vs 83%), although lymphocyte counts normalized more rapidly (median, 6.4 vs 14.8 months) and more frequently (in 85% vs 50%) in those with unmutated immunoglobulin genes. Increasing lymphocytosis was associated with notable reductions in

lymph node and spleen size and frequent improvement in cytopenias.

Favorable Toxicity Profile Toxic effects were predominantly grade 1 or 2. The most common adverse events of any grade were diarrhea (49%), upper respiratory tract infection (33%), fatigue (32%), and cough (31%). The most common grade 3 or 4 nonhematologic adverse events were pyrexia, hypertension, and sinusitis, each occurring in 5% of patients. Grade 3 or 4 hematologic toxic effects consisted of neutropenia in 15% of patients, anemia in 6%, and thrombocytopenia in 6%. Neutropenia did not require treatment discontinuation and was managed with growth factor treatment in 5 of 13 patients. Bleeding events of grade 3 or higher occurred in 4 patients.

A total of 8 patients died within 30 days after receiving the last dose of ibrutinib, 3 due to pneumonia, 1 from systemic inflammatory response, 1 from sarcoma, and 3 from CLL progression.

The authors concluded, “Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.”

They further noted, “Ibrutinib has a favorable therapeutic index, which may facilitate its use in combination with other agents for the treatment of CLL. However, the durable remissions obtained thus far suggest that many patients may be treated successfully with monotherapy. Randomized clinical trials of ibrutinib in patients with CLL or small lymphocytic lymphoma are ongoing.” n

Disclosure: The study was supported Pharmacyclics, Janssen, and others. For full disclosures of the study authors, visit www. nejm.org.

Reference 1. Byrd JC, Furman RR, Coutre SE, et al: Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369:32-42, 2013.

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The ASCO Post | AUGUST 15, 2013

PAGE 26

Journal Spotlight Hematology

Ibrutinib Produces High Response Rate in Patients with Refractory Mantle Cell Lymphoma

By Matthew Stenger

I

brutinib is a first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase, a mediator of the B cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. As reported in The New England Journal of Medicine, Michael L. Wang, MD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues found that single-agent ibrutinib resulted in a high response rate and prolonged responses while exhibiting a favorable toxicity profile in patients with relapsed/refractory mantle cell lymphoma (MCL).1 Dr. Wang told The ASCO Post, “This is a collective effort of bench scientists who devoted many years of data as well as many patients and their families who have bravely fought against mantle cell lymphoma. We owe the success of this study to many clinical investigators, research nurses, and data coordinators. We also received critical support from government and industry.”

Study Details In a phase II study, 111 patients with relapsed or refractory MCL received ibrutinib at 560 mg/d. Patients were enrolled in two groups consisting of those who had previously received at least two cycles of bortezomib therapy (n = 48) and those who had received fewer than two complete cycles of bortezomib (Velcade) or no prior bortezomib (“no prior bortezomib group,” n = 63).

Patients had a median age of 68 years, 76% were male, 86% had intermediate- or high-risk disease based

on simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score, 86% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 45% had refractory disease, 72% had advanced disease, and 39% had at least one lymph node ≥ 55 cm in diameter. Patients had received a median of three

tients with lymph nodes ≥ 5 cm and in 63% of those who had received prior lenalidomide. The overall response rate and complete response rate were found to improve over time with continued therapy.

After an estimated median followup of 15.3 months, the estimated median response duration among re-

[The Bruton’s tyrosine kinase] inhibitor ibrutinib is a highly active new agent showing durable singleagent activity in relapsed and refractory mantle cell lymphoma.

Ibrutinib provides the opportunity for treatment with less intensive and more effective regimens.

—Michael L. Wang, MD, and colleagues

prior therapies (at least 3 in 55%), with 89% having received rituximab (Rituxan), 30% hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, 24% lenalidomide (Revlimid), and 11% stem cell transplantation.

5Response was observed in 75 patients (68%), with complete response in 21% of patients and partial response in 47%. Response rates did not differ between patients with no prior bortezomib therapy (68%, including complete response in 19%) and those with prior bortezomib therapy (67%, including complete response in 23%) and also did not vary according to other baseline characteristics or risk factors associated with chemotherapy treatment failure.

Response was observed in 63% of pa-

Ibrutinib in Mantle Cell Lymphoma ■ Ibrutinib treatment produced responses in 68% of patients, including a

complete response in 21%, and response rates did not differ according to whether or not patients had received prior bortezomib therapy.

■ Estimated median duration of response was 17.5 months, estimated

median progression-free survival was 13.9 months, and median overall survival was not reached.

■ Treatment was associated with a favorable toxicity profile.

sponders was 17.5 months (95% confidence interval [CI] = 15.8 months to not reached), with a median time to response of 1.9 months (range, 1.4–13.7 months) and a median time to complete response of 5.5 months (range, 1.7–11.5 months).

The estimated median progression-free survival was 13.9 months (95% CI = 7.0 months to not reached) among all patients, 17.5 months among those with partial response as best response, and not reached for those with complete response. Median overall survival was not reached.

At 18 months, the estimated overall survival rate was 58%.

At the estimated follow-up duration of 15.3 months, 46 patients (41%) were still receiving treatment. Reasons for discontinuation included disease progression in 50 patients (45%, including 2 patients who discontinued treatment within 30 days after the first dose and 1 with unconfirmed progression of disease), patient or investigator decision in 7 patients (6%, including 1 patient who proceeded to stem cell transplantation), and adverse events in 8 patients (7%, including 2 patients with subdural hematoma, and 1 each with

pneumonia, elevated bilirubin, sepsis, metastatic adenocarcinoma, respiratory failure, and cardiac arrest).

Favorable Toxicity Profile The majority of adverse events observed were grade 1 or 2. The most common nonhematologic treatmentrelated adverse events of any grade were diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), and dyspnea (27%). The most common grade 3 or higher nonhematologic adverse events were diarrhea (6%), fatigue (5%), abdominal pain (5%), and dyspnea (5%).

Grade 3 or higher hematologic adverse events were also infrequent and included neutropenia in 16% of patents, thrombocytopenia in 11%, and anemia in 10%. Grade 3 bleeding events occurred in five patients (5%).

Subdural hematoma occurred in four patients (grade 1 in one patient, grade 2 in one, and grade 3 in two) and were associated with falls, head trauma, or both in all cases; all four patients had received either aspirin or warfarin within 2 days of the event.

A total of 16 patients (14%) died during the trial. Twelve died from disease progression and 4 due to an adverse event (2 from pneumonia, 1 from sepsis, and 1 from a cardiac arrest that was not considered drugrelated).

The investigators concluded, “[The Bruton’s tyrosine kinase] inhibitor ibrutinib is a highly active new agent showing durable singleagent activity in relapsed and refractory mantle cell lymphoma. The favorable toxicity profile suggests that ibrutinib provides the opportunity for treatment with less intensive and more effective regimens than those currently available.” n

Disclosure: The study was supported by Pharmacyclics, Janssen Biotech; to conduct research only. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. June 19, 2013 (early release online).

ASCOPost.com | AUGUST 15, 2013

PAGE 27

News Hematology

PET/CT Superior to Bone Marrow Biopsy for Diagnosis, Prognosis in Lymphoma

A

more precise method for determining bone marrow involvement in patients with diffuse large B-cell lymphoma has been identified by researchers in a study published recently in The Journal of Nuclear Medicine.1 Imaging with 18F–fluorodeoxyglucose positronemission tomography/computed tomography (FDG PET/CT), when compared to bone marrow biopsy, was more sensitive, showed a higher negative predictive value, and was more accurate, changing treatment plan for 42% of patients with bone marrow involvement in the study.

“In our study, we showed that in diffuse large B-cell lymphoma, 18F-FDG PET/CT has better diagnostic performance than bone marrow biopsy to detect bone marrow involvement and provides a better prognostic stratification,” said Louis Berthet, MD, lead author of the study. “While bone marrow biopsy is considered the gold standard to evaluate bone marrow involvement by high-grade lymphomas, 18F-FDG PET/CT is in fact the best method to evaluate extension of the disease, as well as avoid invasive procedures.”

patients with positive 18F-FDG PET/ CT results and negative biopsy results, 11 were upstaged to stage IV by PET/ CT, which changed their treatment plans. 18F-FDG PET/CT was also determined to be an independent predic-

tor of progression-free survival.

“Our findings add to the literature to prove the significance of 18F-FDG PET/CT in cancer evaluation and to democratize this imaging method,” said Dr. Berthet. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Berthet L, Couchet A, Kanoun S, et al: J Nucl Med 54:1244-1250, 2013.

Study Details The retrospective study included 133 patients diagnosed with diffuse large-cell B-cell lymphoma. All patients received both a whole-body 18FFDG PET/CT scan, as well as a bone marrow biopsy to determine bone marrow involvement.

A final diagnosis of bone marrow involvement was made if the biopsy was positive, or if the positive PET/ CT scan was confirmed by a guided biopsy, by targeted magnetic resonance imaging or, after chemotherapy, by the concomitant disappearance of focal bone marrow uptake and uptake in other lymphoma lesions on 18F-FDG PET/CT reassessment. Progressionfree survival and overall survival were then analyzed.

Results A total of 33 patients were considered to have bone marrow involvement. Of these, 8 were positive according to the biopsy and 32 were positive according to the PET/CT scan. 18FDG PET/CT was more sensitive (94% vs 24%), showed a higher negative predictive value (98% vs 80%), and was more accurate (98% vs 81%) than bone marrow biopsy. Among the 26

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The ASCO Post | AUGUST 15, 2013

PAGE 28

Journal Spotlight Hematology

New Guidelines Issued in the Treatment of Multiple Myeloma-Related Bone Disease

By Jo Cavallo

T

he International Myeloma Working Group (IMWG) has developed clinical practice recommendations for the management of multiple myelomarelated bone disease based on published study data through August 2012.

Consensus of the interdi sciplinar y panel of clinical experts on the plasma cell cancer was used to propose additional guidelines in situations in which there were insufficient published data. The recommendations were recently published in the Journal of Clinical Oncology ( JCO).1

IMWG Recommendations Included in the recommendations is the use of bisphosphonates for all multiple myeloma patients receiving front-line therapy, regardless of the presence of osteolytic bones lesions on conventional radiography. The IMWG made the recommendation even though it is unknown whether bisphosphonates offer any advantage to patients with no bone disease as determined by magnetic resonance

imaging or positron-emission tomography/computed tomography.

The panel also recommended the use of intravenous zoledronic acid and pamidronate in the prevention of skeletal-related events over oral bisphosphonates, such as clodronate (not available in the United States), in newly diagnosed myeloma patients because of their antimyeloma effects and survival benefits. Other recommendations include: ■ Intravenous bisphosphonates should be administered every 3 to 4 weeks during initial therapy.

Discontinuation of bisphosphonate therapy may be considered after 1 to 2 years in patients who have achieved complete remission or very good partial response.

■ Patients with active disease should continue to receive zoldronic acid or pamidronate. and the treatment should resume after disease relapse if it was discontinued in patients achieving complete or very good partial response.

■ Although bisphosphonates are well tolerated, patients should be made aware of any symptoms suggesting adverse events, including osteonecrosis of the jaw, and phy-

International Myeloma Working Group Recommendations ■ The use of intravenous bisphosphonates should be considered for all

multiple myeloma patients receiving frontline antimyeloma therapy, regardless of the presence of osteolytic bone lesions on conventional radiography.

■ Intravenous bisphosphonates provide greater protection against skeletalrelated events and greater survival benefits than oral bisphosphonates.

■ Between 70% and 80% of newly diagnosed multiple myeloma patients

have osteolytic lesions, putting them at increased risk for skeletal-related events, such as spinal cord compression, and diminishing their quality of life.

sicians should monitor patients for renal toxicity. All myeloma patients treated with bisphosphonates should have creatinine clearance, serum electrolytes, and urinary albumin monitored.

■ Balloon kyphoplasty should be considered in patients with symptomatic vertebral compression fractures.

■ The use of low-dose radiation (up to 30 Gy) can be used as palliative treatment for uncontrolled pain, impending pathologic fracture, or spinal cord compression, and vertebral column instability.

According to the report, osteolytic lesions are found in 70% to 80% of newly diagnosed multiple myeloma

patients, putting them at increased risk for skeletal-related events, such as spinal cord compression, requiring surgery or palliative radiotherapy to the bone.

“Skeletal-related events impair survival, undermine quality of life, and increase treatment costs,” said panel members. n

Disclosure: For full disclosure of the study authors, visit www.jco.ascopubs.org.

Reference

1. Terpos E, Morgan G, Dimopoulos MA, et al: International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma-related Bone Disease. J Clin Oncol 31:2347-2357, 2013.

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The ASCO Post | AUGUST 15, 2013

PAGE 30

Journal Spotlight Thoracic Oncology

Crizotinib Improves Progression-free Survival vs Pemetrexed or Docetaxel in Advanced ALK-positive NSCLC

By Matthew Stenger

I

n a phase III trial reported by Alice T. Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital, Boston, and colleagues in The New England Journal of Medicine, crizotinib (Xalkori) improved progressionfree survival compared with standard chemotherapy in previously treated patients with advanced ALK-positive non–small cell lung cancer (NSCLC).1 Crizotinib treatment was also associated with a higher response rate and greater patient-reported reductions in symptoms and improvement in global quality of life.

Study Details In this open-label trial, 347 patients with locally advanced or metastatic ALK-positive NSCLC who had received one prior platinum-based regimen were randomly assigned to receive oral crizotinib at 250 mg twice daily (n = 173) or chemotherapy (n = 174) consisting of IV pemetrexed (Alimta) at 500 mg/ m2 (n = 99) or docetaxel 75 mg/m2 (n = 72) every 3 weeks (1 crizotinib and 3 chemotherapy patients did not receive study treatment). Patients in the chemotherapy group received pemetrexed unless their prior chemotherapy regimen contained pemetrexed or their tumor had predominantly squamous histologic features.

Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study.

Patients in the crizotinib and chemotherapy groups were well matched for age (median, 51 and 49 years, 84% and 87% < 65 years), sex (43% and 45% male), race (52% white in both, 46% and 45% Asian), smoking status (62% and 64% never-smokers), histology (95% and 94% adenocarcinoma), Eastern Cooperative Oncology Group

(ECOG) performance status (0 or 1 in 91% and 92%), metastatic disease (95% and 91%), and presence of brain metastases (35% and 34%).

Prolonged Progression-free Survival Median progression-free survival, the primary endpoint, was 7.7 months in the crizotinib group vs 3.0 months in the chemotherapy group (hazard ratio [HR] = 0.49, P < .001). In a subgroup analysis, crizotinib was associated with significantly prolonged progression-free survival compared with both pemetrexed (HR = 0.59,

At the time of data cutoff, the median follow-up for overall survival was 12.2 months in the crizotinib group and 12.1 months in the chemotherapy group.

On interim analysis, median overall survival did not differ between the crizotinib and chemotherapy groups (20.3 months, 95% confidence interval [CI] = 18.1 months to not reached, vs 22.8 months, 95% CI = 18.6 months to not reached, HR = 1.02, P = .54).

The authors noted that the overall survival findings are likely influenced by the high degree of crossover to crizotinib from the chemotherapy group.

[T]his study showed that crizotinib … prolonged progression-free survival, increased response rates, and improved the quality of life in patients with advanced, previously treated ALKpositive NSCLC. —Alice T. Shaw, MD, PhD

P < .001) and docetaxel (HR = 0.30, P < .001). Crizotinib was associated with progression-free survival benefit in subgroup analyses according to ECOG performance status, presence or absence of brain metastases and prior epidermal growth factor receptor kinase inhibitor therapy, and other baseline characteristics.

Response rates in the intention-totreat population were 65% with crizotinib and 20% with chemotherapy (P < .001). In the as-treated population, response rates were higher with crizotinib than with either type of chemotherapy (66% with crizotinib compared with 29% for pemetrexed and 7% for docetaxel; both P < .001).

Second-line Crizotinib in Advanced Lung Cancer ■ Crizotinib significantly prolonged progression-free survival vs pemetrexed or docetaxel as second-line treatment for advanced ALK-positive NSCLC.

■ Significant improvements in symptoms, delay to symptom worsening, and global quality of life were reported in crizotinib patients.

■ The absence of an overall survival benefit with crizotinib at interim analysis may reflect the high frequency of crossover to crizotinib after progression in chemotherapy patients.

High Crossover Rate The duration of study drug treatment was longer in the crizotinib group (median, 31 vs 12 weeks). Of the 174 patients randomized to chemotherapy, 112 (64%) received crizotinib after disease progression. A total of 85 patients (49%) in the crizotinib group and 28 patients (16%) in the chemotherapy group were still receiving the study treatment at the time of data cutoff. More patients in the crizotinib group than in the chemotherapy group (58 vs 17) continued treatment beyond RECIST-defined progression, and the duration of such therapy was longer with crizotinib than with chemotherapy (median, 15.9 vs 6.9 weeks).

Adverse Events The safety analysis was not adjusted for the longer duration of treatment with crizotinib. The most common adverse events of any grade with crizotinib with an incidence ≥ 5% greater than that with chemotherapy were vision disorder (60% vs 9%), diarrhea (60% vs 19%), nausea (55% vs 37%),

vomiting (47% vs 18%), constipation (42% vs 23%), elevated liver aminotransferases (38% vs 15%), edema (31% vs 16%), upper respiratory infection (26% vs 13%), dysgeusia (26% vs 9%), and dizziness (22% vs 8%). The most common adverse events with chemotherapy with an incidence ≥ 5% greater than that with crizotinib were fatigue (33% vs 27%), alopecia (20% vs 8%), dyspnea (19% vs 13%), and rash (17% vs 9%).

The most common grade 3 or 4 adverse events were elevated aminotransferases (16%) and dyspnea (4%) in crizotinib patients and fatigue (4%) and dyspnea (3%) in chemotherapy patients. Grade 3 or 4 neutropenia occurred in 13% of crizotinib patients, including one with febrile neutropenia, and in 19% of chemotherapy patients, including 9% (n = 16) = 16) 16) with febrile neutropenia. Three patients in the crizotinib group (2%) had treatmentrelated interstitial lung disease of grade 3 or higher, with two of the cases being fatal.

Treatment-related adverse events led to discontinuation of study drug in 6% of crizotinib patients and 10% of chemotherapy patients. Treatment-related death occurred in three patients in the crizotinib group (including the two who died from interstitial lung disease and one patient who died from ventricular arrhythmia) and in one patient in the chemotherapy group (due to sepsis). An additional crizotinib patient had hepatic dysfunction and subsequently died from hepatic failure after the data cutoff date.

Improved Symptoms, Global Quality of Life Evaluation with the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ-C30) and corresponding lung cancer instrument (QLQ-LC13) showed that crizotinib patients had significantly greater overall reductions from baseline in the symptoms of alopecia, cough, dyspnea, fatigue, chest pain, arm or shoulder pain, and other pain (all P < .001), a significant significant delay in median time to deterioration in cough, dyspnea, and chest pain (5.6 vs 1.4 months, HR = 0.54, P < .001), and a significantly greater overall improve-

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Journal Spotlight

ment from baseline in global quality of life (P < .001).

With regard to global quality of life, the crizotinib group showed a statistically significant and clinically mean-

ingful (≥ 10-point) improvement from baseline in cycle 4 and a statistically significant (but < 10-point) improvement in cycles 2 through 12 and cycle 14. In contrast, the chemotherapy

group showed no significant change from baseline at any time point. The crizotinib group had a significantly greater overall improvement from baseline compared with the chemo-

therapy group for all functional domains except for cognitive functioning.

With regard to the high crossover rate from chemotherapy to crizotinib continued on page 36

Where Are We with ALK Inhibition in Lung Cancer?

By Fred R. Hirsch, MD, PhD

T

he prospective phase III PROFILE 1007 study compared the ALK inhibitor crizotinib (Xalkori) to chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) with ALK gene–rearranged tumors refractory to previous chemotherapy. The study showed a clear superiority for crizotinib in terms of progression-free survival (median, 7.7 vs 3.0 months), response rate (65% vs 20%), and symptomatic improvement in this population of patients.

Game-changing Study Although the results may not be so surprising given the initial data from the phase I/II study of crizotinib (PROFILE 1001), the phase III trial is clearly a game-changing study, since it is the first published randomized trial of crizotinib and it verifies the benefit of an oral ALK inhibitor as single-agent therapy in this particular subgroup of patients. Even though this study—similar to the phase I/II study—was done in chemotherapy-refractory patients, the results will certainly be transferable to clinical practice in first-line therapy.

The fact that PROFILE 1007 showed a significant symptomatic improvement for patients treated with crizotinib is also an important finding, demonstrating that patients not only had prolonged progression-free survival, but actually are doing better on the drug. This study included only patients with good performance status (Eastern Cooperative Oncology Group [ECOG] 0–1), but it is my strong belief that the drug also will benefit ALK-positive patients with poorer performance status. A safety and efficacy single-arm study in patients with poor performance status would most likely verify this.

Another interesting finding in the trial is the outcome on chemotherapy, and particularly the better progression-free survival in the pemetrexed Dr. Hirsch is Professor of Medicine and Pathology, University of Colorado Cancer Center, Aurora, Colorado.

(Alimta)-treated group compared to historical data. This finding verifies the previously reported hypothesis that patients with ALK-rearranged NSCLC do better with pemetrexed—but, of course, still not as well as with an ALK inhibitor. There might be a synergistic effect and/or some biologic association between the two agents, which will be studied in a clinical trial by the Southwest Oncology Group.

ALK Diagnostic Methods While the PROFILE 1007 study verifies the benefit of crizotinib as single-agent therapy in ALK-positive patients, the results raise some important questions. One question is, How should patients be screened for ALK-gene rearrangement? The U.S. Food and Drug Administration (FDA) has already

with ALK-FISH to determine eligibility for crizotinib therapy or enrollment in clinical studies.

Furthermore, several recent reports have described patients who are ALK-FISH “negative” according to the defined criteria but IHC-positive and who have had dramatic responses to crizotinib. Some of these patients have an “atypical” ALK-FISH pattern that does not fit into the positive category—illustrating the challenges in interpretation of ALK-FISH. In addition, the therapeutic relevance of having NSCLC tumors with less than 15% gene-rearranged cells is still not entirely clear.

Last, but not least, the use of ALK-IHC would reduce screening costs significantly, and IHC is now routinely used for other indications

Until further mature data are reported, crizotinib is a therapeutic option for patients with ALKpositive advanced NSCLC that should not be missed.

—Fred R. Hirsch, MD, PhD

defined the companion diagnostics for eligibility for crizotinib therapy— namely, Abbott’s ALK–fluorescence in situ hybridization (FISH) assay—using specific criteria, which include 15% or more gene-rearranged cells in the tumor specimen. However, the FDA does not define the method for screening for ALK rearrangement among patients with advanced NSCLC. Over the past few years, many studies have compared the defined ALKFISH assay with other ALK diagnostic methods, and a very strong correlation has been found between ALK-FISH and ALK-immunohistochemistry (IHC). In many countries (ie, Japan, European countries), it is recommended that patients be screened with IHC and that positive cases be confirmed

in almost every pathology laboratory around the country. Still, a standardized methodology must be identified for processing and interpreting the IHC assay if it is to be used for screening.

Certainly, the results from the crizotinib studies have moved the therapeutic scenario in lung cancer toward personalized therapy based on molecular testing. The College of American Pathology, International Association for the Study of Lung Cancer, and Association for Molecular Pathology have recently released guidelines for molecular testing in lung cancer, which include guidelines for tissue acquisition, processing, and assay recommendations and interpretations.

Resistance Issues The PROFILE 1007 study results are very encouraging with regard to the prospect that we might be able to “cure” molecularly defined subgroups of patients in the future—even those with advanced lung cancer, which historically have a dismal prognosis. However, almost all patients will sooner or later develop drug resistance.

Thus, the challenge is to overcome the resistance, and to do that, we need to learn more about resistance mechanisms in order to optimally combine molecularly targeted agents with each other or with conventional chemotherapy. To that end, more clinical studies will need to include rebiopsy for renewed molecular testing at the time of disease progression. In fact, some would argue that rebiopsy at time of progression should be standard practice in patients treated with EGFR tyrosine kinase inhibitors or ALK inhibitors, since we know that some treatable molecular/morphologic changes occur as acquired resistance mechanisms to some targeted therapies.

Potential for ‘Cure’ Based on preliminary clinical results that have been presented, there is reason to believe that some of the newgeneration ALK inhibitors are more specific ALK inhibitors than crizotinib and are able to overcome resistance to crizotinib. Other early studies seem to encourage the combination of crizotinib with other molecularly targeted agents.

Thus, the field is rapidly moving toward the potential for “cure” for defined subsets of patients with advanced lung cancer. However, until further mature data are reported, crizotinib is a therapeutic option for patients with ALK-positive advanced NSCLC that should not be missed. Molecular testing of primary NSCLC tumors has become crucial for decisions about therapy for the many patients with advanced NSCLC. n

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

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PAGE 36

Journal Spotlight Thoracic Oncology

Low-dose CT Screening for Lung Cancer: Details of First Round of Screening in National Lung Screening Trial

By Matthew Stenger

T

he National Lung Screening Trial found that 3 years of annual screening with low-dose helical computed tomography (CT) reduced lung cancer mortality compared with chest radiography in older persons who were heavy smokers.1 The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial also recently showed that mortality from lung cancer did not differ between subjects screened with radiography and those receiving usual care,2 supporting earlier findings with chest radiography screening. In a report in The New England Journal of Medicine, the National Lung Screening Trial Research Team described the screening, diagnosis, and limited treatment results from the initial round of screening in the National Lung Screening Trial.3

Study Design In the trial, 52,344 participants aged 55 to 74 years with a history of at least 30 pack-years of smoking (either current smokers or smokers within the prior 15 years) underwent annual screening for 3 years with low-dose CT (n = 26,309) or chest radiography (n = 26,305). = 26,305).

26,305). These These subjects accounted for 98.5% and 97.4%, respectively, of subjects initially randomized. Com-

Crizotinib in ALK-positive NSCLC continued from page 31

and the absence of a difference in overall survival at interim analysis, the investigators noted that median overall survival among all study patients from the time that second-line therapy was initiated was “remarkably high, at lon-

Visit

pliance with screening did not differ between the two groups according to age, sex, race/ethnic group, smoking status, or educational level.

For low-dose CT, all noncalcified nodules with long-axis diameters of 4 mm or greater in the axial plane

slightly with increasing age and increasing number of pack-years in both groups. Negative results with clinically significant abnormalities were found in 2,695 CT subjects (10.2%) and in 785 radiography subjects (3.0%).

During follow-up, lung cancer was

The National Lung Screening Trial initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancers is achievable at U.S. screening centers that have staff experienced in chest CT. —The National Lung Screening Trial Research Team

were considered to be positive for potential lung cancer. For radiography, all noncalcified nodules and masses were considered to be positive.

Screening results were classified as positive, negative with clinically significant abnormalities, negative with minor abnormalities, or negative with no abnormalities.

Major Findings Positive screening results were found in 7,191 CT subjects (27.3%) and in 2,387 radiography subjects (9.2%). Rates of positivity increased ger than 20 months, suggesting that the addition of crizotinib either before or after second-line chemotherapy may contribute to improving survival.”

Conclusions The investigators concluded, “[T]his study showed that crizotinib … prolonged progression-free

diagnosed in 292 subjects in the CT group (1.1%) and in 190 in the radiography group (0.7%). In the CT group, 270 subjects (92.5%) had a true-positive screening result, 18 (6.2%) had a false-negative screening result, and 4

(1.4%) missed the screening visit. Sensitivity and specificity values for CT were 93.8% and 73.4%, respectively.

In the radiography group, 136 subjects (71.6%) had a true-positive screening result, 49 (25.8%) had a false-negative result, and 5 (2.6%) missed the screening visit. Sensitivity and specificity values for radiography were 73.5% and 91.3%, respectively.

In the CT group, the positive predictive value for positive findings leading to a biopsy was 52.9% but the overall positive predictive value for all positive findings was only 3.8%. Positive predictive values were 3.8% for nodules of 4 mm and increased to 41.3% for those with a diameter of more than 30 mm. mm. Th Thee positive predictive value for noncalcified hilar or mediastinal adenopathy was 18.5%. Overall, the negative predictive value was 99.9%.

In the radiography group, positive predictive values were 70.2% for a positive finding that led to a biopsy procedure, but only 5.7% for all

Lung Cancer Screening ■ Low-dose CT screening resulted in more positive results, diagnostic

procedures, invasive procedures, and cancer diagnoses than radiography.

■ The difference in numbers of cancers diagnosed reflected the greater number of stage IA cancers detected by CT.

survival, increased response rates, and improved the quality of life in patients with advanced, previously treated ALK-positive NSCLC. The apparent lack of a survival benefit probably reflects the confounding effects of crossover, effects that have been observed in other randomized trials of molecularly targeted agents

in patients with NSCLC.” n

Disclosure: The study was supported

by Pfizer. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Shaw AT, Kim D-W, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013.

website at ASCOPost.com

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Journal Spotlight

positive screening findings. Positive predictive values were 5.8% for pulmonary nodules and increased from 1.0% to 39.3% as diameter increased from 4 to 6 mm to more than 30 mm.

The positive predictive value for noncalcified hilar or mediastinal adenopathy was 9.3%. Overall, the negative predictive value was 99.8%.

The investigators concluded, “The National Lung Screening Trial initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancers is achievable at U.S. screening centers that have staff experienced in chest CT.” n

Disclosure: For full disclosures of the study authors, visit www.nejm.org.

References 1. Aberle DR, Adams AM, Berg CD, et al: Reduced lung-cancer mortality with B:8.25” low-dose computed tomographic screenT:7.5” ing. N Engl J Med 365:395-409, 2011.

S:6.75” 2. Oken MM, Hocking WG, Kvale PA, et al: Screening by chest radiograph

and lung cancer mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) randomized trial. JAMA 306:18651873, 2011.

3. The National Lung Screening Trial Research Team: Results of initial lowdose computed tomographic screening for lung cancer. N Engl J Med 368:19801991, 2013.

See commentary on page 38.

Diagnostic Procedures At least one diagnostic procedure was performed in 6,369 (90.4%) of CT group subjects and 2,176 (92.7%) of radiography group subjects with positive screening findings. For the CT group and the radiography group, CT was performed in 5,153 (73.1%) and 1,546 (65.8%) subjects, FDG– positron-emission tomography was performed in 728 (10.3%) and 179 (7.6%), 155 (2.2%) and 83 (3.5%) underwent percutaneous cytologic or biopsy procedures, 306 (4.3%) and 107 (4.6%) underwent bronchoscopy, and 297 (4.2%) and 121 (5.2%) underwent a diagnostic surgical procedure. Overall, 10,313 imaging procedures, including 7,288 CT examinations, were performed in the CT group, compared with 3,657 imaging procedures, including 2,158 CT examinations, in the radiography group.

The difference between the CT group and the radiography group in number of diagnosed cancers was almost completely accounted for by a greater number of stage IA cancers diagnosed in the CT group (132 vs 46). There were no major differences in the numbers of stage IB (26 and 24), IIA (10 and 3), IIB (12 and 10), IIIA (34 and 29), IIIB (30 and 27), or IV (44 and 46) cancers diagnosed in the two groups.

More bronchioloalveolar carcinomas (38 and 8) and adenocarcinomas (123 and 71) were diagnosed in the CT group. A total of 277 CT group and 181 radiography group subjects were treated with some combination of surgery, chemotherapy, and radiotherapy, with 117 CT subjects and 40 radiography subjects with stage IA disease receiving surgery alone.

The investigators noted, “As expected, more positive screening results, more diagnostic procedures, more biopsies and other invasive procedures, and more lung cancers were seen in the low-dose CT group than in the radiography group during the first screening round. In addition, more early-stage lung cancers, but similar numbers of late-stage cancers, were diagnosed in the low-dose CT group.”

Cabozantinib is not approved for the use under investigation in this trial.

INVESTIGATIONAL PHASE 3 TRIAL Cabozantinib phase 3 trial in hepatocellular carcinoma (HCC) KEY ELIGIBILITY CRITERIA • Histologic diagnosis of HCC • Received prior sorafenib • Child Pugh A • Progression following at least 1 prior systemic therapy for HCC • Up to 2 prior systemic therapies for HCC

PRIMARY ENDPOINT Overall Survival HCC (N~760) • Received prior sorafenib • Child Pugh A • Progression following at least 1 prior systemic therapy for HCC • Up to 2 prior systemic therapies for HCC

Randomization 2:1 (Cabozantinib:Placebo)

Cabozantinib 60 mg QD

Placebo QD

Global, randomized, double-blind, placebo-controlled trial

Visit www.Celestialclinicaltrial.com or call 1-855-292-EXEL to learn more about this trial. © 2013 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 05/13 [MA0036v01]

The ASCO Post | AUGUST 15, 2013

PAGE 38

Perspective Continued from page 37

Evolving Issues in Low-dose CT Lung Cancer Screening

By James L. Mulshine, MD, and Jeffrey Schneider, MD

O

ver a decade has passed since the start of the National Lung Cancer Screening Trial and more than 2 years since the first report indicating that this randomized study had demonstrated a significant reduction in lung cancer mortality with low-dose computed tomography (CT) screening.1 That favorable result has been reinforced with follow-up data,2 which have been complemented by other reports showing that this service can be delivered with more efficient management approaches (defined after the start of the National Lung Screening Trial).3,4 Moreover, techniques have evolved so that radiation exposures associated with low-dose CT screening can be comparable to routine mammography.

Broad Adoption Following the lead of the National Comprehensive Cancer Network (NCCN), a number of professional organizations have endorsed lowdose CT screening in the high-risk group studied in the National Lung Screening Trial.5-9 A number of centers are collaborating to implement screening by adopting a disciplined approach incorporating best screening practices.10 In contemplating the broad adoption of low-dose CT screening, the medical community has been concerned with the information conveyed to potential screening candidates. Several observations are relevant in this regard.

First, a measure of screening benefit is the number of individuals needed to screen in order to prevent a lung cancer death. This measure of benefit is important since it relates to the absolute screening benefit, incorporating both relative risk reduction and absolute risk. For the National Lung Screening Trial, low-dose CT was associated with a number of inDr. Mulshine is Professor, Internal Medicine, and Vice President of Research at Rush Medical College, Rush University, Chicago, and Dr. Schneider is Director of the Thoracic Oncology Program and Associate Professor of Medicine at SUNY Health Sciences Center at Stony Brook and Winthrop-University Hospital, New York.

dividuals needed to screen of 320. By comparison, in the 50- to 59-year-old age group in which screening mammography has been universally recommended and reduces breast cancer mortality by 14%, the number of individuals needed to screen to prevent a breast cancer death is 1,339.11 The National Lung Screening Trial was designed to determine whether low-dose CT could reduce lung cancer mortality by 20%. A recent report suggested the benefit of low-dose CT could exceed this, if a more precise study entry tool were employed.12

Cost and Manageability Moving beyond the question of low-dose CT efficacy, the most frequently discussed concern arises over the issue of the cost and manageability of population-based lowdose CT, particularly in relation to the high rate of so-called false-

have begun to cover lowdose CT screening.

In light of the critical recommendation of the U.S. Preventive Services Task Force regarding coverage for this service as stipulated by the Affordable Care Act, it is worth noting that the National James L. Mulshine, MD Jeffrey Schneider, MD Lung Screening Trial found that low-dose CT was associated Am J Roentgenol 198:351-358, 2012.

5. Wood DE, Eapen GA, Ettinger with a significant all-cause mortality reduction of 6.7%. This is a criti- DS, et al: Lung cancer screening. J Natl cal parameter for prevention trials Compr Canc Netw 10:240-265, 2012.

6. Wender R, Fontham ET, Barrera E and a benchmark that no previous cancer screening approach has ever Jr, et al: American Cancer Society lung cancer screening guidelines. CA Cancer achieved.

Conclusion With continued improvement of CT imaging, tailored surgical approaches, refined screening eligibility criteria, and fuller integration of tailored smoking cessations ef-

Ongoing focus on quality control and continuous process improvement are essential, as for all highquality cancer screening services. â&#x20AC;&#x201D;James L. Mulshine, MD, and Jeffrey Schneider, MD

positive scans attributable to small pulmonary nodules. In 2002, the National Lung Screening Trial applied a nodule size criterion of just 4 mm to define a positive scan. A recent report reviewing the diagnostic workup efficiency in over 21, 000 prospective screening subjects from the International Early Lung Cancer Action Program (I-ELCAP) suggested that moving the invasive diagnostic workup threshold from 4 mm to nodules greater than 8 mm would have reduced diagnostic workups by 75%, while not significantly eroding curability.13 With regard to the issue of lung cancer screening cost, a detailed actuarial analysis showed that screening of all individuals at risk by National Lung Screening Trial criteria (while including the provision for smoking cessation counseling at screening) can be provided at a cost that is lower than that of mammographic screening.14 Major payers

forts, the full benefit of lung cancer screening could continue to improve. However, ongoing focus on quality control and continuous process improvement are essential, as for all high-quality cancer screening services. n

Disclosure: Drs. Mulshine and Schneider reported no potential conflicts of interest.

References 1. Aberle DR, Adams AM, Berg CD, et al: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395-409, 2011.

2. The National Lung Screening Trial Research Team: Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 368:1980-1991, 2013.

3. van Klaveren R, Oudkerk M, Prokop M, et al: Management of lung nodules detected by volume CT scanning. N Engl J Med 361:2221-2229, 2009.

4. Wagnetz U, Menezes RJ, Boerner S, et al: CT screening for lung cancer: Implication of lung biopsy recommendations.

J Clin 63:107-117, 2013.

7. Jaklitsch MT, Jacobson FL, Austin JH, et al: The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg 144:33-38, 2012.

8. Bach PB, Mirkin JN, Oliver TK, et al: Benefits and harms of CT screening for lung cancer: A systematic review.

JAMA 307:2418-2429, 2012.

9. Travis WD, Brambilla E, Noguchi M, et al: International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6:244-285, 2011.

10. Lung Cancer Alliance: National framework for excellence in lung cancer screening and continuum of care. Available at http://www.lungcanceralliance. org/assets/docs/am-i-at-risk/NationalFramework.pdf. Accessed July 11, 2013.

11. Warner E: Breast cancer screening. N Engl J Med 365:1025-1032, 2011.

12. Tammemägi MC, Katki HA, Hocking WG, et al: Selection criteria for lung-cancer screening. N Engl J Med 368:728-736, 2013.

13. Henschke CI, Yip R, Yankelevitz DF, et al: Definition of a positive test result in computed tomography screening for lung cancer: A cohort study. Ann Intern Med 158:246-252, 2013.

14. Pyenson B, Sander M, Jiang Y, et al: An actuarial analysis shows that offering lung cancer screening as an insurance benefit would save lives at relatively low cost. Health Aff (Millwood) 31:770779, 2012.

The ASCO Post | AUGUST 15, 2013

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Women in Oncology Diane E. Meier, MD: From Early Lessons in Critical Thinking to ‘Palliative Care Everywhere’

By Ronald Piana

Formative Years

Diane E. Meier, MD, FACP

Although the world is full of suffering, it is full also of the overcoming of it.

—Helen Keller Optimism, 1903

S

hortly past 8:00 AM on July 1977, Diane E. Meier, MD, FACP, began the first day of her medical internship. Within minutes she would experience another first: the death of a patient assigned to her service. Although 36 years have passed, Dr. Meier recalls with clarity the page that sent her running after her resident to the coronary care unit. At the bedside, she watched as her colleagues tried to save an 89-year-old man with end-stage congestive heart failure.

For more than an hour, they used every medical tool and skill at their disposal trying to save their patient’s life. When the cardiology fellow finally called the code, Dr. Meier remembers leaving the old man covered in tubes on the bloodstained bed. His wife was seated outside as she and the other young doctors walked past— Dr. Meier said that the memory of that man’s death is still with her.

Another invisible tool that she carries in her medical armamentarium is the memory of her grandfather, a man of deep and passionate beliefs about fairness and justice in the world. He died alone, without warning. “I never got to say goodbye, to thank him, to tell him how much we loved him,” said Dr. Meier. “His memory helps me remember that every sick person and every old person is a fellow human being who could have been my grandfather,” she added.

Dr. Meier grew up in Chicago in an atmosphere of vivid social activism.

Her father’s parents were socialists in the early part of the 20th century. Even after leaving the Socialist Party they remained politically active, helping those most in need.

“During World War II, my grandfather sponsored refugees who were fleeing Europe to escape Hitler. He bent the law to save people. You were supposed to commit $15,000 per refugee so they would not ‘burden our society.’ Of course, that was cost-prohibitive, so he put up the same $15,000 repeatedly to save as many people as possible,” said Dr. Meier.

The relentless nature of activism had a huge effect on the family. “My father’s brother became a historian in African American history, actually founding the field of African American studies. My father became a statistician who later was the driving force behind the development of the randomized controlled trial as a standard of evidence for drugs and devices,” noted Dr. Meier. “He was

sort of frowned upon. I think that is one of the reasons it took so long for fundamental changes in pain management to get the attention they deserve.”

Medical Education Dr. Meier graduated from Oberlin College in 1973 and received her medical degree from Northwestern Medical School. But medicine wasn’t her first career choice.

“When at Oberlin, I planned on becoming a teacher; in fact, I almost had the credits needed to become certified in secondary education. During my junior year, I worked for a semester teaching children with learning disabilities at an inner-city school in Philadelphia,” said Dr. Meier. During that time, it became painfully obvious to her that spending 6 hours a day with disadvantaged kids would not begin to undo the harms of the social and economic context they lived in for the other 18 hours a day.

“The teachers were powerless to truly make a difference preparing these challenged kids for the future. The exter-

We’ve made dramatic progress in the integration of palliative care into medical school curricula and the consciousness of the medical world.

— Diane E. Meier, MD, FACP

a major influence on the levels of rigorous evidence ultimately adopted for the FDA approval process.”

Dr. Meier said that social consciousness was simply the air she breathed. “My father would take me along with him as he went door-todoor, campaigning for various political candidates. From a young age we were taught the virtue of critical thinking and never to accept received wisdom at face value,” said Dr. Meier.

She continued, “That was the conversation at the dinner table, and it was troubling when I was a young medical student to find that the critical thinking approach was really not the standard.”

She found that the medical establishment in some ways was a tight-knit guild. “People go along to get along, and knocking the established way is

nal forces were just too great, and I just wasn’t comfortable in a world in which I was powerless. So I decided the best way for me to make a difference was in the field of medicine,” said Dr. Meier.

Although she was not a good fit for the medical school format of memorization over critical thinking, she was eventually able to leverage her medical degree to address one of the most difficult challenges facing the U.S. healthcare system—how we care for the sickest and most vulnerable of our patients.

“During my residency program, it was difficult to think about focusing on one organ or one disease without thinking about the person influenced by that disease. It didn’t make sense to write a stack of prescriptions without first knowing if the patient could afford them,” said Dr. Meier.

Early Mentors Like most doctors who pursue careers in the rigorous academic environment, Dr. Meier credits early mentors with shaping her career in palliative care. “As a resident, one of my cardiology attendings, Dr. Jack McAnulty, taught me how to stop and listen carefully to the patient’s heart sounds. He also taught me how to pay attention in general,” said Dr. Meier.

More lessons were learned along the way. For instance, Dr. Meier credits Dr. Christine Cassel, who is the current President and CEO of the National Quality Forum, with teaching her that even the most difficult social problems are resolvable with determination, leadership, and strategy.

Those early lessons about dealing with the unmet palliative needs of old and very sick patients were reinforced during what she calls her “first real job,” at Mount Sinai School of Medicine in New York in 1983. Her Department Chairman, Dr. Robert Butler, had conducted research that exposed the unregulated nursing home industry, and his work with older patients became the underpinnings for many of the person-centered therapies used in palliative care today.

“From Dr. Butler I learned that the academic model (grants, research, and publication) was necessary but far from sufficient to ensure quality care for all Americans. He never pushed me to do anything I didn’t want to do until I told him I was too busy to apply for the new Project on Death in America Faculty Scholar’s Program, a new initiative to support medical leaders in the development of the new field of palliative medicine. He refused to take no for an answer. Because of his mentorship, in midcareer, I found my calling in palliative care medicine,” said Dr. Meier.

Growth of Palliative Care “The palliative care field has undergone a dramatic growth process.

Twelve years ago, there were virtually no supportive palliative care programs in hospitals. Today, basically every hospital in the country has a service,” said Dr. Meier.

However, Dr. Meier noted that the road to acceptance of palliative care as a

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PAGE 41

Women in Oncology subspecialty was not always smooth. As a pioneer in the field, she recalls attending a 1995 retreat with her colleagues to begin hammering out a working model for a palliative care program.

“I remember sitting around a big table at the first retreat discussing what had brought us to this work,” she said.

“Each person’s story was rooted in family experiences that were transformed into professional mission and commitment.”

In 1997, Dr. Meier and a team of colleagues were finally able to open a palliative care consultation service. “I remember worrying about being able to help the pain patients, as I’d never been taught to manage pain in medical school. I also worried that my medical school colleagues would think that I was doing something “soft” and unimportant,” she commented.

Those feelings of inadequacy were short-lived, as the demand for palliative care services soon exploded. “It was gratifying on many levels. Our existence as a clinical service seemed to be the catalyst for permitting our other colleagues to point to the problems, acknowledge the suffering of their patients and families, and, equally important, recognize the limits of their cure-at-all-costs medical model,” said Dr. Meier.

A Needed Accelerant Despite the growing recognition that palliative care was an essential component in the full continuum of care, the model suffered growing pains due largely to one factor: money. As with other socalled “cognitive” services, provider reimbursement for palliative care was, and remains, dismally low—too low, in fact, to support the full interdisciplinary team required for high-quality palliative care delivery. It took demonstrating the business case for palliative care before most hospitals began to invest in these services.

“However, we’ve made dramatic progress in the integration of palliative care into medical school curricula and the consciousness of the medical world.

Although the quality component of palliative care was established early on, it wasn’t until these programs demonstrated a strong business case that there was a surge of uptake in hospitals across the country,” explained Dr. Meier.

Dr. Meier explained that although hospitals are financially incentivized to offer palliative care services, delivery of palliative care outside of hospitals has been slow to take off, until health-care reform. “But the passage of the Affordable Care Act changed that structure by rewarding quality of care over volume. All

of sudden, there are financial incentives for community health systems to safely and effectively manage the sickest and most vulnerable patients where they live, in their homes and communities. Palliative care fits right into that model, for instance, by keeping more patients at home instead of in the hospital, offering much better quality for complex and vulnerable

patients, and because it helps such patients prevent symptom crises and emergencies, markedly reducing emergency department and hospital utilization—a huge cost saving.” said Dr. Meier.

An indefatigable thinker and doer, Dr. Meier is currently involved in a 10-year plan to further expand the reach and impact of palliative care ser-

vices beyond the hospital—to people’s homes, nursing homes, assisted living facilities, doctor’s offices, and cancer centers. “Our plan, which I call ‘Palliative Care Everywhere’ for short, is to take the model we used in hospitals over the past decade and deploy it over every other care setting in the continued on page 42

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The ASCO Post | AUGUST 15, 2013

PAGE 42

Journal Spotlight

Oncofetal Protein SALL4 Is a Marker of Aggressive Hepatocellular Carcinoma and a Potential Therapeutic Target

By Matthew Stenger

H

epatocellular carcinomas with characteristics of embryonic stem cell and progenitor cell gene expression are associated with particularly poor prognosis. SALL4 is an oncofetal protein that is expressed in the human fetal liver and normally silenced in the adult liver, but re-expressed in a subgroup of patients with hepatocellular carci-

noma. As reported by Kol Jia Yong, MD, of Cancer Science Institute of Singapore, and colleagues in The New England Journal of Medicine, a series of studies showed that the SALL4 gene is a marker of a subtype of hepatocellular carcinoma with progenitor-like features, associated with poor prognosis, and a potential therapeutic target.1

Study Details In these studies, specimens from patients with primary hepatocellular carcinoma were screened for the expression of SALL4, and clinicopathologic analysis was performed to assess correlations with clinical outcomes. Loss-offunction studies examined the role of SALL4 in hepatocarcinogenesis and its potential as a target for therapy, and the

potential therapeutic effects of a peptide that targets SALL4 were evaluated.

Immunohistochemistry analysis of 179 hepatocellular carcinoma specimens (87% grade 1 or 2 tumors) and matched nonneoplastic specimens (Singapore cohort) showed significantly more SALL-expressing cells in the hepatocellular carcinoma specicontinued on page 43

Targeted Suppression of a Reactivated Developmental Pathway in Hepatocellular Cancer

By James L. Abbruzzese, MD

T

his issue of The ASCO Post summarizes the results of an important study recently published in The New England Journal of Medicine by Yong and colleagues. As outlined, investigators from the National University of Singapore Yong Loo Lin School of Medicine have identified reexpression of SALL4 as a biomarker of aggressive hepatocellular cancer in Asian patients with the disease.

Reactivated Pathways These investigators also provide supporting mechanistic data to suggest that SALL4 targeting can be accomplished through inhibition of SALL4’s interaction with its epigenetic co-repressor NuRD (comprising histone deacetylase 1 and histone deacetylase 2 [HDAC1 and HDAC2] complex. Inhibition of the SALL4/NuRD interaction increased expression of PTEN, resulting in dephosphorylation of AKT and thereby leading to inhibition of hepatocellular carcinoma cell growth and tumor formation.

The study is important in that it Dr. Abbruzzese is Professor and Chairman, Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Diane E. Meier, MD continued from page 41

country. We need to analyze, define, and communicate the ability to deliver palliative care models beyond the hospital. We need to do a much better job developing and providing front-line providers with the tools they need so they can develop these programs and ensure their quality,” she said.

again demonstrates that pathways that are active during embryonic organogenesis and repressed in adulthood are often reactivated during carcinogenesis and that detecting such altered expression allows us to identify patients whose prognosis is negatively affected. Furthermore, as beautifully demonstrated in this study, developing a detailed understanding of the mechanism whereby SALL4 re-expression alters hepatocellular carcinoma biology can lead to a novel promising approach to treat a disease like hepatocellular carcinoma, which is enormously heterogeneous and therefore extraordinarily difficult to treat.

Asian patients with hepatocellular carcinoma typically have underlying liver disease due to chronic infection with hepatitis B virus, whereas Western patients are more likely to have hepatitis C virus infection or alcohol as hepatocarcinogens. Whether these etiologic differences affect SALL4 expression should be determined.

James L. Abbruzzese, MD

A particularly interesting aspect of the study is the development of a potentially therapeutic protein generated by fusing the SALL4/NuRD inhibitory peptide with the transactivator of transcription (TAT) protein transduction domain. This domain is known to be a cell-penetrating peptide that when fused with other peptides can facilitate transit across the cell membrane; it also carries a nuclear localization signal that allows translocation of the fused protein into the cell nucleus.

Using this system, the investigators demonstrated convincing suppression of tumor growth using a xenograft model of hepatocellular carcinoma. However, it would have been exciting to also demonstrate that the fusion proteins could be detected in the cancer cells growing in the mice after intraperitoneal administration, and that the downstream consequences of inhibiting the SALL4/NuRD interaction (upregulation of PTEN and dephosphorylation of AKT) selectively occurred in the nonmutant SALL4/NuRD inhibitory fusion peptide–treated tumors in vivo.

Nevertheless, these results are exciting. In addition to further study in Asian patients with hepatocellular carcinoma, the frequency that SALL4 is overexpressed should also be examined in Western patient populations.

How is this undertaking going to cover the country’s vast health-care landscape and empower the multiple levels of providers needed for its success? “We are in the process of developing a massive, open, online interactive course teaching doctors, nurses, social workers, and other professionals the core skills of palliative care medicine,” said Dr. Meier.

Dr. Meier’s tireless and innovative work in the palliative care movement has demonstrated that change is possible, even within the challenges of our broken health-care system. She noted with satisfaction that despite the emotional and physical demands of palliative care medicine, the field is attracting a growing number of young doctors eager to make a difference for our sickest

Cell-penetrating Peptide

Future Challenge The future challenge may be for preclinical scientists to further refine the TAT protein delivery system for clinical use or to develop a small molecule that can mimic the effects of the peptide used to competitively inhibit the interaction between SALL4 and the NuRD complex. Alternatively, patients with high expression of SALL4 may be particularly good candidates for small molecules already known to inhibit PI3K/AKT signaling.

Whatever approach is taken, it is encouraging to see that patients with hepatocellular carcinoma may be able to benefit from ongoing efforts to provide precise therapies for these otherwise dauntingly complex malignancies. n Disclosure: Dr. Abbruzzese reported no potential conflicts of interest.

and most vulnerable patients.

Does her impossibly demanding schedule leave time for restorative leisure activities? “I’m an avid reader. I just finished Speak, Memory, the autobiography of Vladimir Nabokov. Now I want to go back and read everything he wrote. And I try to garden, but the deer and rabbits make that a bit difficult,” she said with a laugh. n

ASCOPost.com | AUGUST 15, 2013

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Journal Spotlight Gastrointestinal Oncology

Oncofetal Protein continued from page 42

mens (P < .001), with 56% (95 of 171) exhibiting SALL4 positivity at various expression levels. A similar pattern of differential SALL4 expression (P < .001) was found in 228 matched neoplastic and nonneoplastic specimens in another cohort of patients (Hong Kong cohort) and in analysis of pooled global gene-expression data from public databases (P = .003).

patocytes. Gene-set enrichment analysis showed that genes upregulated in hepatocellular carcinoma associated with poor survival, genes in an embryonic stem cell signature, and genes upregulated in metastasis, hepatoblastoma, and a proliferation subclass of hepatocellular carcinoma were signifi-

[O]ur study shows that the oncofetal protein SALL4 plays an important role in the extensive network of heterogeneous cellular pathways underlying hepatocarcinogenesis.

Associated with Poor Survival Clinicopathologic analysis of the Singapore and Hong Kong hepatocellular carcinoma specimens showed that patients with a high level of SALL4 expression had worse prognosis than patients with a low level of SALL4 expression.

On univariate analysis, absence of SALL4 protein conferred a significant survival advantage in the Singapore cohort (P = .02) and presence of SALL4 was associated with poor survival in the Hong Kong cohort (P = .002).

On multivariate analyses, SALL4 was an independent prognostic factor for overall survival (hazard ratio [HR] = 2.87, P = .03) in the Singapore cohort and an independent predictor of both overall survival (HR = 1.52, P = .05) and early recurrence (HR = 1.67, P = .01) in the Hong Kong cohort.

Progenitor-like Characteristics Hierarchical cluster analysis of global gene-expression data on hepatocytes, fetal liver tissue, and hepatocellular carcinomas showed that high-SALL4 hepatocellular carcinomas clustered tightly with fetal livers, whereas low-SALL4 hepatocellular carcinomas clustered with normal he-

cytes and fetal liver tissues. They found that SNU-398 cells treated with scrambled shRNA clustered closely with human fetal liver tissue (both expressing high levels of SALL4), whereas SALL4-knocked-down SNU-398 cells clustered with human hepatocytes.

These findings suggest that downregu-

—Kol Jia Yong, MD, and colleagues

cantly enriched in the high-SALL4 hepatocellular carcinoma subgroup.

Overall, these findings suggest that hepatocellular carcinomas that express SALL4 have a gene-expression pattern similar to that of hepatic progenitor cells and thus are poorly differentiated, aggressive, and associated with poor prognosis.

Role in Cell Survival, Tumorigenesis Loss-of-function studies confirmed the role of SALL4 in cell survival and tumorigenicity. SALL4 knockdown studies using shRNA resulted in reduced cell viability, increased apoptosis, and reduced tumorigenicity of hepatocellular carcinoma cells.

The investigators then performed microarray analysis of gene-expression profiles of SNU-398 hepatocellular carcinoma cells treated with control scrambled shRNA or SALL4-specific shRNA and hierarchical clustering analysis of these profiles and profiles derived from normal human hepato-

Hepatocellular Carcinoma Subtype ■ SALL4 is a marker of a subtype of hepatocellular carcinoma with

progenitor-like features, associated with poor prognosis, and a potential therapeutic target.

■ Downregulation of SALL4 can render hepatocellular carcinoma more hepatocyte-like in terms of gene expression.

■ A novel peptide was found to inhibit the oncogenic activity of SALL4.

lation of SALL4 can render hepatocellular carcinoma more hepatocyte-like in terms of gene expression.

Studies with Inhibitory Peptide Studies to develop a targeted agent to inhibit the oncogenic activity of SALL4 were guided by the recognition that SALL4 functions as a transcription repressor by recruiting histone deacetylase (HDAC)-containing nucleosome remodeling and HDAC (NuRD) complex and that the tumor suppressor PTEN is one of the genes repressed by SALL4. Further, the lossof-function microarray data provided evidence that the PTEN-AKT pathway is involved in SALL4-induced hepatocarcinogenesis, with PI3K signaling events mediated by AKT being significantly affected by SALL4 downregulation (P = .02).

The investigators had recently characterized a SALL4 12-amino acid peptide as a competitive inhibitor of the interaction between SALL4 and NuRD that acts to block the NuRD-mediated SALL4-repression function. In studies to determine the effect of the SALL4 peptide on the SALL4-PTEN-AKT pathway, the addition of nonmutant SALL4 peptide to SNU-398 cells reduced the number of viable cells. The addition of a PTEN inhibitor abrogated this effect and maintained cell viability, with these findings indicating that PTEN plays an

important role in the SALL4 peptide– induced loss of tumor-cell viability in hepatocellular carcinoma.

SALL4 peptide had no effect on SNU-387 cells with undetectable endogenous SALL4 expression. Additional analysis showed that SALL4 peptide induced marked increases in PTEN protein levels in SNU-398 cells but had a negligible effect in the lowSALL4 SNU-387 cells. The increase in PTEN expression was associated with a marked reduction in phosphorylated AKT protein levels (not observed in the low-SALL4 SNU-387 cells), suggesting that the increase in PTEN expression acted to block PI3K survival signaling by dephosphorylating AKT. This effect was abrogated by the addition of a PTEN inhibitor, supporting the role of SALL4 in regulating this pathway.

The investigators then administered nonmutant and mutant SALL4 peptides to nonobese diabetic mice with severe combined immunodeficiency and transplanted SNU-398 cells. The nonmutant peptide reduced the tumorigenicity of the SNU-398 hepatocellular carcinoma cells, with tumor burden at 18 days after treatment being significantly smaller in mice receiving nonmutant peptide compared with those receiving mutant peptide.

As noted by the investigators, the absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma. They concluded, “[O]ur study shows that the oncofetal protein SALL4 plays an important role in the extensive network of heterogeneous cellular pathways underlying hepatocarcinogenesis. A 12-amino acid peptide can block the oncogenic role of SALL4 and hence has therapeutic potential in SALL4positive hepatocellular carcinoma.” n

Disclosure: For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Yong KJ, Gao C, Lim JSJ, et al: Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N Engl J Med 368:2266-2276, 2013.

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The ASCO Post | AUGUST 15, 2013

PAGE 44

ASCO Annual Meeting Issues in Oncology

ASCO Studies Support Limited Use of ‘Routine’ Imaging

By Caroline Helwick

T

he overuse of imaging in oncology workup and surveillance is a timely concern, as health-care dollars shrink and the risk for second malignancies becomes clearer. At this year’s

ASCO Annual Meeting, several studies showed that although many routine imaging studies may be unnecessary, physicians can be slow to adopt new recommendations.

Impact of ASCO ‘Top 5’ on Breast Cancer Imaging In the workup of women diagnosed with breast cancer, local practice patterns have not been affected by the

Trebananib (AMG 386) Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

TRINOVA-2: A Phase 3, Randomized, Double-Blind Trial of Pegylated Liposomal Doxorubicin (PLD) Plus Trebananib (AMG 386) or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

TRINOVA-3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Trebananib (AMG 386) With Paclitaxel and Carboplatin as First-Line Treatment of Women With FIGO Stage III-IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Primary Endpoint: • Progression-free survival (PFS)

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Key Secondary Endpoint: • Overall survival (OS) Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

R A N D O M I Z A T I O N

Trebananib15 mg/kg IV QW + PLD 50 mg/m2 IV Q4W

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + PLD 50 mg/m2 IV Q4W

OS

R A N D O M I Z A T I O N

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

ENDPOINTS

Primary

PFS 2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Key Secondary

Placebo IV QW Monotherapy

OS

*Subjects with FIGO stage IIIC or IV disease undergoing planned interval debulking surgery (IDS) will receive 3 cycles of therapy prior to IDS and 3 cycles of therapy following IDS

Trebananib is an investigational agent that has not been approved by regulatory agencies for the use under investigation for this trial.

Trebananib is an investigational agent that has not been approved by regulatory agencies for the use under investigation for this trial.

Key Inclusion Criteria: • Subjects must have had one to three prior chemotherapeutic regimens • Radiographically documented disease progression either on or following the last dose of prior chemotherapeutic regimen • ECOG performance status of 0 or 1

Key Inclusion Criteria: • FIGO Stages III-IV epithelial ovarian, primary peritoneal or fallopian tube cancer with an indication for first-line treatment with paclitaxel and carboplatin • No prior use of any anticancer therapy or experimental therapy for epithelial ovarian, primary peritoneal or fallopian tube cancer • ECOG performance status of 0 or 1

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2009-017946-30 • www.ClinicalTrials.gov (NCT01281254)

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2011-001112-53 • www.ClinicalTrials.gov (NCT01493505)

© 2013 Amgen Inc. All rights reserved.

recently published ASCO recommendation for limited imaging, Canadian investigators showed.1 “Imaging for metastatic disease remains overutilized in stage II and II disease,” said Demetrios Simos, MD, of the Ottawa Hospital Research Institute and University of Ottawa. He noted

Demetrios Simos, MD

that since most patients will have no suspicious findings, metastatic disease is unlikely to be detected by perioperative imaging. Excessive imaging is expensive, creates anxiety for the patient, and can delay treatment, he said.

Evidence-based guidelines for radiologic staging generally state that in the absence of findings suggestive of distant metastases, focused radiologic staging should be limited to patients with at least pathologic stage II disease. In keeping with published guidelines, ASCO has included the limited use of imaging in early breast cancer among its “Top 5 List” for fiscal responsibility. The study examined whether this “Top 5” recommendation has impacted practice patterns.

Investigators reviewed the charts of 200 patients, 100 before and 100 after the recommendation, for which they found 614 imaging tests reported. Overall, 83.5% of patients had at least one imaging test to look for metastatic disease, including 83% before the ASCO recommendation and 84% after. Metastastic lesions, however, were detected in only 2 of the 200 patients, and both had stage III disease, Dr. Simos reported.

The local Cancer Care Ontario evidence-based guideline for staging tests in primary breast cancer recommends no routine imaging for patients with stage I disease. However, of 98 stage I patients, 55 received chest x-rays, 57 received bone scans, and 46 received abdominal imaging. A similar pattern emerged for stage II patients, although bone scans were actually reduced in this group. About half of stage III patients received CT scans of the chest, abdo-

ASCOPost.com | AUGUST 15, 2013

PAGE 45

ASCO Annual Meeting men, and pelvis, where none of these would be recommended.

“The purpose of the study was to not only quantify and report the amount of imaging done—excessive according to the guidelines—but also to see if there was any change in physician practice pattern brought about by the ASCO ‘Top 5’ publication,” Dr. Simos explained to The ASCO Post. “We showed that relative to the guidelines, imaging is overused with minimal yield and that there was no real change in this practice following the ASCO ‘Top 5’ publication.”

Intense Follow-up after Colorectal Cancer Resection In the postsurgical follow-up of primary colorectal cancer patients, regular measurement of carcinoembryonic antigen (CEA) and regular CT scanning were more effective at detecting recurrence than minimal symptom-based follow-up. However, the combination of the two modalities was not more effective than either alone, in the randomized Follow-up after Colorectal Surgery (FACS) trial.2 David Mant, MD, of Oxford University, noted that patients with colorectal cancer experience anxiety surrounding disease monitoring, and economic modeling has suggested that intensive follow-up may not be cost-effective. “Intensive follow-up seems like a bad idea unless there’s a clear benefit,” he commented. “We did a trial to assess that benefit.”

The study included 1,202 patients who underwent curative treatment for primary colorectal cancer and had no residual disease. They were randomized to one of four follow-up regimens: minimal follow-up (primary care, symptombased, involving a single CT scan at 12– 18 months), or follow-up primarily by CEA monitoring (CEA every 3 months for 2 years, then every 6 months in years 3 to 4, with a single CT scan at 12 to 18 months), or primarily by CT (CT every 6 months for 2 years, then annually for another 3 years), or CEA plus CT (CEA

as in the CEA follow-up group plus CT as in the CT follow-up group).

The outcome was defined as the proportion of patients with recurrence treated surgically with curative intent.

Altogether, this occurred in 6% of patients, which was lower than expected, probably because patients were “rigorously staged” up front, he said. By surveillance arm, the proportion was 2.3% among patients with minimal follow-up, 6.7% of those followed by CEA, 8.0% of patients followed by CT scan, and 6.6% followed by CEA plus CT. There were no differences by disease stage.

“About 1 in 14 participants in the three intensive follow-up arms had recurrences

Tim Maughan, MD

that could be treated surgically with curative intent. We saw about a 4% difference for minimal follow-up vs the other arms, and no additive benefit for CEA plus CT, vs either alone,” he reported.

At time of analysis, 59% of patients with recurrence treated surgically with curative intent were alive, with no difference between the arms.

Tim Maughan, MD, Professor of Clinical Oncology at Oxford University, discussed the study after its presentation emphasizing that while minimal follow-up was less effective, there was no difference between the three intensive protocols. “This challenges our current practice of repeated CT scans,” he said. After 3 years, few recurrences (1%–2%) were detected, he added.

“The FACS trial showed that clinical appointments add nothing to the detection of resectable recurrence, and multiple CT scans add nothing over a

New Findings on Imaging in Solid Tumors ■ In the workup of patients with early breast cancer, 83% of patients received imaging tests outside of ASCO’s “Top 5” guidelines for fiscal responsibility.

■ For surveillance after curative resection, patients with colorectal cancer can

be followed primarily by CEA or CT scans—the combination is not necessary.

■ Routine surveillance imaging yielded no improvement in overall survival compared to clinical surveillance in patients with classical Hodgkin lymphoma at 8 years of follow-up.

■ Routine CT scans are not necessary in the follow-up of patients with diffuse large B-cell lymphoma after treatment.

single CT scan with regular CEA measurements—only the risk of radiationinduced malignancy. The study also suggests that the benefit of follow-up is similar across stages I to III, and this could change our practice.”

No Benefit for Routine Imaging in Hodgkin Lymphoma No benefit was observed for routine surveillance imaging over clinical surveillance for monitoring classical Hodgkin lymphoma patients for relapse, in a multicenter study reported by Sai Ravi Pingali, MD, of the Medical College of Wisconsin in Milwaukee.3 “We were unable to detect an overall survival benefit associated with routine surveillance imaging, although the power is limited by the small number of deaths and relapses. Relapses in both clinical surveillance and routine surveillance imaging groups were effectively salvaged with autologous stem cell transplant. The costs associated with routine surveillance imaging are significant, and the potential risks from routine surveillance imaging must also be considered,” Dr. Pingali said.

The study included 241 Hodgkin lymphoma patients achieving complete remission between 2000 and 2010 and followed for at least 2 years with routine surveillance imaging (n = 164) or clinical surveillance (n = 77).

With routine surveillance imaging, the intended plan of surveillance was radiologic imaging, clinical exam, and labs; the clinical surveillance group underwent clinical exams and labs, with

attributed to relapse. In the clinical surveillance group six patients died, none from Hodgkin lymphoma. All relapsed patients were successfully retreated.

Mean number of scans was 1.14 in the clinical surveillance group and 4.25 in the routine surveillance imaging group. To detect one relapse required 18 scans and 124 scans, respectively.

The cost per relapse was nearly $19,000 more with routine surveillance imaging surveillance, not including the costs associated with false-positives.

Routine CT Scans in Diffuse Large B-cell Lymphoma A multicenter cohort of 644 patients newly diagnosed with diffuse large Bcell lymphoma showed that CT scans,

Carrie A. Thompson, MD

typically a routine part of follow-up after treatment, may be unnecessary. For the vast majority of patients, relapses were detected based on symptoms, abnormal blood tests, or abnormal findings on physical exam, reported Carrie A. Thompson, MD, of the Mayo Clinic, Rochester, Minnesota.

Only 1.5% of patients in remission had a relapse that was detected solely through a scheduled imaging scan.4 n

Disclosure: Dr. Maughan is a consultant or advisor for Sanofi and has received research funding from Merck Serono. Drs. Simos, Mant, Pingali, and Thompson reported no potential conflicts of interest.

Sai Ravi Pingali, MD

radiologic tests to evaluate concerning signs and symptoms.

At 8 years, no overall survival differences were observed (P = .47). At 5 years, when scans are typically discontinued, more than 95% of each group was alive and the curves were essentially superimposable. The type of chemotherapy and receipt of consolidation radiotherapy (which did differ at baseline) did not affect survival.

There were five deaths in the routine surveillance imaging group, only one

References 1. Simos D, Hutton B, et al: 2013 ASCO Annual Meeting. Abstract 6597. Presented June 3, 2013.

2. Mant D, Perera R, et al: Effect of 3-5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer. 2013 ASCO Annual Meeting. Abstract 3500. Presented June 1, 2013.

3. Pingali SR, Jewell S, et al: Clinical or survival benefit to routine surveillance imaging for classical Hodgkin lymphoma patients in first complete remission. 2013 ASCO Annual Meeting. Abstract 8505. Presented June 1, 2013.

4. Thompson CA, Maurer MJ, et al: Utility of post-therapy surveillance scans in DLBCL. 2013 ASCO Annual Meeting. Abstract 8504. Presented June 1, 2013.

FOR THE TREATMENT OF PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (mCRPC) WHO HAVE PREVIOUSLY RECEIVED DOCETAXEL

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss

of consciousness could cause serious harm to themselves or others.

Adverse Reactions The most common adverse drug reactions (â&#x2030;Ľ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ďŹ&#x201A;ush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-4) and in 6% of patients on placebo (no grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe

Convenient, oral, once-daily administration • Dosed as four 40 mg capsules (160 mg) without food restrictions or steroid requirements. Each capsule should be swallowed whole. Patients should not chew, dissolve, or open the capsules1,2 Comparable overall rate of grade 3-4 adverse reactions • No increased overall rate of grade 3-4 adverse reactions with XTANDI vs placebo (47% vs 53%, respectively)1 37% reduced risk of death • HR = 0.63 (95% CI, 0.53-0.75); P < 0.00011 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.3

in XTANDI patients and included nonpathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event.

Drug Interactions: Effect of Other Drugs on XTANDI Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible.

Effect of XTANDI on Other Drugs XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans.

Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is

coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed March 11, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Learn L earn more more a att XtandiHCP.com XtandiHCP.c com

© 2013 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 013E-076-7984-1 5/13 XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma Inc.

The ASCO Post | AUGUST 15, 2013

PAGE 48

Announcements Gastrointestinal Oncology

New Campaign Addresses Rise in Young-onset Colon Cancer

T

he Colon Cancer Alliance has partnered with Bowel Cancer UK and the Colon Cancer Prevention Project to launch the international Never Too Young awareness campaign, addressing the rise in young-onset

(younger than 50 years) colon cancer diagnoses and mortality rates.

This global collaboration comes with a decisive mission: educating the public that youâ&#x20AC;&#x2122;re never too young for colon cancer, and arming people with the resources

and tools to incite change. The campaign features interviews with experts in the field, draws on information from recent research on the topic. and features young survivors who share their colon cancer experiences firsthand.

â&#x20AC;&#x153;After focusing on the young-onset issue at the Colorectal Cancer Alliance National Conference last year, we heard so many stories and knew we needed to take action,â&#x20AC;? said Colon Cancer Alliance Interim CEO Jasmine Greenamyer.

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information.

------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

--------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI 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 and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@.

-------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures.

The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

--------------------------------- ADVERSE REACTIONS ------------------------------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 WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo.

All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders Asthenic Conditionsa

9.0 44.4 9.3 Peripheral Edema

1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4

24.3 4.0 Arthralgia

17.3 1.8 Musculoskeletal Pain

1.3

0.3 Muscular Weakness 9.8

6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1

0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9

0.0

Dizzinessb Spinal Cord 7.4 6.6

3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0

0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0

0.3 Upper Respiratory Tract Infectiond Lower Respiratory

2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0

Anxiety

0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8

1.0 Pollakiuria 4.8 0.0

0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin

0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.

Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms.

Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.com | AUGUST 15, 2013

PAGE 49

Announcements

â&#x20AC;&#x153;Weâ&#x20AC;&#x2122;re letting people know that colon cancer in the under 50 population is on the rise, and that knowledge is crucial.

This campaign will make a difference for so many families worldwide.â&#x20AC;?

According to the American Cancer Society, the average age of colon cancer diagnosis is 68 for men and 72 for women, and rates of diagnosis for those over

Jasmine Greenamyer

MEDPC9886 - Xtandi Brief PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.625"w Ă&#x2014; 11.375"h Trim: 8.125"w Ă&#x2014; 10.875"h Output @ 100% Giant Creative Strategy

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers.

Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ

DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @.

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @.

-------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI 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 XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI 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 XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment.

Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@.

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

50 are decreasing in the United States.

But this isnâ&#x20AC;&#x2122;t the case across the board, with approximately 15,000 new cases of young-onset colon cancer every year, and rising. Because colon cancer is less common in younger populations and often takes longer to diagnose, it often presents at more advanced and fatal stages in young-onset cases.

Live: 7"w Ă&#x2014; 10"h

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8&

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember.

If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only Š 2012 Astellas Pharma US, Inc. XTANDIŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

â&#x20AC;&#x153;Colon cancer in the under 50 population, while rare, has documented rises to prove it is an emerging issue,â&#x20AC;? said Andrew Kennedy, MD, Director of Radiation Oncology Research at Sarah Cannon Research Institute in Nashville. â&#x20AC;&#x153;The decline in colon cancers in patients over age 50 is thought to be secondary to more screening of this group. It is not felt that colon cancer is a common entity in patients under 50, so this group is not as quickly screened when symptoms first appear, and risk factors are not talked about as often.â&#x20AC;?

To learn more about the campaign, visit www.nevertooyoung.org. n

Never Too Young Campaignâ&#x20AC;&#x2122;s Collaborative Effort

T

he Colon Cancer Allianceâ&#x20AC;&#x2122;s mission is to knock colon cancer out of the top three cancer killers. The group works to promote prevention, fund cutting-edge research and provide the highest quality patient support services.

For more information, visit www. ccalliance.org Bowel Cancer UK is a charity that aims to save lives and improve the quality of life for all those affected by bowel cancer. For more information, visit www.bowelcanceruk. org.uk The Colon Cancer Prevention Projectâ&#x20AC;&#x2122;s mission is to eliminate preventable colon cancer death and suffering by increasing screening rates through education, advocacy, health systems improvement and survivor support. More information at www.

ColonCancerPreventionProject.org

The ASCO Post Follow us on

@ASCOPost

The ASCO Post | AUGUST 15, 2013

PAGE 50

In the Clinic Thoracic Oncology

Afatinib as First-line Treatment for Metastatic NSCLC with EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations

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.

Indication On July 12, 2013, afatinib (Gilotrif) was approved for first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.1,2 The safety and efficacy of afatinib have not been established in patients with tumors carrying other EGFR mutations. FDA concurrently approved the therascreen EGFR RGQ PCR Kit (Qiagen) for detection of EGFR exon 19 deletions and exon 21 (L858R) substitution mutations.

Approval was based on demonstration of improved progression-free survival in an international openlabel phase III trial in which 345 patients with EGFR-mutant metastatic NSCLC were randomly assigned to receive oral afatinib at 40 mg once daily (n = 230) or pemetrexed (Alimta)/ cisplatin (n = 115).2,3 Overall, 65% of patients were female, the median age was 61 years, 26% were Caucasian, and 72% were Asian.

The majority of patients had either

OF NOTE Afatinib binds to the kinase domains of EGFR, HER2, and HER4 and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. an EGFR exon 19 deletion (49%) or exon 21 (L858R) substitution (40%).

Randomization was stratified according to EGFR mutation status (exon 19 deletion vs exon 21 L858R vs “other”) and race (Asian vs non-Asian). The primary endpoint was progressionfree survival as assessed by an independent review committee.

After a median follow-up of 16.4

months, median progression-free survival was 11.1 months in the afatinib group and 6.9 months in the chemotherapy group (P < .001). Median progression-free survival among those with exon 19 deletions and L858R mutations was 13.6 months in the afatinib group and 6.9 months in the chemotherapy group (HR = 0.47, P = .001). Objective response rates were 50.4% and 19.1% in the afatinib and chemotherapy groups, respectively. There was no statistically significant difference in overall survival between the two groups. (See page 56 for a comprehensive report on the study.)

How It Works Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting

disease, severe hepatic impairment, persistent ulcerative keratitis, symptomatic left-ventricular dysfunction, and severe or intolerable adverse events occurring at a dose of 20 mg/d.

The dose should be increased by 10 mg and decreased by 10 mg in patients requiring concomitant treatment with P-glycoprotein inducers (eg, rifampin, St. John’s wort) and inhibitors (eg, amiodarone, clarithromycin, nicardipine), respectively.

Safety Profile The most frequent adverse events of any grade with afatinib in the phase III trial were diarrhea (96% vs 23% in chemotherapy group), rash/ dermatitis acneiform (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%), decreased appetite (29% vs 55%), and pruritus (21% vs 1%). The most

Afatinib, New Option in Non–Small Cell Lung Cancer ■ Afatinib (Gilotrif) was approved for first-line treatment of patients with

metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDAapproved test.

■ The recommended dose of afatinib is 40 mg once daily at least 1 hour before or 2 hours after a meal.

in downregulation of ErbB signaling.

Afatinib inhibits autophosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR or those expressing EGFR exon 19 deletion mutations or exon 21 L858R mutations.

How It Is Given The recommended dose of afatinib is 40 mg once daily at least 1 hour before or 2 hours after a meal. Treatment should be withheld for adverse events of grade 3 or higher, persistent diarrhea of grade 2 or higher not responsive to antidiarrheal medication, prolonged or intolerable grade 2 cutaneous reactions, and grade 2 or higher renal dysfunction. Treatment should be resumed at a 10-mg lower dose after resolution of the adverse reaction.

Treatment should be permanently discontinued for life-threatening bullous, blistering, or exfoliative skin lesions, confirmed interstitial lung

frequent grade 3 or 4 adverse events in afatinib recipients were rash/dermatitis acneiform (16% vs 0%), diarrhea (15% vs 2%), paronychia (11% vs 0%), and stomatitis (9% vs 1%).

The trial excluded patients with an abnormal left-ventricular ejection fraction; ventricular dysfunction occurred in 2.2% of afatinib patients (all grade 1 or 2).

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 http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Serious adverse events occurred in 29% of afatinib patients, with the most common being diarrhea (7%), vomiting (5%), and dyspnea, fatigue, and hypokalemia (2% each). Adverse events led to dose reduction in 57% of afatinib patients, with the most common reasons being diarrhea (20%), rash/acne (19%), paronychia (14%),

OF NOTE Afatinib carries warnings/precautions for diarrhea, bullous and exfoliative skin disorders, interstitial lung disease, hepatic toxicity, keratitis, and embryofetal toxicity. and stomatitis (10%), and to discontinuation in 14%, with the most common reasons being diarrhea (1.3%), interstitial lung disease (0.9%), and paronychia (0.9%). Fatal adverse events in afatinib patients included pulmonary toxicity/interstitial lung disease–like adverse events (1.3%), sepsis (0.4%), and pneumonia (0.4%).

Afatinib carries warnings/precautions for diarrhea, bullous and exfoliative skin disorders (severe lesions observed in 0.15% of patients), interstitial lung disease (observed in 1.5% of patents), hepatic toxicity (fatal in 0.18% of patients), keratitis (observed in 0.8% of patients), and embryofetal toxicity. Patients should have periodic liver function testing. Nursing mothers should discontinue treatment or nursing. n References 1. U.S. Food and Drug Administration: Afatinib. Available at http://www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm. Accessed July 19, 2013.

2. GILOTRIF™ (afatinib) tablets prescribing information,Boehringer Ingelheim Pharmaceuticals, Inc, July 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl. pdf. Accessed July 19, 2013.

3. Sequist LV, Yang J-CH, Yamamoto N, et al: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. July 1, 2013 (early release online).

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The ASCO Post | AUGUST 15, 2013

PAGE 56

JCO Spotlight Thoracic Oncology

LUX-Lung 3: Afatinib Prolongs Progression-free Survival vs Cisplatin/Pemetrexed in Advanced Lung Adenocarcinoma

By Matthew Stenger

A

fatinib (Gilotrif) is an oral selective ErbB family inhibitor that irreversibly blocks signaling from EGFR/ ErbB1, HER2/ErbB2, and ErbB4 and has exhibited broad-spectrum activity against EGFR mutations in preclinical studies. A phase II study of afatinib in EGFR-mutation positive lung adenocarcinoma showed high response rates and progression-free survival.

tients with EGFR-mutant stage IIIB/ IV lung adenocarcinoma.1

In a phase III study (LUX-Lung 3) reported in Journal of Clinical Oncology, Lecia V. Sequist, MD, of Massachusetts General Hospital and Harvard Medical School and colleagues found that first-line afatinib increased progression-free survival compared with standard cisplatin plus pemetrexed (Alimta) chemotherapy in a predominantly East Asian population of pa-

Study Details

Lecia V. Sequist, MD

In this international study, 345 patients with EGFR-mutant advanced lung adenocarcinoma were randomly assigned (2:1) to afatinib at 40 mg/d (n = 230) or six cycles of cisplatin plus pemetrexed (n = 115) at standard dos-

Further Support for Front-line Targeted EGFR Therapy

By Melissa L. Johnson, MD

L

UX-Lung 3 is the sixth, and largest, prospective, randomized trial to evaluate targeted EGFR inhibition vs front-line platinum doublet chemotherapy for patients with EGFR muta-

Melissa L. Johnson, MD

tions. LUX-Lung 3 distinguishes itself from the previous trials (see Table 1) by using afatinib (Gilotrif), a secondgeneration EGFR inhibitor that binds covalently to EGFR/HER1, HER 2, and HER 4; other studies have examined the first-generation inhibitors erlotinib (Tarceva) and gefitinib (Iressa). Notably, afatinib has in vitro activity against EGFR T790M, which is associated with resistance to gefitinib and erlotinib.

In addition, LUX-Lung 3 is the first trial to use cisplatin and pemetrexed (Alimta) as its comparator chemotherapy arm, the platinum doublet many would select as “best” for fit patients with adenocarcinoma.

LUX-Lung 3 also adopted a more “global” approach to enrollment, with patients accrued in Asia, Europe, Dr. Johnson is Assistant Professor, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.

North/South America, and Australia, in comparison to the other trials evaluating this question, which were conducted exclusively in Asian or European countries.

LUX-Lung 3 reported impressive median progression-free survival and response rates, not only for patients treated with afatinib, but also for those who received cisplatin/pemetrexed.

Patient-reported symptoms of cough and dyspnea improved more readily with afatinib than with chemotherapy.

However, the vast majority of patients who received afatinib also experienced treatment-related adverse events—diarrhea, rash, and irritation of the skin, mucosa, and nails. There were four afatinib-related deaths. Yet, with supportive measures and dose reductions, fewer patients discontinued afatinib

than chemotherapy (52% of patients required one dose reduction and 19% required more than one).

Unanswered Questions Is it clinically meaningful that LUX-Lung 3 reported longer progression-free survival results with afatinib vs chemotherapy than most of the previous trials comparing EGFR inhibitors to chemotherapy in patients with EGFR mutations? The study authors suggest that afatinib may have achieved longer progression-free survival due to its ability to selectively inhibit EGFR T790M clones in addition to the more common sensitizing mutations—ie, EGFR exon 19 deletion and L858R point mutations.

I think it is still difficult to extrapolate from the existing data about

the efficacy of afatinib vs gefitinib or erlotinib. Recall that the patient population in LUX-Lung 3 was different from the others in which this question has been investigated. Furthermore, each trial chose a different comparator chemotherapy regimen.

A more clinically instructive trial would be a direct comparison of afatinib and erlotinib.

While that trial may never be done, a step in the right direction is LUX-Lung 7, a trial comparing afatinib to gefitinib for patients with untreated EGFR-mutant adenocarcinoma, currently recruiting patients (NCT01466660). In the meantime, LUX-Lung 3 strengthens the body of evidence supporting front-line targeted EGFR therapy for patients with EGFR mutations. n

Table 1: Trials of EGFR Inhibitors in EGFR-mutant Lung Cancer Median Progression-free Survival

Hazard Ratio (95% confidence interval)

Study

EGFR Inhibitor

Chemotherapy

Objective Response Rate

LUX-Lung 3 (N = 345)

Afatinib

Cisplatin/pemetrexed

56% vs 23%

11.1 vs 6.9 mo

0.58 (0.34–0.65)

Cisplatin/carboplatin

EURTAC (N = 174)

Erlotinib

Docetaxel/gemcitabine

58% vs 15%

10.4 vs 5.4 mo

0.47 (0.28–0.78)

OPTIMAL (N = 165)

Erlotinib

Carboplatin/gemcitabine

83% vs 36%

13.1 vs 4.1 mo

0.16 (0.10–0.26)

WJOTG (N = 172)

Gefitinib

Cisplatin/docetaxel

62% vs 32%

9.2 vs 6.3 mo

0.49 (0.34–0.71)

NEJ002 (N = 230)

Gefitinib

Carboplatin/paclitaxel

74% vs 31%

10.8 vs 5.4 mo

0.30 (0.22–0.41)

IPASS (N = 261)

Gefitinib

Carboplatin/paclitaxel

71% vs 47%

9.5 vs 6.3 mo

0.48 (0.36–0.64)

Adapted from Solomon BJ: Targeting the epidermal growth factor receptor. 2012 ASCO Annual Meeting. Presented June 4, 2012.

ASCOPost.com | AUGUST 15, 2013

PAGE 57

JCO Spotlight

es given every 21 days.

The afatinib and chemotherapy groups were generally well-matched for age (median, 61.5 vs 61 years), sex (64% vs 67% female), race (72% East Asian in both, 26.5% vs 26% white), smoking status (67% vs 70% never, 30% vs 28% former), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 in 100% vs 99%), adenocarcinoma stage (IIIB with pleural effusion in 9% vs 15%, IV in 91% vs 85%), and EGFR mutations (exon 19 deletion in 49% vs 59%, L858R in 40% vs 41%, and other in 11% vs 10%).

groups (HR = 1.12, P = .60; .60; 25th percentile, 16.6 vs 14.8 months).

At disease progression, most patients in the afatinib group crossed over to chemotherapy (62%) and most in the chemotherapy group crossed over to EGFR tyrosine kinase inhibitor treatment (65%). With regard to patient-reported outcomes, afatinib

treatment was associated with significant delay to clinically meaningful worsening of cough (HR = 0.60, P = .007) and dyspnea (HR = 0.68, P = .01) compared with chemotherapy.

Adverse Events The most common treatment-related adverse events of any grade were

diarrhea (95% vs 15%), rash/acne (90% vs 6%), stomatitis/mucositis (72% vs 15%), and paronychia (57% vs 0%) in the afatinib group and nausea (66% vs 18%), decreased appetite (53% vs 21%), fatigue (47% vs 18%), and vomiting (42% vs 17%) in the chemotherapy group. The most common continued on page 58

Prolonged Progression-free Survival Median follow-up at the time of primary analysis was 16.4 months.

Median progression-free survival on independent review was 11.1 months in the afatinib group and 6.9 months in the chemotherapy group (hazard ratio [HR] = 0.58, P = .001). Median progression-free survival among those with the most common activating EGFR mutations—ie, exon 19 deletions and L858R mutations (n = 308)—was 13.6 months in the afatinib group and 6.9 months in the chemotherapy group (HR = 0.47, P = .001). Subgroup analyses showed the progression-free survival benefit for afatinib persisted among most subgroups examined (by age, sex, race, and ECOG performance status).

Response rates on independent review were 56% with afatinib and 23% with chemotherapy (P = .001) .001) and median durations of response were 11.1 and 5.5 months, respectively. Overall survival data are considered preliminary, and median overall survival had not been reached in either group. Overall survival did not significantly differ between the afatinib and chemotherapy

Afatinib in Advanced NSCLC ■ Afatinib significantly prolonged progression-free survival compared with cisplatinpemetrexed in first-line treatment of metastatic EGFRmutant non–small cell lung cancer.

■ Afatinib treatment was

associated with a significantly higher response rate and improved patient-reported outcomes.

■ Afatinib could be considered a

standard option in this setting.

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PAGE 58

Journal Spotlight Breast Cancer

Age Not Linked to Recurrence in Observation or Trastuzumab Groups with HER2-positive Breast Cancer

By Matthew Stenger

A

vailable data suggest that younger age is an independent risk factor for disease recurrence and death in women with breast cancer. However, there has not been adequate study of the interaction of age with human

Program for Young Women with Breast Cancer at Dana-Farber Cancer Institute, Boston, and colleagues found that age was not strongly associated with risk of early recurrence or benefit from trastuzumab (Herceptin) therapy.1 The analysis included 1,703 women randomly assigned to 1 year of trastuzumab and 1,698 randomly assigned to observation after completion of chemotherapy in the HERA trial. Analyses of outcomes used 2-year median data and dichotomized age at ≤ 40 years vs > 40 years.

Younger vs Older Subgroups Ann H. Partridge, MD, MPH

epidermal growth factor receptor 2 (HER2) status or anti-HER2 treatment. In an analysis of outcomes in the HERA trial in women with early-stage invasive HER2-positive breast cancer, Ann H. Partridge, MD, MPH, Associate Professor of Medicine at Harvard Medical School and Director of the

LUX-Lung 3 continued from page 57

grade 3 or higher adverse events were rash/acne (16% vs 0%), diarrhea (14% vs 0%), paronychia (11% vs 0%), and stomatitis/mucositis (9% vs 1%) in the afatinib group and neutropenia (18% vs < 1%), fatigue (13% vs 1%), and leukopenia (8% vs < 1%) in the chemotherapy group.

Treatment was discontinued due to treatment-related adverse events in 8% of afatinib patients and in 12% of chemotherapy patients. Three cases of potentially treatment-related intersti-

Overall, younger women were more likely to have had no assessment of nodal status (15% vs 10%, due to receipt of neoadjuvant therapy), less likely to have node-negative disease (28% vs 34%), and more likely to have estrogen receptor (ER)-positive (51% vs 44%) and progesterone receptor (PR)-positive disease (41% vs 32%).

In addition, younger women were

Age and Breast Cancer Recurrence Risk ■ Age was not significantly associated with risk of early recurrence or

prediction of benefit from trastuzumab in women with early-stage HER2positive breast cancer.

■ Additional study is necessary to determine whether age is predictive of later recurrence.

treated more often with taxanes (32% vs 25%), anthracyclines (97% vs 93%), and hormonal therapy (56% vs 49%).

No Difference in Survival

by Age Uncontrolled Cox proportional hazards models showed no significant differences in disease-free survival for patients aged ≤ 40 vs > 40 years in the observation group (hazard ratio [HR] = 1.16, P = .27) or in the trastuzumab group (HR = 1.18, P = .30). No effect of age on disease-free survival was observed when age was analyzed as a continuous variable in either the observation group (HR = 0.99,

[P]atients with lung adenocarcinoma with EGFR mutations have significant [progression-free survival], tumor response, and lung cancer–related symptom benefits when treated with first-line afatinib.

tial lung disease-like events and four potentially treatment-related deaths (due to respiratory decompensation in two patients, sepsis in one, and unknown cause in one) were observed among afatinib patients. There were no

P = .07) or trastuzumab group (HR = 1.004, P = .60).

Similarly, there were no significant differences in overall survival for patients aged ≤ 40 vs > 40 years in the observation group (HR = 1.05, P = .85) or trastuzumab group (HR = 1.44, P = .20). Analysis of age as a continuous variable also showed no significant effect of age on overall survival in the observation group (HR = 1.00, P = .89) or trastuzumab group (HR = 1.02, P = .16).

On multivariate analysis controlling for prognostic and predictive factors, there was no significant difference in disease-free survival for age ≤ 40 vs mor response, and lung cancer–related symptom benefits when treated with first-line afatinib compared with cisplatin plus pemetrexed. Afatinib could be considered a standard option for such patients.” n

—Lecia V. Sequist, MD, and colleagues

Disclosure: The study was supported by Boehringer Ingelheim. For full disclosures of the study authors, visit jco.ascopubs.org.

treatment-related fatal toxicities in the chemotherapy group.

The investigators concluded, “[P]atients with lung adenocarcinoma with EGFR mutations have significant [progression-free survival], tu-

Reference 1. Sequist LV, Yang J-CH, Yamamoto N, et al: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol July 1, 2013.

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PAGE 59

Journal Spotlight

> 40 years in the observation group (HR = 1.18, P = .22) or trastuzumab group (HR = 1.11, P = .53). Similarly, there was no significant difference in overall survival by dichotomized age in the observation group (HR = 1.01, P = .97) or trastuzumab group (HR = 1.18, P = .58).

When an interaction term for dichotomized age and trastuzumab treatment was added to multivariate models including all patients in both treatment groups, the P values for the interaction terms were 0.89 for disease-free survival and 0.55 for overall survival, indicating that age was not a predictive factor for trastuzumab benefit. A subpopulation treatment effect pattern plot analysis of 3-year disease-free survival according to age and treatment group confirmed that differences in 3-year disease-free survival percentages between the observation and trastuzumab groups did not differ significantly across age subgroups (P = .6 for interaction).

overall survival in trastuzumab patients are hypothesis-generating and warrant further investigation.

They concluded, “In [this] retrospective analysis of a large randomized controlled trial of women with earlystage HER2-positive breast cancer, age was not strongly associated with risk of early recurrence or prediction of ben-

efit from trastuzumab therapy. Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes.” n

Disclosure: Dr. Partridge has had an unpaid consultant or advisory role with Genentech. For full disclosures of all study authors, visit jco.ascopubs.org.

Reference 1. Partridge AH, Gelber S, PiccartGebhart MJ, et al: Effect of age on breast cancer outcomes in women with human epidermal growth factor receptor 2-positive breast cancer: results from a Herceptin adjuvant trial. J Clin Oncol. June 10, 2013 (early release online).

See related commentary on page 60.

Factors Associated with Survival On multivariate analysis, factors significantly associated with improved disease-free survival were ERpositive tumors in the observation group and tumor size ≤ 2 cm in both the observation and trastuzumab groups. Factors associated with worse disease-free survival were nodal status not assessed and positive nodal status in the observation and trastuzumab groups and grade 3 tumors in the trastuzumab group.

Factors significantly associated with overall survival in the two groups were similar except that the effect of tumor size ≤ 2 cm was borderline significant in the observation group. In addition, receipt of taxane therapy was associated with significantly poorer overall survival (HR = 2.65, P < .001) and receipt of anthracyclines with significantly better overall survival (HR = 0.29, P = .007) in the trastuzumab group.

The investigators noted that the analysis is limited by the relatively short follow-up and that results for patients with ER-positive disease, in particular, might change with longerterm follow-up. Longer-term followup will need to adjust for the crossover to trastuzumab among observation group patents after the demonstration of efficacy of trastuzumab in HERA. They also emphasize that the unanticipated associations of taxane treatment with reduced overall survival and anthracycline treatment with prolonged

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PAGE 60

Perspective Continued from page 59

Is Age Truly Relative in HER2-positive Breast Cancer?

By Carey K. Anders, MD

B

reast cancer arising in younger women has increasingly become the subject of intense study, and often debate, over the past decade. Retrospective studies have illustrated that breast cancer in young women is more commonly an aggressive subtype (ie, triple-negative/basal-like, HER2enriched), higher grade, lymph-node positive, and associated with poorer outcome compared to that in older counterparts.1-3 Limitations of the large majority of studies informing us on the characteristics and behavior of breast cancer in young women include the retrospective nature of the data collected and the heterogeneity of commonly “outdated” treatment regimens.

In sum and consistent with guidelines set forth by the FDA, ASCO, and the National Comprehensive Cancer Network, patients across the entire age spectrum with early-stage, HER2-positive breast cancer should be considered for chemotherapy/trastuzumab

Compelling New Data

since they derive equivalent benefit from combination therapy.

Perhaps the next most relevant questions after reviewing this important analysis are: (1) how do these results correlate with prior reports? and (2) how do these results affect clinical care moving forward?

was no significant difference in recurrence-free survival by age (P = .42).

Taken together, these data are consistent with and supportive of the findings of Partridge et al that age was not strongly associated with risk of early recurrence or prediction of benefit from trastuzumab therapy.

Looking Back

Looking Ahead

With regard to the first question, several studies have addressed agerelated differences in gene expression and prognosis by breast cancer subtype, including the HER2-positive subset. Specifically, a large-scale genomic analysis of over 750 primary breast cancers initially identified over 350 gene sets unique to breast cancers arising in a younger host (≤ 45 years of age as compared to those aged ≥ 65 years) in a non–subtypespecific manner.3 More recently, these data were reexamined and showed that age-specific gene expression differences were negligible when corrected for intrinsic breast cancer subtype and other significant prognostic factors (ie, hormone receptor status, grade, etc).5 Moreover, Azim et al examined the prognostic effect of age among approximately 3,000

Moving forward, there are several points to consider. Breast cancer is a disease of aging, with a median age at diagnosis of 61 years.7 As such, one may choose to look at these data from the other side of the age spectrum— ie, that women aged > 40 years, including elders with adequate cardiac reserve, derive similar benefit from chemotherapy and trastuzumab as their younger counterparts.

Additional information that is not apparent from the body of work on age and breast cancer includes the response by age to newer HER2directed agents, including lapatinib (Tykerb), ado-trastuzumab emtansine (Kadcyla), and pertuzumab (Perjeta), and whether younger women with estrogen receptor–positive and/or triple-negative breast cancer derive similar benefit from anticancer

Partridge et al sought to ask a very relevant question in a recent study published in the Journal of Clinical Oncology in the context of the Herceptin Adjuvant (HERA) Trial: Is age a prognostic and/or predictive factor among over 3,000 patients with early-stage, HER2-positive breast cancer treated with chemotherapy with or without trastuzumab (Herceptin)?4 Perhaps the most compelling and clinically relevant results of this analysis were that (1) age, as either a dichotomous (≤ 40 vs > 40 years) or continuous variable was not prognostic for disease-free survival or overall survival in the chemotherapy/trastuzumab treatment arm; (2) age was not an independent prognostic factor (for disease-free or overall survival) among patients treated with chemotherapy/trastuzumab; and (3) age was not a predictive factor for trastuzumab benefit.

Dr. Anders is Assistant Professor of Medicine and Co-Director, UNC Brain Metastases Specialty Clinic, Division of HematologyOncology, University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center

patients with early-stage breast cancer and found that patients aged ≤ 40 years (compared with those aged > 40 years) experienced significantly worse recurrence-free survival (P < .0001).6 When the subset of only HER2-positive patients (n = 432) was examined, there

Perhaps the next most relevant questions are: (1) how do these results correlate with prior reports? and (2) how do these results affect clinical care moving forward?

—Carey K. Anders, MD

agents (ie, endocrine therapy and/or chemotherapy). Moreover, we will need to assess the effect of age on response to newer small-molecule targeted agents on the horizon (ie, PI3K inhibitors, mTOR inhibitors).

These questions provide fertile areas for research as we continue to close the gap in reducing the impact of age on breast cancer prognosis and improve our ability to provide optimal therapy. n

Disclosure:Dr. Anders reported potential conflicts of interest.

no

References 1. Colleoni M, Rotmensz N, Robertson C, et al: Very young women (<35 years) with operable breast cancer: features of disease at presentation. Ann Oncol 13:273-279, 2002.

2. Carey LA, Perou CM, Livasy C, et al: Race, breast cancer subtypes and survival in the Carolina Breast Cancer Study. JAMA 295:2492-2502, 2006.

3. Anders CK, Hsu D, Broadwater G, et al: Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancer with shared patterns of gene expression. J Clin Oncol 26:3324-3330, 2008.

4. Partridge AH, Gelber S, Piccart-Gebhart MJ, et al: Effect of age on breast cancer outcomes in women with human epidermal growth factor receptor 2-positive breast cancer: Results from a Herceptin adjuvant trial. J Clin Oncol. June 10, 2013.

5. Anders CK, Fan C, Parker JS, et al: Breast carcinomas arising at a younger age: Unique biology or a surrogate for aggressive intrinsic subtypes? J Clin Oncol 29:e18-e20, 2011.

6. Azim H, Michiels S, Bedard PL, et al: Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res 18:13415-1351, 2012.

7. Howlader N, Noone AM, Krapcho M, et al: SEER Cancer Statistics Review, 1975-2010, National Cancer Institute, Bethesda, Maryland. Based on November 2012 SEER data submission, posted to the SEER website April 2013.

Available at http://seer.cancer.gov/ csr/1975_2010. Accessed July 17, 2013.

ASCOPost.com | AUGUST 15, 2013

PAGE 61

Issues in Oncology Health-care Policy

AACR Cautions Diminished NIH Funding Jeopardizes Ability to Eradicate Cancer Health Disparities

R

ecently the American Association for Cancer Research (AACR) hosted a congressional briefing to highlight the significance of federally funded biomedical research in improving our understanding of cancer health disparities and developing targeted interventions to eliminate them.

fective strategies for eliminating the disparities in cancer that represent a major public health problem in our country,” said William G. Nelson,

MD, PhD, Director of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and past Co-Chair of the AACR’s International Confer-

ence on the Science of Cancer Health Disparities. “Restoring funding to the NIH and NCI is vitally important ... to eliminate cancer health disparities.” n

Margaret Foti, PhD, MD (hc)

William G. Nelson, MD, PhD

Disproportionate Burden on Minorities and Underserved “Even though cancer research has enabled tremendous advances against cancer, more than 1.6 million Americans will be diagnosed with this terrible disease this year, and a disproportionate amount of the suffering and deaths due to cancer will fall on racial and ethnic minorities, the poor, and the medically underserved,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. “The AACR is committed to eliminating cancer health disparities by fostering research into their underlying causes. This briefing highlights the reason why it is important that the administration and Congress provide sustained funding increases to the federal agencies, including the NIH and the NCI, that are integral to ensuring health equity for all patients with cancer.”

“The decline in funding for NIH and NCI could not come at a worse time because the opportunities have never been greater for turning our growing scientific knowledge into ef-

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PAGE 62

Journal Spotlight Molecular Biology

Whole-exome Sequencing of NCI-60 Cell Line Panel Provides Genomic Resource for Cancer Biology and Pharmacology

By Matthew Stenger

T

he NCI-60 cell lines, which represent cancers of the lung, colon, brain, ovary, breast, prostate, and kidney, as well as leukemia and melanoma, are the most frequently studied human tumor cell lines in cancer research and have generated the most extensive

Ogan D. Abaan, PhD

cancer pharmacology database worldwide. As recently reported by Ogan D. Abaan, PhD, postdoctoral fellow at the National Cancer Institute, and colleagues in Cancer Research, NCI investigators have performed a comprehensive analysis of coding variants in the NCI-60 panel identified by wholeexome sequencing.1 This work provides a list of possible cancer-specific variants for use by the research community and identifies pharmacogenomic correlations between specific variants in cancer-related genes and anticancer agents as an illustration of how such data can be used to generate and validate hypotheses for therapeutic strategies. Some of the basic and representative findings in this research effort are described below.

Genomic Variants The whole-exome sequencing variants identified in the NCI-60 lines were divided into two groups: type I variants (> 1.2 1.2 million) corresponding to common (and possibly germline) variants and type II variants (60,005) enriched for acquired cancer-specific variants.

The overall pattern of mutation was divergent among cell lines, ranging from 172 to 9,205 type II variants.

Cell lines with known microsatellite instability had very high type II variant counts, although the colon cancer cell line HCC2998, which is not known to have microsatellite instability, had the highest number of type II variants. In contrast to known microsatellite instability cell lines, nearly all of these variants were single-

nucleotide variants, suggesting that the hypermutation arises from a non–microsatellite instability mechanism.

HCC2998 harbors a POLE exonuclease domain missense variant coding for a P286R mutation in POLε.

Other data indicate that impaired POLε proofreading results in a high rate of single-nucleotide substitutions and increased tumor formation, and POLE mutations have been reported in colorectal cancer. HCC2998 thus seems to exemplify this phenomenon—providing a tool for further research and exemplifying the utility of the whole-exome sequencing data.

Analysis of the NCI-60 wholeexome sequencing variants according to gene mutations already present in the Catalogue of Somatic Mutations in Cancer (COSMIC) database showed that most of the variants in the 10 most frequently mutated genes are already annotated in COSMIC, but numerous novel variants in the 10 genes were also observed. Absence of normal tissue

for each gene with at least five cell lines containing a type II variant. TP53, the most frequently mutated gene in the NCI-60 panel, showed strong correlation with drug response. MDM2 inhibitors were effective in cell lines with wild-type p53, with two clinically relevant MDM2 inhibitors (including nutlin-3) showing the greatest negative correlation with mutant p53.

In contrast, another compound (NSC-670177) showed significant selectivity for p53 mutant cells. However, the compound known as RITA (NSC-652287), initially identified as a DNA cross-linking agent, showed little evidence of selective activity in p53 wild-type cell lines status and limited correlation with nutlin-3 activity.

These findings raise doubt about claims that RITA acts specifically as a p53-reactivating compound and that it could potentially be useful for induction of tumor cell apoptosis.

As an example of how the entire NCI-60 database can be used for que-

New NCI-60 Cell Line Analysis ■ The research effort provides a comprehensive analysis of coding variants in the NCI-60 cell line panel identified by whole-exome sequencing, providing a list of possible cancer-specific variants.

■ The study also identifies pharmacogenomic correlations between specific

variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and anticancer agents such as nutlin, vemurafenib, erlotinib, and bleomycin, showing how the data can be used to validate and generate novel hypotheses for further investigation.

makes it impossible to validate these variants as somatic, but they are also not found in other established databases.

Pharmacogenomic Analyses In addition to mutational data, the study provides drug sensitivity data for tens of thousands of compounds.

It profiles the influence of specific variants for TP53, BRAF, KRAS, NRAS, PIK3CA, PTEN, and ERBBs on response to clinically relevant targeted agents (nutlin, vemurafenib [Zelboraf], selumetinib, hypothemycin, rapamycin, wortmannin, perifosine, erlotinib [Tarceva], afatinib [Gilotrif], lapatinib [Tykerb], and neratinib) and identifies aspects of the findings that merit further investigation.

For example, in one set of studies, activity of compounds was assessed

rying drug response parameters, the investigators cited analysis of the EGFR inhibitor erlotinib, which has activity that is highly correlated with gefitinib (Iressa) and lapatinib in the NCI-60 panel. Overall, high expression of EGFR and ERBB2 were determinants of NCI60 cell line response to erlotinib.

However, the colon and central nervous system cell lines were generally insensitive to erlotinib despite high EGFR and ERBB2 expressions. This can be explained by taking into account mutations in the MAPK or PI3K pathways, a common mechanism of resistance, which are present in all seven colon and four of six central nervous system NCI-60 cell lines.

Potential Effects of Common Variants on Drug Response As noted by the investigators, the

power of whole-exome sequencing (ie, instead of focused sequencing of preselected genes) was also shown by the coincidental finding of a significant correlation between a germline in-frame deletion (delCAATGT) in ATAD5 in some cell lines and the increased sensitivity of these lines to the DNA-damaging agent bleomycin and bleomycin analogs—a finding showing that common variants in the human population may have a significant effect on drug response. ATAD5 is essential for maintaining genome stability and is known to be mutated in endometrial cancer.

Genotype calls identified 10 cell line heterozygous (5) or homozygous (5) for the delCAATGT deletion, 3 of which are renal cell lines (ACHN, CAKI-1, RXF393) in which early studies suggest activity of dimethane sulfonate analogs. It was also observed that additional germline variants in ATAD5 are present exclusively in the same 10 cell lines.

In searching possible haplotypes in the HapMap database, the investigators discovered a region of linkagedisequilibrium spanning more than 300 kb. They noted, “[T]his particular haplotype could be a response modifier during chemotherapy with DNA-damaging agents. These results illustrate the discovery potential of exonic variant data when integrated with previously available NCI-60 databases.”

The investigators concluded: “As new cancer genes are identified through large-scale sequencing studies, the data presented here for the NCI-60 will be an invaluable resource for identifying cell lines with mutations in such genes for hypothesis-driven research. To enhance the utility of the data for the greater research community, the genomic variants are freely available in different formats and from multiple sources including the CellMiner [discover. nci.nih.gov/cellminer] and Ingenuity [www.ingenuity.com] websites.” n Disclosure: For full disclosure of the study authors, visit cancerres.aacrjournals.org.

Reference 1. Abaan OD, Polley EC, Davis SR, et al: The exomes of the NCI-60 panel. Cancer Res 73:4372-4382, 2013.

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Astellas and the Flying Star logo are trademarks of Astellas Pharma Inc. Tarceva is a trademark of OSI Pharmaceuticals, LLC, Farmingdale, NY 11735, USA, an affiliate of Astellas Pharma US, Inc. Š2013 OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc., and Genentech, Inc. All rights reserved. 013E-071-8094 TAR0001879200 5/13

The ASCO Post | AUGUST 15, 2013

PAGE 64

Global Perspective Health-care Disparities

Program Aims to Overcome Barriers to Early Cancer Care in Colombia

By Armando Sardi, MD, FACS, and Rachel Joseph, MPH

A

ccording to a report from the International Agency for Research on Cancer’s GLOBOCAN project, one woman dies every minute from breast cancer and one woman dies every 2 minutes from cervical cancer.1 The majority of these deaths occur in developing countries, where access to health care is limited and continuity of care is poor.2 Colombia is no exception. There, breast cancer and cervical cancer are the two leading causes of cancer-related death in women.2-4

ly mobilized to meet the needs of all women requiring cancer care.

In response to this need in Cali, Partners for Cancer Care and Prevention, a 501(c)3 nonprofit organization based in Baltimore, launched its women’s health program in 2011. Using data from epidemiologic research,

The implications of late diagnosis are grave, including threats to family stability and socioeconomic viability as well as notable increases in mortality. The potential for improved outcome by providing early diagnosis and expedient treatment is significant.

Cali, Colombia Poverty is related to inferior cancer outcomes.5 Cali, the third largest city in Colombia, is home to more than 2,500,000 individuals; 40% live in poverty.6,7 In Cali, 20 women per 100,000 are diagnosed with cervical cancer annually, an incidence twice that in the United States. Eight women per 100,000 die annually from cervical cancer, 4.5 times greater than mortality rates in the United States.1,8 Breast cancer also presents a significant threat. In Cali alone, 48 women per 100,000 are diagnosed annually, and 13.7 women per 100,000 die each year (30% higher than the national death rate).1,9 The incidence of breast cancer in Colombia is not greater than in the United States; however, Colombian women are diagnosed with advanced disease twice as often as North American women.1,10 The implications of late diagnosis are grave, including threats to family stability and socioeconomic viability as well as notable increases in mortality.11,12 The potential for improved outcome by providing early diagnosis and expedient treatment is significant.

A 2011 ruling by the Colombian government ensures that all Colombian women (regardless of income) are guaranteed state-sponsored health coverage.13 However, the existing health infrastructure is not adequateDr. Sardi is Chief of Surgical Oncology and Director of The Institute for Cancer Care at Mercy Medical Center, Baltimore. He is also President and Co-founder of Partners for Cancer Care and Prevention, formerly known as the United Hands for Health Foundation.

Ms. Joseph is Executive Director of Partners for Cancer Care and Prevention.

health literacy, limited financial resources, and insufficient knowledge of the HMO system that authorizes care constitute major obstacles. As a result, many do not enter into care until their cancer is advanced and requires more expensive and invasive intervention.

Impaired Patient Flow: More than

—Armando Sardi, MD, FACS, and Rachel Joseph, MPH

the group created a baseline profile of the sociodemography of prospective breast health patients in Cali (see sidebar). The organization then assessed the barriers to timely access, early detection, and high-quality treatment services, and created a plan of action, as highlighted below.

Barriers to Care Physician Training: Each year, Colombia trains only a small number of surgical and medical oncologists. The number of trainees is not commensurate with the number of patients needing care. Moreover, regulations limit treatment of breast cancer patients by general surgeons.

Equipment Deficits/Customs Regulations: There is a limited supply of vital diagnostic equipment, including biopsy needles, a portable ultrasound to perform ultrasound-guided biopsies, and a gamma-detecting probe to perform sentinel node biopsies. In spite of this, Colombia’s national customs regulations prohibit importation of medical machinery over 5 years old.

Delayed Screening: Patients’ poor

24 months may elapse from screening mammography, diagnostic procedures, and reporting of test results to actual diagnosis and initiation of treatment.

Barriers to timely referral include: • Patient (vs provider) accountability for communication of screening and diagnostic test results • HMO denial of physician and patient petitions for treatment, and lengthy subsequent appeals processes • Poor communication between providers within the local referral network • Limited availability of providers, appointments, and equipment Deficient Histopathologic Reporting: Review of 49 cases revealed insufficiently standardized histopathologic reporting leading to a lack of information necessary for timely implementation of appropriate treatment. Hormone receptor status, margins, and grade of differentiation are frequently omitted from such reports.

Plan of Action Cali boasts a strong network of hospitals and health centers, local govern-

mental support of cancer control, and a mobilized private sector. These interests are collaborating with the support and coordination of our pilot program.

Partners for Cancer Care and Prevention and collaborators have set clear pilot goals. In 2013, the team aims to provide 100% of women needing breast cancer diagnostic services with prompt, accurate diagnoses and linkage to care. Strategies include: Patient Navigation: The pilot facility provides a critical point of entry into the health system for socioeconomically marginalized women. In 2013, Partners for Cancer Care and Prevention secured grant support from the Susan G. Komen Foundation to launch a patient navigation pilot initiative (which began in July 2013) to improve continuity and quality of breast cancer care and ensure that no woman who enters the facility for breast health services is lost to follow-up between screening, diagnosis, and treatment.

Knowledge gained will be used to enhance treatment initiation, adherence, and success.

Facility Capacity: Partners for Cancer Care and Prevention, local hospital personnel, and local academic institutions have partnered to increase diagnostic and treatment skills of providers.

• Pathology: Based on international pathology reporting standards, local protocols for specimen collection, preparation, and documentation were assessed and revised.14 In addition, five hospital bacteriologists were trained in rapid fine-needle aspiration quality checks. Followup review and training will occur in 6 months.

The GLOBOCAN Project

T

he International Agency for Research on Cancer developed the GLOBOCAN project to provide contemporary estimates of the incidence of, mortality, prevalence, and disability-adjusted life years (DALYs) from major type of cancers, at national level, for 184 countries of the world. For more information, visit http:// globocan.iarc.fr/

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PAGE 65

Global Perspective

• Health Professional Education: A week-long series of 21 breast disease management lectures was provided to hospital staff, including hands-on guidance in surgical/diagnostic techniques. In the coming year, Partners for Cancer Care and Prevention will support monthly remote grand rounds and training in evidence-based breast cancer management.

• Diagnostic/Treatment Capacity: Partners for Cancer Care and Prevention secured donations of medical supplies and equipment totaling $20,000 in 2012–2013, including a five-headed microscope for pathol-

ogist/cytologist quality control and training, which was donated to the partner facility for use in ongoing cancer program activities.

Program Needs Currently, Partners for Cancer Care and Prevention seeks: Educators: experienced nutrition, medical, nursing, and operations professionals with an interest in being a part of a replicable model program to sustain technical support and capacity-building efforts. The organization aims to fund one oncology fellowship based at the pilot site.

Research Partners: At both U.S.

Program Background

P

artners for Cancer Care and Prevention holds that early detection and high-quality treatment of breast and cervical cancer save lives. The organization exists to build community capacity for the creation of high-quality, holistic breast and cervical health programs managed by the local health establishment.

Two-phase Pilot Program In 2012, the staff of the oldest hospital in Colombia partnered with Calibased government and public health leaders and Partners for Cancer Care and Prevention to initiate a program to serve Cali’s poorest women. The organization’s ultimate goal is to replicate this women’s cancer pilot program in lowresource communities throughout Colombia and Latin America. Design and implementation are ongoing in two phases: Phase 1 will tackle breast health (March 2013), and phase 2, cervical health (October 2013).

In preparation, Partners for Cancer Care and Prevention and hospital staff engaged in epidemiologic research to assess feasibility and appropriateness of future interventions. Data collection included 105 sociodemographic surveys of patients requesting breast health services, 3 key-informant interviews of hospital breast health program leadership, 1 key-informant interview of a community-based patient navigator, and a review of 49 randomly selected histopathologic reports of breast cancer cases assessed at the partner hospital.

Patient Population Profile Of 105 women completing a 30-item questionnaire (convenience sample), 80% had children, and 40% had three or more. Nearly half had only primary school education, and 70% were unemployed. More than 20% ceased working as a consequence of disease progression.

About 25% reported a family history of breast cancer. Sixty-nine percent had physical symptoms of breast disease prior to receiving their first mammogram, with 38% reporting two or more symptoms (nipple discharge, breast mass, peau d’orange, breast pain). n

and Colombian academic institutions to document and disseminate program activities to advance knowledge on a broader scale.

Sponsors: Partners for Cancer Care and Prevention currently has partnerships with ReNew Life and the Susan G. Komen Foundation. The group welcomes interested corporate and independent partnership opportunities. n Disclosure: Dr. Sardi and Ms. Joseph reported no potential conflicts of interest.

References

1. International Agency for Research on Cancer: The GLOBOCAN project. Available at http://globocan. iarc.fr. Accessed July 23, 2013.

2. American Cancer Society: Global Cancer Facts and Figures, 2nd ed.

Atlanta, American Cancer Society, 2011. Available at www.cancer.org.

Accessed July 23, 2013.

3. Forouzanfar MH, Foreman KG, Delossantos AM, et al: Breast and cervical cancer in 187 countries between 1980 and 2010: A systematic analysis.

Lancet 378:1461-1484, 2011.

4. Piñeros M, Gamboa O, Hernández-Suárez G, et al: Patterns and trends in cancer mortality in Colombia 1984-2008. Cancer Epidemiol 37:233-239, 2013.

5. Knaul FM, Frenk J, Shulman L, for the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries: Closing the Cancer Divide: A Blueprint to Expand Access in Low and Middle Income Countries. Boston, Harvard Global Equity Initiative, October 2011.

6. Populations, CO: The population of Cali, Colombia. Available at http://populations.co/populationsby-city/city-populations/cali/. Accessed July 23, 2013.

7. DANE: Boletin: Censo general 2005, perfil Cali, Valle del Cauca.

2010. Available at www.dane.gov.co.

Accessed July 23, 2013.

8. Universidad del Valle: Registro Poblacional de Cáncer de Cali, Colombia; C53, Cuello Uterino. 2008.

Provided by Fundación Hemato— Oncólogos, Cali, Colombia.

9. Universidad del Valle: Registro Poblacional de Cáncer de Cali, Colombia; C50, Mama. 2008. Provided

by Fundación Hemato—Oncólogos, Cali, Colombia.

10. Piñeros M, Sánchez R, Cendales R, et al: Patient delay among Colombian women with breast cancer.

Salud Pública de México 51(5):372380, 2009.

11. Williams-Brennan L, Gastaldo G, Cole DC, et al: Social determinants of health associated with cervical cancer screening among women living in developing countries: A scoping review. Arch Gynecol Obstet 286:14871505, 2012.

12. De Boer AGEM, Taskila T, Ojajarvi A, et al: Cancer survivors and unemployment: A meta-analysis and metaregression. JAMA 301:753-762, 2008.

13. Guerrero R, Amarís AM: Financing cancer care and control: Lessons from Colombia. Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries Working Paper and Background Note Series, No. 1, Harvard Global Equity Initiative, 2011.

14. Lester SC, Bose S, Chen YY, et al: Protocol for the examination of specimens from patients with invasive carcinoma of the breast. College of American Pathologists. Available at http://www.cap.org. Accessed July 23, 2013.

For more information about Partners for Cancer Care and Prevention, please visit the organization’s website (pfccap.org) or e-mail either Executive Director Rachel Joseph (rjoseph@pfccap. org) or President and Co-founder Dr. Armando Sardi, Director of the Institute for Cancer Care and Chief of Surgical Oncology at Mercy Medical Center, Baltimore (asardi@mdmercy.com).

Download The ASCO Post iPad App FREE from iTunes today!

The ASCO Post | AUGUST 15, 2013

PAGE 66

Announcements

American Association for Cancer Research Foundation Appoints New Executive Director

T

he American Association for Cancer Research (AACR) recently announced the appointment of Mitchell R. Stoller as Executive Director of the AACR Foundation for the Prevention and Cure of Can-

Mitchell R. Stoller

cer. In his role, Mr. Stoller will lead strategy and work closely with the AACR Foundation Board of Trustees to manage the development and expansion of fundraising and program activities for the foundation.

Decades of Experience Mr. Stoller has been dedicated to solving complex strategic challenges for a number of nonprofit organizations for three decades, including the Marrow Foundation (Be the Match) and the Lance Armstrong Foundation (LiveSTRONG). He currently serves on the Board of Directors of the LiveSTRONG Foundation.

“I am absolutely delighted that Mitch is joining the AACR. He brings to this important role more than 30 years of experience as a senior leader of not-for-profit organizations,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. “He has the vision to significantly expand and diversify the AACR Foundation’s donor base and create new and innovative philanthropic opportunities so that we can fund more urgently needed, groundbreaking cancer research.”

Mission to Accelerate Progress in Research “I am honored and excited to join the AACR to help lead its foundation,” said Mr. Stoller. “The mission of the AACR Foundation, to accelerate progress in the conquest of cancer by providing financial support for research, education, and communication, is vitally important at a

time when federal funding for cancer research is flat and the number of people receiving a cancer diagnosis is increasing every year. I look for-

ward to working with Dr. Foti, the foundation board of trustees, and my colleagues at the AACR to create new fundraising and public aware-

ness programs for the AACR, to expand and strengthen existing initiatives, and to help fund lifesaving cancer research.” n

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PAGE 67

Announcements

Michael J. Stamos, MD, Elected ASCRS President, Terry C. Hicks, MD, Chosen President-Elect

M

ichael J. Stamos, MD, Orange, California, was elected President of the American Society of Colon and Rectal Surgeons (ASCRS) at the

Societyâ&#x20AC;&#x2122;s Annual Meeting in Phoenix, succeeding Alan G. Thorson, MD, Omaha. Dr. Stamos is the John E. Connolly Professor and Chair of the

Department of Surgery at the University of California Irvine School of Medicine. He moved from the University of California, Los Angeles, faculty

Michael J. Stamos, MD

to the UC Irvine Medical Center in 2002 to establish the Division of Colon & Rectal Surgery.

Other new officers and members elected to serve on the organizationâ&#x20AC;&#x2122;s governing Executive Council are: Terry C. Hicks, MD, New Orleans, Louisiana, President-Elect: Dr. Hicks is Associate Chairman, Department of Colon and Rectal Surgery, Ochsner Clinic, New Orleans, and Clinical Professor of Surgery, LSU School of Medicine.

Martin A. Luchtefeld, MD, Grand Rapids, Michigan, Vice President. Dr. Luchtefeld is currently Chief of the Division of Colon and Rectal Surgery at the Spectrum Health Medical Group, Grand Rapids, Michigan.

Patricia L. Roberts, MD, Burlington, Massachusetts, Treasurer: Dr. Roberts is Chair of the Division of Surgery at Lahey Clinic and Professor of Surgery at Tufts University School of Medicine.

Elisa H. Birnbaum, MD, St. Louis, Missouri, Member-at-Large: Dr. Birnbaum is a Professor of Surgery at Washington University School of Medicine, St. Louis. She is also the Director of the Pelvic Floor Center in the Section of Colon and Rectal Surgery.

David A. Margolin, MD, New Orleans, Louisiana, Member-at-Large: Dr. Margolin is Director of Colorectal Research at the Ochsner Clinic, New Orleans. His professional interests include laparoscopic colon and rectal surgery, inflammatory bowel disease, complex anorectal conditions and incontinence.

Thomas E. Read, MD, Burlington, Massachusetts, Member-at-Large: Dr. Read is a senior staff surgeon in the Department of Colon and Rectal Surgery at the Lahey Clinic Medical Center in Burlington, Massachustts, and Program Director of the Residency in Colon and Rectal Surgery. He is Professor of Surgery at Tufts University School of Medicine. n

The ASCO Post | AUGUST 15, 2013

PAGE 68

Journal Spotlight Risk Factors

Infertility in Men Raises Their Risk for Cancer

By Jo Cavallo

A

cohort study of 2,238 men who were evaluated for infertility at a clinic in Texas from 1989 to 2009 found that those men who had azoospermia, a condition in which no measurable sperm is present, had a 2.2-fold higher cancer risk compared with those who were nonazoospermic. The study was published online in the journal Fertility and Sterility.1

Study Details In all, 451 men had azoospermia and 1,787 were not azoospermic (mean age at evaluation = 35.7 years). The researchers

found 29 cases of cancer, including testicular, prostate, and intestinal cancers, as well as lymphoma and melanoma, during an average follow-up of nearly 7 years.

The standardized incidence rate of cancer among infertile men was 1.7 times that of the general population, and when stratified by azoospermic status, men with azoospermia had substantially elevated risk of cancer (standardized incidence rate = 2.9). In contrast, men without azoospermia had an increased risk of 1.4 times that of men in the overall population.

Infertility, Azoospermia, and Cancer ■ Infertile men, especially men with azoospermia, had a greater risk of

developing cancer, including testicular, prostate, and intestinal cancers, lymphoma, and melanoma.

■ Between 10% and 15% of infertile men have azoospermia.

■ Infertility may signal other health problems, including cancer, and infertile men should maintain healthy habits and be monitored and possibly screened for diseases like cancer.

“There are some data [showing] that the defects in sperm production are also seen in cancer syndromes, and based on that hypothesis, we linked the men in the cohort to the Texas Cancer Registry to see if the cancer incidence was higher in these azoospermic men than in nonazoospermic infertile men,” said Michael Eisenberg, MD, Assistant Professor of Urology at the Stanford School of Medicine and lead author of the study. According to Dr. Eisenberg, between 10% and 15% of infertile men will have azoospermia.

Infertility May Signal Other Health Problems Infertility may signal other health problems. Infertile men should be vigilant about maintaining healthy lifestyles and be monitored and possibly screened for diseases like cancer, said Dr. Eisenberg.

“As our understanding of azoospermia and cancer increases, we can target

Michael Eisenberg, MD

some of these men to undergo genetic screenings and, hopefully, identify the ones at greatest risk [for developing cancer]. Unfortunately, this [understanding] is just in its infancy,” said Dr. Eisenberg. n

Disclosure: Dr. Eisenberg reported no potential conflicts of interest. For full disclosures of all study authors, visit www.fertstert.org.

Reference 1. Eisenberg ML, Betts P, Herder D, et al: Increased risk of cancer among azoospermic men. Fertil Steril. June 24, 2013 (early release online).

Advocacy

News

TV Celebrity Valerie Harper Joins Lung Cancer Foundation in Raising Awareness

A

ctress and lung cancer advocate Valerie Harper and her husband Tony Cacciotti joined other lung cancer advocates and supporters recently at the Lung Cancer Foundation of America’s “Day at the Races” at the Del Mar Race Track in Del Mar, California. Ms. Harper is currently fighting lung cancer that has occurred in the lining of her brain.

A Forgotten Cancer Kim Norris, a lung cancer widow and the President and cofounder of the Lung Cancer Foundation of America (LCFA), said lung cancer is a forgotten cancer, and because of an overall 5-year survival rate of only 15%, there are few survivors to stand up and speak out in support of research funding for the disease. “Val and Tony’s participation in the fight against lung cancer means so much to people affected by lung cancer,” she said.

LCFA’s Day at the Races helped to educate the public about lung cancer and featured a special “Breath Of Life” race to support lung cancer research.

The poor survival rate for lung cancer

is a direct result of the lack of funding for lung cancer research. It is estimated that 60% of new lung cancer diagnoses will be in nonsmokers—a combination of 45% to 50% former smokers (many who quit 10, 20, even 30 years prior to the onset of lung cancer) and 15% of people who have never smoked. Lung cancer is the only cancer that stigmatizes its victims, Ms. Norris said, adding that somehow society believes that lung cancer victims bring it upon themselves.

Poor State of Funding The Lung Cancer Foundation of America was established by two lung cancer survivors and a lung cancer widow. Working with many of the top lung cancer researchers and clinicians in the country, they have seen how lung cancer researchers are trying diligently to unlock the secrets unique to lung cancer.

They have also witnessed the inordinate amount of time researchers spend in an effort to secure money to pay for the research, an effort that distracts them from their primary research function.

From L to R: Kim Norris, President, Lung Cancer Foundation of America; Fred R. Hirsch MD, PhD, University of Colorado and Treasurer, International Association for the Study of Lung Cancer; Valerie Harper, actor and lung cancer advocate; Robert A. Figlin, MD, FACP, Cedars-Sinai Medical Center, Los Angeles, and Board Member, Lung Cancer Foundation of America. Photo credit: Samantha Norris.

According to the LCFA cofounders, the poor state of funding for lung cancer research also discourages new researchers, leaving a potential gaping hole in future lung cancer research programs.

LCFA’s mission is the dramatic improve-

ment in survivorship of lung cancer patients through the funding of transformative science, with the ultimate goal of curing the disease.

For more information, visit http:// www.lcfamerica.org. n

NOW ENROLLING A Phase 3 Trial for Newly Diagnosed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It is thought to target EGFRvIII, a constitutively activated deletion mutant that is found only in tumors. About a third of glioblastoma patients are found to express EGFRvIII, and its presence has been linked to poor long-term survival1-3 • ACT IV is an international, randomized, double-blind, controlled, phase 3 study of rindopepimut added to standard of care temozolomide in patients with newly diagnosed EGFRvIII-positive glioblastoma Rindopepimut Every 2 weeks x 2, then monthly

+

1:1 Randomization

Diagnosis/Resection Chemoradiation EGFRvIII-positive glioblastoma

Temozolomide Days 1-5 in 28 day cycle 6-12 cycles

Treat until tumor progression, intolerance, or withdrawal of consent

Blinded KLH Control Every 2 weeks x 2, then monthly

+

N=~440

Temozolomide Days 1-5 in 28 day cycle 6-12 cycles KLH=keyhole limpet hemocyanin.

Key Inclusion Criteria

Key Exclusion Criteria

• Newly diagnosed glioblastoma

• Evidence of metastatic disease, diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease

• Attempted resection followed by chemoradiation with temozolomide • Provide a tumor specimen which tests positive for EGFRvIII at the protocol specified central laboratory • ECOG PS ≤ 2, and dexamethasone ≤ 2 mg/day (or equivalent) for ≥ 3 days prior to randomization

• Other treatments for glioblastoma • Unequivocal progression during chemoradiation therapy Key Trial Endpoints: • Primary: Overall Survival (OS) • Secondary: Progression-free Survival (PFS)

ECOG PS=Eastern Cooperative Oncology Group Performance Status.

For more information visit glioblastomastudy.com and http://www.clinicaltrials.gov/show/NCT01480479 or e-mail info@celldextherapeutics.com.

1. Pelloski CE, Ballman KV, Furth AF, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. 2007;25(16):2288-2294. 2. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(31):4722-4729. 3. Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324-333. ©2013 Celldex Therapeutics, Inc.

All rights reserved.

6/13

JA

The ASCO Post | AUGUST 15, 2013

PAGE 70

Future of Oncology A Look Ahead: The Next Decade in Pediatric Oncology A Conversation with Michael P. Link, MD

By Jo Cavallo

Michael P. Link, MD

T

he past 10 years have seen dramatic advances in cancer care, especially in better screening methods and earlier detection, genomic sequencing, and more effective therapies, which have led to increased survival rates in both childhood and adult cancers. According to the National Cancer Institute (NCI), among adults, the 5-year relative survival rate for all cancers combined is about 68%, and among children, the 5-year relative survival rate for all childhood cancers combined is nearing 81%.1 The number of cancer survivors in the United States is also at an all-time high at nearly 14 million, and is expected to climb to almost 18 million by 2022.2 However, despite progress in survival rates, the incidence of children diagnosed with all forms of cancer, including difficult-to-treat brain malignancies, has risen from 11.5 cases per 100,000 children in 1975 to 14.8 per 100,000 children in 2004,3 necessitating the need for not just more effective therapies, but ones that are less toxic as well to mitigate potential late effects of cancer treatment.

The ASCO Post talked with Michael P. Link, MD, Past President of ASCO and the Lydia J. Lee Professor in Pediatric Cancer at Stanford University School of Medicine, about how pediatric oncology and longterm survivorship care might change over the next 10 years, resulting in not just more cures but in extended quality of life for young cancer survivors.

Advances to Come Which areas in pediatric oncology will see the greatest advances over the next decade?

First, we have to realize how well we’ve done. We are now curing close to 80% of children with cancer. We’ve made the greatest progress in leukemia and lymphoma and in solid tumors like Wilms tumor—the most common childhood kidney cancer.

However, there are several areas of concern. For example, we have not made as much progress as we would like in childhood brain tumors, which, in aggregate, are the most common solid tumors seen in children.

In neuroblastoma, one of the most common tumors seen in infants and toddlers, we cure many of the patients with early-stage disease, but patients with more advanced-stage disease are

and incorporation of new drugs that target those pathways characterize the direction of current research and will lead to better therapies in the future.

Reducing Late Effects Will progress be made in the ability to reduce the long-term side effects of treatment without jeopardizing potential cures?

Yes. In the management of some tumors we have been able to reduce the exposure to radiation, and in some cases, eliminate radiation entirely. One of the reasons for our focus on radiation is because of its effect on children’s growth and the risk of secondary solid malignancies. We have

These are the key advances I hope to see over the next decade in pediatric oncology: improvements in the molecular understanding of cancer, more targeted drugs with fewer toxicities, comprehensive survivorship care plans, a multidisciplinary approach to treating pediatric cancers, and a high rate of participation in clinical trials.

—Michael P. Link, MD

still a major challenge. Even with very intensive therapies, including bone marrow transplantation, the majority of those children still die.

Even where we have made progress in treating these tumors, the improvement in outcome has come at a high cost. For children with medulloblastoma, we have a much better understanding of the tumors and we are now curing more patients. But the cost in terms of long-term treatment effects is quite high, so we need better therapies with fewer long-term toxicities. Being cognizant of treatment side effects, particularly long-term effects, and improving on that by modifying our therapies has been a theme for the past couple of decades and will be a continuing theme in the next decade.

Finally, the incorporation of targeted therapies into treatment regimens has already resulted in better treatment for some difficult-to-treat childhood cancers. Improved understanding of childhood cancers on the molecular level, identification of molecular pathways that drive the cancer,

shown that where we have developed effective chemotherapeutic regimens, such as in lymphoma or Wilms tumor, we have been able to reduce the use of radiation without adversely affecting survival.

Similarly, we have designed successful regimens that reduce exposure to aklylating agents and anthracyclines to reduce the incidence of infertility and cardiomyopathy among survivors.

A big part of why we have been so successful in treating pediatric cancers is our understanding of the underlying molecular biology of these diseases and our ability to categorize patients into high-, low-, and intermediate-risk groups based on the molecular characterization of the tumor. That risk stratification is not ascertainable just from the histology of the cancer.

Acute lymphoblastic leukemia (ALL) is really the prototype for risk stratification. We now know that certain subtypes of the disease are associated with a very favorable prognosis,

and for those children, our strategy has been to try to figure out the minimum therapy necessary to cure them while reducing the long-term side effects.

At the other end of the spectrum, we have children with very high-risk subtypes of ALL. When we’ve used more intensive therapies to treat those patients, we’ve been able to cure many of them. The biology of the tumor on a molecular level often tells us a lot about the individual case and allows us to tailor treatment to the patient’s risk of treatment failure. So that is a paradigm we hope to apply to all of the pediatric cancers.

Cancer Causes Is there now a better understanding of the causes of childhood cancers?

A major hope in treating adult cancers is based on understanding the causes of those cancers and then using that information to do something about preventing them. But it doesn’t work that way in childhood cancers.

For example, many cases of childhood ALL actually begin in utero; thus, strategies for prevention would have to target the pregnant mother.

If we had convincing evidence that some environmental exposure was a key predisposing factor to the cancer, we could do something about that, but I don’t think there is much hope for that in the near future.

Key to the prevention of some childhood cancers is our understanding of cancer predisposition genes.

As we understand more about what makes people susceptible to cancers, we may be able to screen those people more carefully and detect cancers at an earlier stage, when they are more treatable.

There is probably more that pediatricians can do to prevent cancer in adults than to prevent childhood cancers. If we immunize children against hepatitis B and human papillomavirus, we can do a lot about preventing liver cancer, cervical cancer, and much of oropharyngeal cancer. I am not sure we have the same weapons to prevent any childhood cancers, unless and until we get a suitable vaccine against Epstein-Barr virus.

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PAGE 71

Future of Oncology Survivorship Care How might long-term survivorship care planning and surveillance be improved in the next decade for children with cancer?

This is a critical area because as we have more and more cancer survivors in the general population, they really need to be cared for appropriately. A key advance will be the development of a model of care for how best to do this.

For example, it would be good to have clinics that incorporate internists as well as pediatric oncologists on staff who can look at a person’s health-care history, including treatment for cancer. The problem with transferring a patient to a family practitioner after a child is cured of cancer is that the primary care practitioner may not understand the long-term ramifications of the childhood cancer and its treatment.

One way we are trying to improve care is by giving patients passports that they take with them after they leave our care, which outline the diagnosis and treatment exposures that

the patient has experienced, as well as the late effects the internist needs to look for based on the patient’s treatment regimen and what health screening tests might be appropriate.

Hopefully, widespread use of electronic medical records will help make certain that survivors get more appropriate care.

Hallmarks of Pediatric Care How does cancer care for children and young adults differ from cancer care for older adults, and how might that change over the next 10 years?

One of the programs we have pioneered is a very comprehensive family-centered, multidisciplinary approach to treating pediatric cancers, which is now becoming the standard for adult medical oncology as well. In the past, patients saw different practitioners at different times, but it is a model that pediatricians abandoned a long time ago. Now, patients are seen by all of the specialists right from the start, and a therapy plan is agreed on, with all of the physicians involved in

the decision-making together as opposed to sequentially. That has become one of the hallmarks of pediatric cancer care.

A second hallmark is the importance of participation in clinical trials, and this is a major factor underpinning the progress we have made in pediatric cancers. I hope that those elements will continue.

I also hope that children—and adolescents and young adults—are referred to cancer centers that provide the most comprehensive care for their specific types of cancer. These patients could do better if they get the right therapy in the right place, as well as supportive care appropriate to their psychosocial needs. That’s another area to be targeted in the future.

In summary, these are the key factors I hope to see over the next decade in pediatric oncology: improvements in the molecular understanding of cancer, more targeted drugs with fewer toxicities, comprehensive survivorship care plans, a multidisciplinary approach to treating pediatric can-

cers, and a high rate of participation in clinical trials.

One other element essential to improved cancer care is the importance of research funding for progress against childhood cancers. Although we cure the majority of children with cancer, I do not want people to think that we have solved the problem of pediatric cancers. We haven’t. n

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

References 1. National Institutes of Health: Yesterday, Today & Tomorrow: NIH Research Timelines. Available at http:// report.nih.gov/nihfactsheets/default. aspx?csid=75. Accessed July 19, 2013.

2. National Cancer Institute: Cancer Survivorship Research/Cancer Control and Populations Sciences: Survivorshiprelated statistics and graphs. Available at cancercontrol.cancer.gov/ocs/prevalence. Accessed July 19, 2013.

3. National Cancer Institute FactSheet: Childhood cancers. Available at cancer.gov/cancertopics/factsheet/sitestypes/childhood. Accessed July 19, 2013.

Psychosocial Oncology

News

Study Evaluates Post-Traumatic Stress Symptoms in Young Adults with Cancer

R

esearchers at the University of Michigan recently reported that young adults with cancer should try to stay occupied with school, work, and other usual activities during the year after their cancer diagnosis to become less vulnerable to post-traumatic stress symptoms.

The study was recently reported in Psycho-Oncology.1

and principal investigator Brad Zebrack, PhD, MSW, MPH, of the School of Social Work at the Univer-

Overview of Study Researchers surveyed 215 adolescents and young adults with cancer to address the challenges in coping with a life-threatening illness and treatment. At 6 and 12 months, respectively, 39% and 44% reported moderate to severe levels of psychological distress.

Few studies have examined the prevalence and predictors of post-traumatic stress symptoms in young adults.

Lead study author Minyoung Kwak

Brad Zebrack, PhD, MSW, MPH

sity of Michigan in Ann Arbor, Michigan, assessed post-traumatic stress symptoms among respondents ages 15 to 39 years at 6 and 12 months following their cancer diagnosis.

The study’s participants answered questions about their backgrounds and the frequency and severity of symptoms.

Early Screening for Psychological Distress Important Ms. Kwak noted the elevated levels of post-traumatic stress symptoms among young cancer patients occurred during the first 6 months postdiagnosis, but did not change significantly six months later.

Previous research in older adults has indicated that post-traumatic stress symptoms decreased within a relatively short period. The recent findings in young adults were consistent with studies indicating that a greater proportion of adolescent and young adult cancer patients experience psychological distress when compared to older adults with cancer.

These findings also revealed that those who maintained employment or school attendance after diagnosis experienced significantly lower levels of post-traumatic stress symptoms at

the 12-month follow-up compared to those who were unemployed or not in school.

“Remaining occupied in school or work may provide adolescents and young adults with a social support system and sense of control over their lives that serves to buffer the traumatic aspects of cancer and its treatment,” Ms. Kwak said. The findings, she said, emphasize the importance of early screening and intervention for psychological distress among young cancer patients. n Disclosure: Ms. Kwak and Dr. Zebrack reported no potential conflicts of interest.

Reference 1. Kwak M, Zebrack BJ, Meeske KA, et al: Prevalence and predictors of posttraumatic stress symptoms in adolescent and young adult cancer survivors: A 1-year follow-up study. Psycho-Oncology 22(8): 1798-1806, 2013.

To prevent SREs in patients with BREAST CANCER and bone metastases

vs zoledronic acid

Better prevent SREs1 MEDIAN TIME TO FIRST SRE IN BREAST CANCER1*

27 26.4 At

Months (study end)

median time not yet reached

Months

XGEVA® 120 mg Q4W (n = 1,026)

XGEVA® acts precisely to bind RANK Ligand, a key mediator of bone resorption, and inhibit osteoclast formation, function, and survival1

zoledronic acid 4 mg Q4W (n = 1,020)

HR = 0 0.82; 82; P = 0 0.010, 010 0 superiority

• XGEVA® reduced the risk of first SRE by 16% vs zoledronic acid in patients with other solid tumors or multiple myeloma (P < 0.001, noninferiority; P = 0.060, NS for superiority)1* XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma Convenient 120 mg subcutaneous injection administered once every 4 weeks1 Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia1 Approximately 70% of patients are expected to have $0 out-of-pocket cost for XGEVA®2† *Data from the international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046) and in patients with bone metastases from other solid tumors (excluding breast and prostate cancer) or multiple myeloma (N = 1,776). The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.1 † Estimated amount of Medicare beneficiaries with supplemental coverage and commercially insured patients with no OOP cost; based on XGEVA® payor mix and coverage of XGEVA® and other similar products. Does not include costs related to office visit, physician, staff, or administrative charges associated with administering XGEVA®.

INDICATION XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATION Hypersensitivity • XGEVA is contraindicated in patients with clinically significant hypersensitivity to any component of the product. ®

Hypocalcemia • XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct preexisting hypocalcemia prior to XGEVA® treatment.

Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels.

Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ) • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion.

Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®.

Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. A number of reports note that patients were also receiving treatment with glucocorticoids at the time of fracture. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Interruption of XGEVA® therapy should be considered, pending a risk/ benefit assessment, on an individual basis.

Pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. XGEVA® (denosumab) prescribing information, Amgen. 2. Data on file, Amgen.

©2013 Amgen Inc. All rights reserved. 2/13 72978-R1-V1 www.XGEVA.com

S:9.5”

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information).

DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

CONTRAINDICATIONS: Hypersensitivity. Xgeva is contraindicated in patients with clinically significant hypersensitivity to any component of the product (see Adverse Reactions).

WARNINGS AND PRECAUTIONS: Hypocalcemia. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels.

In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva (see Adverse Reactions). These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture.

Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis.

PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth (see Use in Specific Populations). There are no adequate and well controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. 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.

are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva.

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone a Table 1. Per-patient Incidence of Selected Adverse Reactions of Any Severity growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth (Trials 1, 2, and 3) malalignment; and decreased neonatal growth. At birth out to one month of age, infants Xgeva Zoledronic Acid had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and Body System n = 2841 n = 2836 strength returned to normal; there were no adverse effects on tooth eruption, though % % dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; GASTROINTESTINAL and minimal to moderate mineralization in multiple tissues was seen in one recovery Nausea 31 32 animal. There was no evidence of maternal harm prior to labor; adverse maternal Diarrhea 20 19 effects occurred infrequently during labor. Maternal mammary gland development was GENERAL normal. There was no fetal NOAEL (no observable adverse effect level) established for Fatigue/ Asthenia 45 46 this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis INVESTIGATIONS and led to postnatal impairment of dentition and bone growth. Pregnant RANKL 18 9 Hypocalcemiab knockout mice showed altered maturation of the maternal mammary gland, leading Hypophosphatemiab 32 20 to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in NEUROLOGICAL full Prescribing Information).

Headache 13 14 Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, a decision should be made whether to discontinue nursing or discontinue the drug, 2, and 3, and meeting one of the following criteria: taking into account the importance of the drug to the mother. Maternal exposure • At least 1% greater incidence in Xgeva-treated patients, or to Xgeva during pregnancy may impair mammary gland development and lactation • Between-group difference (either direction) of less than 1% and more than based on animal studies in pregnant mice lacking the RANK/RANKL signaling 5% greater incidence in patients treated with zoledronic acid compared to pathway that have shown altered maturation of the maternal mammary gland, placebo (US Prescribing Information for zoledronic acid) leading to impaired lactation postpartum. However, in cynomolgus monkeys treated b with denosumab throughout pregnancy, maternal mammary gland development Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; (0.71 – 0.9 mmol/L) for phosphorus] however, development and lactation have not been fully evaluated (see Nonclinical Severe Mineral/Electrolyte Abnormalities Toxicology [13.2] in Full Prescribing Information).

• Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment of patients treated with zoledronic acid. Of patients who experienced severe with Xgeva may impair bone growth in children with open growth plates and hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) Use in Specific Populations). at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than eruption. Adolescent primates treated with denosumab at doses 5 and 25 times 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of (10 and 50 mg/kg dose) higher than the recommended human dose of patients treated with zoledronic acid.

120 mg administered once every 4 weeks, based on body weight (mg/kg), had Osteonecrosis of the Jaw abnormal growth plates, considered to be consistent with the pharmacological In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Warnings and Precautions). When events occurring during an extended treatment decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and phase of approximately 4 months in each trial are included, the incidence of mesenteric lymph nodes. Some bone abnormalities recovered once exposure was confirmed ONJ was 2.2% in patients who received Xgeva. The median time to ONJ ceased following birth; however, axillary and inguinal lymph nodes remained absent was 14 months (range: 4 – 25).

6 months post-birth (see Use in Pregnancy).

Postmarketing Experience. Because postmarketing reactions are reported Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) voluntarily from a population of uncertain size, it is not always possible to reliably were 65 years of age or older. No overall differences in safety or efficacy were estimate their frequency or establish a causal relationship to drug exposure. observed between these patients and younger patients.

The following adverse reactions have been identified during post approval use of Xgeva: Renal Impairment. In a trial of 55 patients without cancer and with varying • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. degrees of renal function who received a single dose of 60 mg denosumab, Immunogenicity. As with all therapeutic proteins, there is potential for patients with a creatinine clearance of less than 30 mL/min or receiving dialysis immunogenicity. Using an electrochemiluminescent bridging immunoassay, less were at greater risk of severe hypocalcemia with denosumab compared to than 1% (7/2758) of patients with osseous metastases treated with denosumab patients with normal renal function. The risk of hypocalcemia at the recommended doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to dosing schedule of 120 mg every 4 weeks has not been evaluated in patients 3 years tested positive for binding antibodies. No patient with positive binding with a creatinine clearance of less than 30 mL/min or receiving dialysis (see antibodies tested positive for neutralizing antibodies as assessed using a Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] chemiluminescent cell-based in vitro biological assay. There was no evidence of in full Prescribing Information). altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly OVERDOSAGE: There is no experience with overdosage of Xgeva. dependent on the sensitivity and specificity of the assay. Additionally, the observed HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. incidence of a positive antibody (including neutralizing antibody) test result may be Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. influenced by several factors, including assay methodology, sample handling, timing Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to of sample collection, concomitant medications, and underlying disease. For these temperatures above 25°C/77°F or direct light and must be used within 14 days. reasons, comparison of antibodies to denosumab with the incidence of antibodies Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous to other products may be misleading.

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted shaking of Xgeva.

RESPIRATORY Dyspnea Cough

21 15

18 15

PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva on findings in animals. In utero denosumab exposure in cynomolgus monkeys Advise patients that denosumab is also marketed as Prolia®. Patients should resulted in increased fetal loss, stillbirths, and postnatal mortality, along inform their healthcare provider if they are taking Prolia. with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva Amgen Manufacturing Limited, a subsidiary of Amgen Inc. in pregnant women. Women should be advised not to become pregnant when One Amgen Center Drive taking Xgeva. If this drug is used during pregnancy, or if the patient becomes Thousand Oaks, California 91320-1799 pregnant while taking this drug, the patient should be apprised of the potential ©2010-2013 Amgen Inc. All rights reserved. hazard to the fetus. Women who become pregnant during Xgeva treatment Printed in USA. 68257-R2-V2

with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There ADVERSE REACTIONS: The following adverse reactions are discussed below and was no evidence that various anticancer treatments affected denosumab systemic elsewhere in the labeling: exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 • Hypocalcemia (see Warnings and Precautions) months were not altered by concomitant chemotherapy and/or hormone therapy. The • Osteonecrosis of the Jaw (see Warnings and Precautions) median reduction in uNTx/Cr from baseline to month 3 was similar between patients The most common adverse reactions in patients receiving Xgeva (per-patient receiving concomitant chemotherapy and/or hormone therapy (see Clinical incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, Pharmacology [12.2] in full Prescribing Information). and nausea (see Table 1). The most common serious adverse reaction in patients USE IN SPECIFIC POPULATIONS: receiving Xgeva was dyspnea. The most common adverse reactions resulting in Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Xgeva can cause fetal harm when administered to a pregnant woman based 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 other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were

DOUS3X0360_TT_BC_AdTabloid_ISIUpdate_BS_r14.indd 1

3/19/13 5:07 PM

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Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy.

Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

ASCOPost.com | AUGUST 15, 2013

PAGE 75

Direct from ASCO

Philanthropy Spotlight

Conquer Cancer Foundation Grant Recipient ‘Pays It Forward’ Through Philanthropic Support, Volunteer Service

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r. Dawn Hershman, Associate Professor of Medicine and Epidemiology at Columbia University Medical Center and leader of the Breast Cancer Program at Herbert Irving Comprehensive Cancer Center, is committed to doing what she can to develop, encourage, and support the next generation of oncology researchers. She acts as a professional and scientific mentor to fellows and junior faculty, reviews and critiques grant applications from early-career researchers as a longtime volunteer on the Conquer Cancer Foundation Grant Selection Committee, and is a donor to the Conquer Cancer Foundation.

As she puts it, quite simply, “I cannot think of a better investment than contributing to someone’s future.”

Awards Have Catalyzing Effect on Careers Dr. Hershman’s first encounter with the Conquer Cancer Founda-

tion was as a fellow, when she received a Conquer Cancer Foundation of ASCO Merit Award, which allowed her to attend her first ASCO Annual Meeting. She received a Career Development Award (CDA) in 2002 and an Advanced Clinical Research Award (ACRA) in Breast Cancer in 2007, and went on to participate in ASCO’s Leadership Development Program in 2009.

“I am so grateful to the Conquer Cancer Foundation for the opportunities I have had as a result of the grants I have gotten… I feel that these awards helped me at critical points in my career, and I want to

give back to help others the same way,” she said. “I have also had the opportunity to be the mentor for junior faculty and fellows who have received grants from [the Conquer

Fueling the Next Generation of Oncology Leaders Dr. Hershman made her annual gift during ASCO’s Annual Meeting, which is always a weekend full of ex-

I feel that these awards helped me at critical points in my career, and I want to give back to help others the same way.

—Dr. Dawn Hershman

Cancer Foundation]. It is a thrill to see the excitement that these awards generate in the recipients.”

Being the recipient of a research grant from the Conquer Cancer Foundation can have a catalyzing effect on the career of the young physician-scientist who receives it.

Take the case of the Young Investigator Award (YIA), the Foundation’s flagship grant that provides one year of funding to an oncology researcher during the c h a l l e ng i ng transition from a fellowship to a faculty appointment.

The YIA often serves as springboard to help its recipient obtain additional funding for future work.

As Dr. Hershman explains, “For many investigators who want to have an academic career it is very difficult to get career development awards without preliminary data and a track record of funding. A YIA from [the Conquer Cancer Foundation] is a prestigious award and not only does it give the applicant time and resources to complete preliminary studies, it also is a way for fellows or junior faculty to ‘prove themselves,’” she said.

citement and enthusiasm for advances in the field of oncology. It is also a time when the impact of the Conquer Cancer Foundation’s Grants & Awards program, which this year is celebrating its 30th anniversary, is on full display.

“At ASCO, when you look at researchers [who] are presenting practice-changing results from clinical trials, many have been recipients of [Conquer Cancer Foundation] grants,” said Dr. Hershman.

A recent survey of more than 550 past recipients of Conquer Cancer Foundation YIAs and CDAs found that 98% remain in oncology research with 88% practicing in an academic setting. Over 80% said that their Conquer Cancer Foundation grant was what allowed them to continue to perform clinical research, and 99% of recipients said that their grant was important to advancing their careers.

“There has been so much prog-

ress in the treatment of cancer and we need well trained researchers to help continue the progress,” said Dr. Hershman.

Grant Selection Committee Dr. Hershman has volunteered on the Conquer Cancer Foundation’s Grant Selection Committee for 5 years and served as Chair for the 2012–2013 term. During that time she has seen hundreds of applications for the YIA and CDA award competitions, including a record number in 2013. “Every year I saw more and more outstanding applications, and every year fewer were funded because of a difficult funding environment,” she said. In 2013 the Foundation was able to award 48 YIAs, but those grantees represent only one in four applicants.

Her role on the committee gave Dr. Hershman an up-close view of what ASCO and the field of oncology was missing out on by leaving promising applicants unfunded due to lack of philanthropic support, and she posits a simple solution. “If every ASCO member gave a little bit, we would have been able to fund all of the outstanding grants that were submitted,” she said.

To make a donation to the Conquer Cancer Foundation, visit www .conquercancerfoundation.org/ donate. To learn more about becoming a volunteer on the Grants Selection Committee, email grants@ conquercancerfoundation.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO’s Guideline on Drugs to Lower Breast Cancer Risk

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irect your patients to www.cancer.net/whattoknow so they can learn about ASCO’s recent guideline on drugs to risk of breast cancer for women who have a high risk of developing the disease, including what the recommendations mean for patients and a list of questions to ask the doctor. In addition, patients can view

an infographic that provides a quick overview of this topic. n © 2013. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | AUGUST 15, 2013

PAGE 76

Direct from ASCO

Policy Update Aims to Advance Tobacco Cessation and Control Worldwide

I

n response to scientific advances and the evolving regulatory and policy environment, ASCO recently released an update to its 2003 policy statement on tobacco cessation and control. The statement reviews advancements that have been made since 2003 and outlines a refined set of recommendations based on current challenges and opportunities, including a strong call for oncology professionals to lead by example in combating the tobacco epidemic.

Overall, ASCO’s tobacco control efforts, led by a subcommittee of the Cancer Prevention Committee, aim to help the oncology workforce effectively integrate tobacco cessation and control into their practices, collaborate with other organizations and professional societies to reduce tobacco use and eliminate tobaccocaused disease worldwide, and encourage oncology providers to advocate for tobacco policy change.

Significant Public Health Concern Commenting on the state of tobacco control 10 years after ASCO’s last policy statement on the subject, Carolyn Dresler, MD, MPA, Chair of ASCO’s Tobacco Control Subcommittee and Associate Director

Carolyn Dresler, MD, MPA

for Medical and Health Science at the FDA Center for Tobacco Products, noted that “there are still too many tobacco-related cancer deaths.”

“Smoking rates in the developing world are escalating,” said James L. Mulshine, MD, of Rush University Medical Center and coauthor of the policy update. He added, “Every time a child begins smoking, the potential for adverse health effects are profound, lasting, expensive, debilitating, and tragic.”

In addition to its role as the larg-

est preventable cause of overall death and disability in developed countries, tobacco use is responsible for 30% of all cancer deaths and 80% of lung cancer deaths. It is also associated with an increased risk for at least 17 types of cancer. Moreover, studies have shown that continued tobacco use after cancer diagnosis compro-

James L. Mulshine, MD

mises the effectiveness of treatment by increasing the risk of treatmentrelated complications and a second primary cancer.

Despite the associated risks, tobacco use remains pervasive. Although cigarette use has declined in the United States, the use of tobacco products in general is increasing, particularly in developing countries.

Alarmingly, the rate of reduction of youth tobacco use is no longer rapidly decreasing. In the United States and around the world, the epidemic of tobacco-related disease and death is a growing concern.

In light of these statistics, the policy update calls upon oncologists to take ownership of the issue, recognizing the essential role oncology professionals have in preventing tobacco-related cancers and death, while increasing the effectiveness of cancer treatments.

An Achievable Goal A growing body of evidence shows that tobacco prevention and cessation programs deliver a great return on investment and can reduce rates of smoking and lung cancer.

The California Tobacco Control Program provides an innovative example of how states can implement tobacco control and cessation programs that have a real impact on smoking rates. California’s program, which could serve as a model to other states and the federal government,

uses a variety of methods to address tobacco cessation, including a mass media campaign to encourage smokers to quit, a telephone quitline and counseling services, and subsidized nicotine replacement therapy.

Additionally, the Tobacco Control Program encourages the implementation of smoking restrictions in worksites and public places, funds cessation programs at the local level, and encourages physicians and other health-care professionals to advise their patients to quit smoking and to provide referrals to cessation services.

Ten years after its inception, the California program produced significant results: Per capita cigarette consumption fell by 57% in California compared to only 27% in the rest of the United States. The evidence indicates that these efforts have had a significant impact on tobacco use prevalence.

The results of California’s tobacco control efforts provide a glimpse of the possibility for success. Although

Dr. Dresler noted that the state still has “a ways to go” in improving tobacco control, the California program “significantly altered the trajectory of lung cancer incidence, compared to the rest of the United States,” she said. “It showed that it can be done faster than people in oncology and public health thought was possible.”

ASCO Recommendations Recognizing the complexity of tobacco cessation and control, the recommendations in ASCO’s policy update are multifaceted, covering a broad range of tactics. At the cornerstone of ASCO’s recommendation is an emphasis on educating providers, patients, survivors, and their families on the negative effect tobacco use can have on not just cancer incidence, but cancer treatment outcomes as well. Another key recommendation is focused on improving patient and family access to access evidencebased tobacco cessation therapies

ASCO in

Action Your source for public policy news and information from ASCO Visit our newly designed one-stop source for the latest information on: Policy Information – get the latest news on key legislation and priorities such as access to care, clinical trials and drug shortages Advocacy Tools – take action with ASCO’s ACT Network Position Statements – see ASCO’s positions on current issues

Stay informed by visiting http://ascoaction.asco.org Follow @ascoaction on Twitter

ASCOPost.com | AUGUST 15, 2013

PAGE 77

Direct from ASCO

and counseling through health plan coverage and appropriate reimbursement. Research has shown access to these types of services can greatly improve rates of tobacco cessation.

In addition, solidifying tobacco cessation as a component of high quality cancer care through the assessment and potential expansion of current measures, such as ASCO’s Quality Oncology Practice Initiative (QOPI®) measures remain an important component of overall patient care.

To help strengthen the tobacco cessation and control evidence base, ASCO’s statement advocates for a robust tobacco control research agenda through increased funding and the inclusion of tobacco use status as a core data element in oncology clinical trials.

In order to achieve these goals in the area of tobacco control, ASCO continues to advocate for policies that enhance federal, state, and local regulation of tobacco products.

Finally, the policy update asks the oncology community to make a renewed commitment to serve as responsible members of the global society, advocating for coordination of tobacco cessation and control efforts worldwide.

Oncology Professionals Must Lead by Example The policy update challenges all oncology providers to lead by example by avoiding use of any tobacco and nicotine delivery products, treating tobacco

Nasser H. Hanna, MD

dependence as aggressively as cancer, advocating for the wide availability of cessation services, supporting tobaccofree environments, and refusing to collaborate with or accept support from the tobacco industry.

Reiterating that a significant proportion of all cancer death is tobacco related, Nasser H. Hanna, MD, of Indiana University Health Simon Cancer Center, coauthor of the pol-

icy update, said, “I think that we, as oncologists, have a unique responsibility to be highly engaged in helping to prevent tobacco use.”

Integrating Tobacco Cessation into Oncology Practices To help oncology providers inte-

grate tobacco cessation counseling services into their practices, ASCO has developed a comprehensive toolkit that includes a provider guide, a patient guide, assessment and counseling tools, information about reimbursement, and links to additional resources (including the Quitline,

1-800-QUIT-NOW).

The online resource, available at www.asco.org/tobaccocessationguide, “provides all the tools that the clinicians need to educate themselves and educate their patients on the necessity of stopping smoking,” continued on page 78

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The ASCO Post | AUGUST 15, 2013

PAGE 78

Direct from ASCO

30 Years of Identifying High-Quality Research with Breakthrough Potential

T

oday, cancer research happens on many compelling fronts. At the Conquer Cancer Foundation, our focus is on clinical and translational research— that is, prudently and swiftly translating research findings to enhance the care of patients with cancer in hospitals, clinics, physicians’ offices, and other treatment settings worldwide, and improving quality of life for the rapidly growing community of more than 12 million survivors. Our eyes are always on ambitious researchers and the places where they can make a real tangible difference in the lives of people with cancer, and for 30 years we have identified and

Tobacco Cessation continued from page 77

Dr. Hanna said. Moreover, the toolkit provides a way to quickly assess a patient’s level of addiction to tobacco and outlines a cessation plan, based on the results of that assessment.

While acknowledging that oncologists have an important role in engaging patients in the dialogue about tobacco cessation, Dr. Mulshine noted that they have significant limitations on their time. This may require “a new model of care in which oncologists coordinate tobacco cessation,” working with other health-care specialists “to ensure the tobacco control message is delivered consistently and in a high-quality, impactful way,” he said.

For example, oncology practices may find it helpful to offer patients access to more comprehensive tobacco cessation counseling provided by specially trained nurses or other health-care professionals, with financial support

supported the best and brightest through the Foundation’s Grants and Awards Program.

Application Process Each year, we receive proposals from around the world in a broad range of cancer research areas to the Foundation’s flagship programs: the Career Development Award (CDA) and the Young Investigator Award (YIA). Applications are reviewed by top thought leaders in the field who serve on the Foundation’s Grants Selection Committee. This group of dedicated volunteers spends long hours reviewing hundreds of applications to identify the top researchers in the application pool.

The review panel, consisting of distinguished cancer specialists and biostatisticians, conducts a rigorous peerreview process, modeled on the reviews conducted by the National Institutes of Health. With a commitment to supporting through current initiatives promoting tobacco cessation services that stem from the Affordable Care Act.

Oncologists’ Role in Advocating for Health Policy Change According to Dr. Hanna, an oncologist’s responsibility does not stop at the practice level. He noted, “As those in a position to influence health policy, we must be proactive in our practices, our communities, and at a state, national, and international health policy level.” An oncologist’s voice in the tobacco control policy realm is “unimaginably strong” and valuable, said Dresler, adding that she hopes a realization of that power will encourage many oncologists to take an active role in shaping the future through advocacy efforts. n © 2013. American Society of Clinical Oncology. All rights reserved.

projects of high-quality and breakthrough potential, only the best proposals are selected for funding through the Grants and Awards Program.

We support projects of immediate and compelling relevance. The Conquer Cancer Foundation dedicates resources to areas of inquiry that are not typically funded by other organizations, such as palliative care and rare diseases. And we fund researchers at the dawn of their careers, building a pipeline of researchers and knowledge that will enrich cancer care for years to come.

Together, we can hasten the pace of cancer progress and draw

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

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

closer the discoveries of tomorrow that could have an amazing impact today. As we celebrate the 30th anniversary of the Grants and Awards Program, we invite you to help change the course of cancer by supporting the researchers passionately working to conquer it. Please make a donation today at www .conquercancer foundation.org /donate.

Applications for 2014 CDA and YIA grants are currently being accepted until September 26, 2013. n © 2013. American Society of Clinical Oncology. All rights reserved.

5 most-accessed Top 10Top most-accessed articles recently published articles published in 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

What’s Hot in

JCO

JCO.org Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343

by Kevin S. Hughes, et al

Randomized Phase II Study of the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab With Cisplatin Versus Cisplatin Alone in Patients With Metastatic Triple-Negative Breast Cancer

by José Baselga, et al

International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease

by Evangelos Terpos, et al

Radiation Treatments After Breast-Conserving Therapy for Elderly Patients

by Benjamin D. Smith, et al

Prognosis of Women With Primary Breast Cancer Diagnosed During Pregnancy: Results From an International Collaborative Study

by Frédéric Amant, et al

When hemoglobin falls...

Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks.5* • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo.2,3† • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W.6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa ACC trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.2,3

Aranesp® (darbepoetin alfa) Indication Aranesp® is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use: Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being.

Aranesp® is not for use: • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.

• In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.

• As a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen.

3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799 www.amgen.com

© 2013 Amgen Inc. All rights reserved. Not for Reproduction.

G69514-R2-V2 68701-R2-V2

RBC = red blood cell.

Hb = hemoglobin.

Q3W = once every three weeks.

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks.

• Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions.

Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.

• Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/ or dispense Aranesp® to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance.

• To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions.

• Use ESAs only for anemia from myelosuppressive chemotherapy.

• ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure.

• Discontinue following the completion of a chemotherapy course.

• Aranesp® is contraindicated in patients with: − Uncontrolled hypertension − Pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs − Serious allergic reactions to Aranesp®

• In controlled clinical trials of patients with cancer, Aranesp® and other ESAs increased the risks for death and serious adverse cardiovascular reactions.

These adverse reactions included myocardial infarction and stroke.

• In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.

• Control hypertension prior to initiating and during treatment with Aranesp®.

• For lack or loss of hemoglobin response to Aranesp®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. • Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp®. − This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. − PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp® is not approved). − If severe anemia and low reticulocyte count develop during treatment with Aranesp®, withhold Aranesp® and evaluate patients for neutralizing antibodies to erythropoietin. − Permanently discontinue Aranesp® in patients who develop PRCA following treatment with Aranesp® or other erythropoietin protein drugs.

Do not switch patients to other ESAs. • Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp®.

Immediately and permanently discontinue Aranesp® if a serious allergic reaction occurs.

• Adverse reactions (≥ 1%) in clinical studies in cancer patients receiving chemotherapy were abdominal pain, edema, and thrombovascular events.

Please see Aranesp® brief summary of prescribing information, including Boxed WARNINGS, on the adjacent page.

Visit Aranesp.com for more information.

BRIEF SUMMARY: Consult package insert for complete prescribing information.

Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions.

Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being.

Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.

6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q

1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE

Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp.

Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.

Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy.

Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE

*G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.

Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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

"EWFSTF SFBDUJPOT XFSF BMTP CBTFE PO EBUB GSPN SBOEPNJ[FE EPVCMF CMJOE QMBDFCP DPOUSPMMFE TUVEJFT JODMVEJOH UIF 4$-$ TUVEZ EFTDSJCFE BCPWF UIBU FOSPMMFE QBUJFOUT "SBOFTQ QMBDFCP XJUI OPO NZFMPJE NBMJHOBODJFT .PTU QBUJFOUT XFSF XIJUF NBMF BOE UIF NFEJBO BHF XBT ZFBST SBOHF UP ZFBST PG UIF TUVEZ QPQVMBUJPO XFSF GSPN /PSUI "NFSJDB 8FTUFSO &VSPQF BOE "VTUSBMJB %PTJOH BOE TDIFEVMFT WBSJFE CZ TUVEZ GSPN PODF XFFLMZ UP PODF FWFSZ XFFLT BOE UIF NFEJBO EVSBUJPO PG FYQPTVSF XBT XFFLT SBOHF UP XFFLT

5ISPNCPWBTDVMBS "EWFSTF 3FBDUJPOT JO 1BUJFOUT 3FDFJWJOH $IFNPUIFSBQZ SCLC Study Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

Arterial .ZPDBSEJBM JOGBSDUJPO 7FOPVT 1VMNPOBSZ FNCPMJTN $FSFCSPWBTDVMBS EJTPSEFST

"MM 1MBDFCP controlled Studies

*O BEEJUJPO UP UIF UISPNCPWBTDVMBS BEWFSTF SFBDUJPOT BCEPNJOBM QBJO BOE FEFNB occurred at a higher incidence in patients taking Aranesp compared to patients on QMBDFCP "NPOH BMM QMBDFCP DPOUSPMMFE TUVEJFT BCEPNJOBM QBJO WT BOE FEFNB WT XFSF SFQPSUFE NPSF GSFRVFOUMZ JO QBUJFOUT SFDFJWJOH "SBOFTQ DPNQBSFE UP UIF QMBDFCP HSPVQ *O UIF 4$-$ TUVEZ UIF JODJEFODF PG BCEPNJOBM QBJO WT BOE FEFNB WT JO UIF "SBOFTQ USFBUFE QBUJFOUT compared to those receiving placebo.

1PTUNBSLFUJOH &YQFSJFODF #FDBVTF QPTUNBSLFUJOH SFQPSUJOH PG BEWFSTF SFBDUJPOT JT WPMVOUBSZ BOE GSPN B QPQVMBUJPO PG VODFSUBJO TJ[F JU JT OPU BMXBZT QPTTJCMF UP SFMJBCMZ FTUJNBUF UIFJS GSFRVFODZ PS FTUBCMJTI B DBVTBM SFMBUJPOTIJQ UP ESVH FYQPTVSF The following adverse reactions have been identiямБed during postmarketing use of Aranesp: t 4FJ[VSFT t 13$" t 4FSJPVT BMMFSHJD SFBDUJPOT Immunogenicity "T XJUI BMM UIFSBQFVUJD QSPUFJOT UIFSF JT B QPUFOUJBM GPS JNNVOPHFOJDJUZ /FVUSBMJ[JOH antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and PUIFS &4"T DBO SFTVMU JO 13$" PS TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT

*O DMJOJDBM TUVEJFT UIF QFSDFOUBHF PG QBUJFOUT XJUI BOUJCPEJFT UP "SBOFTQ XBT FYBNJOFE VTJOH UIF #JBDPSF┬о BTTBZ 4FSB GSPN QBUJFOUT XJUI $,% BOE cancer patients were tested. At baseline, prior to Aranesp treatment, binding BOUJCPEJFT XFSF EFUFDUFE JO QBUJFOUT XJUI $,% BOE DBODFS QBUJFOUT

%VSJOH "SBOFTQ UIFSBQZ SBOHF UP XFFLT B GPMMPX VQ TBNQMF XBT UBLFO 0OF BEEJUJPOBM QBUJFOU XJUI $,% BOE BEEJUJPOBM DBODFS QBUJFOUT EFWFMPQFE BOUJCPEJFT DBQBCMF PG CJOEJOH "SBOFTQ /POF PG UIF QBUJFOUT IBE BOUJCPEJFT DBQBCMF PG OFVUSBMJ[JOH UIF BDUJWJUZ PG "SBOFTQ PS FOEPHFOPVT FSZUISPQPJFUJO BU CBTFMJOF PS BU FOE PG TUVEZ /P DMJOJDBM TFRVFMBF DPOTJTUFOU XJUI 13$" XFSF BTTPDJBUFE XJUI UIF presence of these antibodies.

The incidence of antibody formation is highly dependent on the sensitivity and TQFDJmDJUZ PG UIF BTTBZ "EEJUJPOBMMZ UIF PCTFSWFE JODJEFODF PG BOUJCPEZ JODMVEJOH OFVUSBMJ[JOH BOUJCPEZ QPTJUJWJUZ JO BO BTTBZ NBZ CF JOnVFODFE CZ TFWFSBM GBDUPST including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

/P GPSNBM ESVH JOUFSBDUJPO TUVEJFT IBWF CFFO DPOEVDUFE XJUI "SBOFTQ

USE IN SPECIFIC POPULATIONS Pregnancy 1SFHOBODZ $BUFHPSZ $ There are no adequate and well-controlled studies of Aranesp use in pregnant women. *O BOJNBM SFQSPEVDUJPO BOE EFWFMPQNFOUBM UPYJDJUZ TUVEJFT "SBOFTQ JODSFBTFE FBSMZ QPTU JNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFT UIF QPUFOUJBM SJTL UP UIF GFUVT 8IFO "SBOFTQ XBT BENJOJTUFSFE JOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE VQ UP NDH LH EBZ 5IJT BOJNBM EPTF MFWFM PG NDH LH EBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF EFQFOEJOH PO UIF QBUJFOU T USFBUNFOU JOEJDBUJPO 4MJHIUMZ SFEVDFE GFUBM XFJHIUT XFSF PCTFSWFE XIFO IFBMUIZ SBU BOE SBCCJU NPUIFST SFDFJWFE EPTFT PG NDH LH PS NPSF 5IJT EPTF PG NDH LH JT OFBS UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF 8IJMF OP BEWFSTF FGGFDUT on uterine implantation occurred in animals, there was an increase in early postJNQMBOUBUJPO MPTT JO BOJNBM GFSUJMJUZ TUVEJFT *U JT OPU DMFBS XIFUIFS UIF JODSFBTFE QPTU JNQMBOUBUJPO MPTT SFnFDUT B ESVH FGGFDU PO UIF VUFSJOF FOWJSPONFOU PS PO UIF DPODFQUVT /P TJHOJmDBOU QMBDFOUBM USBOTGFS PG "SBOFTQ XBT EFUFDUFE *O B QFSJ QPTUOBUBM EFWFMPQNFOU TUVEZ QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE NDH LH EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBM EPTFT PG NDH LH BOE IJHIFS QVQT IBE EFDSFBTFE GFUBM CPEZ XFJHIUT which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation.

8PNFO XIP CFDPNF QSFHOBOU EVSJOH "SBOFTQ USFBUNFOU BSF FODPVSBHFE UP FOSPMM JO "NHFO T 1SFHOBODZ 4VSWFJMMBODF 1SPHSBN 1BUJFOUT PS UIFJS QIZTJDJBOT TIPVME DBMM ".(&/ UP FOSPMM /VSTJOH .PUIFST *U JT OPU LOPXO XIFUIFS "SBOFTQ JT FYDSFUFE JO IVNBO NJML #FDBVTF NBOZ ESVHT BSF FYDSFUFE JO IVNBO NJML DBVUJPO TIPVME CF FYFSDJTFE XIFO "SBOFTQ JT BENJOJTUFSFE to a nursing woman.

Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established.

Geriatric Use 0G UIF QBUJFOUT XJUI $,% JO DMJOJDBM TUVEJFT PG "SBOFTQ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS 0G UIF QBUJFOUT JO DMJOJDBM TUVEJFT SFDFJWJOH "SBOFTQ BOE DPODPNJUBOU DBODFS DIFNPUIFSBQZ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS /P EJGGFSFODFT JO TBGFUZ PS FGmDBDZ XFSF PCTFSWFE between older and younger patients.

OVERDOSAGE

Aranesp overdosage can cause hemoglobin levels above the desired level, which TIPVME CF NBOBHFE XJUI EJTDPOUJOVBUJPO PS SFEVDUJPO PG "SBOFTQ EPTBHF BOE PS XJUI QIMFCPUPNZ BT DMJOJDBMMZ JOEJDBUFE $BTFT PG TFWFSF IZQFSUFOTJPO IBWF CFFO PCTFSWFE GPMMPXJOH PWFSEPTF XJUI &4"T

Aranesp Placebo Aranesp Placebo O O O O

i$FSFCSPWBTDVMBS EJTPSEFSTw FODPNQBTTFT $F/4 IFNPSSIBHFT BOE DFSFCSPWBTDVMBS BDDJEFOUT JTDIFNJD BOE IFNPSSIBHJD &WFOUT JO UIJT DBUFHPSZ NBZ BMTP CF JODMVEFE VOEFS iUISPNCPFNCPMJD BEWFSTF SFBDUJPOT w

Aranesp┬о EBSCFQPFUJO BMGB

Manufactured by: "NHFO .BOVGBDUVSJOH -JNJUFE B TVCTJEJBSZ PG "NHFO *OD 0OF "NHFO $FOUFS %SJWF 5IPVTBOE 0BLT $" This product, the process of its manufacture, or its use, may be covered by one or NPSF 6 4 1BUFOUT JODMVEJOH 6 4 1BUFOU /P ┬к "NHFO *OD "MM SJHIUT SFTFSWFE 3 7

ASCOPost.com | AUGUST 15, 2013

PAGE 83

JCO Spotlight Thoracic Oncology

First-line Carboplatin/Pemetrexed Improves Survival vs Pemetrexed Alone in Advanced Lung Cancer

By Matthew Stenger

A

significant proportion of patients with advanced non–small cell lung cancer (NSCLC) have poor performance status, and optimal clinical management of these patients has not been established. In an attempt to help define optimal chemotherapy in such patients, Mauro Zukin, MD, of Instituto Nacional de Câncer, Rio de Janeiro, and colleagues conducted a phase III trial of first-line carboplatin plus pemetrexed (Alimta) vs pemetrexed alone in patients with Eastern Cooperative Oncology Group (ECOG) performance status of 2. The study, recently reported in Journal of Clinical Oncology, showed that combination treatment was associated with improved overall survival in this patient population.1 “This study was the first multicenter investigator initiated phase III trial completed in Brazil,” Dr. Zukin told The ASCO Post. “We collaborated since the inception with Dr. Rogerio Lilenbaum from the Yale Cancer Center, who presented the trial results at the ASCO 2012 Annual Meeting.”

Study Details In the trial, conducted in eight centers in Brazil and one in the United States, 205 patients with advanced NSCLC, ECOG performance status of 2, no prior chemotherapy, and adequate organ function were randomly assigned to receive pemetrexed at 500 = 102) 102) or in combinamg/m2 alone (n = 102) tion with carboplatin AUC 5 (n = 103) every 3 weeks for four cycles. Initially, patients could have any histology, with the protocol subsequently being amended to permit enrollment of only patients with nonsquamous histology.

Patients in both the pemetrexed and combination groups had a median age of 65 years (35% and 37% ≥ 70 years) and most were male (59% and 63%), had stage IV disease (95% and 94%), had weight loss ≥ 5% (54% and 58%), and were current or former smokers (77.5% in both); 80% and 82.5% of patients had adenocarcinoma. Similar proportions of patients in both groups had hypertension (45% in both), chronic obstructive pulmonary

disease (18% and 12%), and diabetes (8% and 13%) as comorbidities.

Combination Treatment Prolongs Survival Median follow-up was 27.5 months. Median overall survival was 9.3 months in the combination group vs 5.3 months in the pemetrexed group (hazard ratio [HR] = 0.62, P = .001).

One-year overall survival rates were 40.1% and 21.9%, respectively. Analysis of overall survival excluding patients with squamous cell carcinoma and unknown histology yielded similar results (HR = 0.65, P = .007).

Progression-free survival was also significantly prolonged in the combination group (median 5.8 vs 2.8 months, HR = 0.46, P � .001). � .001). .001). Objective response occurred in significantly more combination group patients

Optimal Chemotherapy for NSCLC and Poor Performance Status ■ First-line carboplatin and pemetrexed significantly prolonged overall

survival vs pemetrexed alone in patients with advanced non–small cell lung cancer and ECOG performance status of 2.

■ The findings suggest that patients in this population should be offered combination therapy.

docetaxel (28% vs 8%).

Subgroup analyses showed median overall survival benefit of combination therapy among elderly patients (9.9 vs 5.3 months, HR = 0.49, P = .006), never-smokers (9.4 vs 4.2 months, HR = 0.54, P = .069), and current/ former smokers (8.8 vs 5.6 months, HR = 0.65, P = .01). Median survival of patients at the center enrolling the greatest number of patients (n = 119)

[O]ur study provides strong evidence that combination chemotherapy is superior to single-agent therapy in all relevant clinical end points. Our results suggest it should be offered to patients with an ECOG performance status of 2.

—Mauro Zukin, MD, and colleagues

(23.8% vs 10.3% among evaluable patients, P = .032).

The median number of treatment cycles was four in both groups, although fewer patients in the pemetrexed group completed the prescribed four cycles (54% vs 71%, P = .012).

The major reasons for discontinuation of study treatment in the pemetrexed and combination groups included early death (14.7% vs 9.7%), early progression (15.7% vs 7.8%), clinical deterioration (12.7% vs 6.8%), and toxicity (0% vs 1.9%).

Approximately 35% of patients in both groups received second-line therapy, with more of these patients in the pemetrexed group receiving platinumbased therapy (69% vs 39%) and more in the combination group receiving

was 7.9 months compared with 5.8 months for the other sites (HR = 1.00, P = .991).

An exploratory analysis according to number of comorbidities showed no significant differences in median overall survival among patients with no comorbidities (n = 69, 6.9 months), one comorbidity (n = 89, 6.3 months), or more than one comorbidity (n = 62, 8.2 months).

Toxicities Hematologic toxicity was mild and rates of grade 3 or 4 nonhematologic toxicities were low in both groups.

The frequencies of grade 3 or 4 anemia (11.7% vs 3.9%), neutropenia (6.8% vs 1.0%), and thrombocytopenia (1.0% vs 0%) were higher in the combination

group, as was the frequency of grade 3 or 4 nausea/emesis (4.9% vs 1.0%).

Febrile neutropenia occurred in 2.9% of pemetrexed patients and 1.0% of combination patients. Grade 3 or 4 dyspnea was more common in the pemetrexed group (10.8% vs 5.8%), and was thought to reflect disease manifestation rather than treatment toxicity.

Four treatment-related deaths occurred in the combination group (due to renal failure, sepsis, pneumonia, and thrombocytopenia) compared with none in the pemetrexed group. Treatment delays (45% vs 21%) and dose reductions (4% vs 3%) were more common in the combination group.

The authors noted that they particularly wanted to address a practice pattern in which patients with poor performance status are given inferior regimens and thus have poorer outcomes, a pattern that tends to reinforce the view that treatment is of limited benefit in such patients. They concluded, “[O]ur study provides strong evidence that combination chemotherapy is superior to single-agent therapy in all relevant clinical end points. Our results suggest it should be offered to patients with an ECOG performance status of 2.” n

Disclosure: Dr. Zukin reported no potential conflicts of interest. For full disclosures of all study authors, visit jco.ascopubs.org.

Reference 1. Zukin M, Barrios CH, Pereira JR, et al: Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non–small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol.

June 17, 2013.

The ASCO Post | AUGUST 15, 2013

PAGE 84

Journal Spotlight Thoracic Oncology

Docetaxel Superior to Erlotinib in Second-line Treatment of Advanced Non–Small Cell Lung Cancer with Wild-type EGFR

By Matthew Stenger

T

here is ongoing debate about the efficacy of erlotinib (Tarceva) in patients with advanced non-small cell lung cancer (NSCLC) whose tumors have wild-type EGFR. In the TAILOR trial, reported in Lancet Oncology by Garassino and colleagues,1 erlotinib was compared with standard docetaxel as second-line treatment in patients with prior platinumbased therapy. The findings suggest that docetaxel is superior to erlotinib in this setting.

Study Details The TAILOR trial, conducted in 52 Italian hospitals, enrolled patients who had metastatic NSCLC, had received platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing.

Of 702 patients screened, 540 were genotyped, and 222 were enrolled.

These patients were randomized to receive erlotinib 150 mg/d (n = 112) or docetaxel 75 mg/m² every 21 days or 35 mg/m² on days 1, 8, and 15 every 28 days (n = 110). Randomization was stratified by center, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation. The primary end point was overall survival.

For the docetaxel vs erlotinib groups, median age was 67 vs 66 years, ECOG performance status was

0 or 1 in 93% vs 92%, histology was squamous in 21% vs 28% and adenocarcinoma in 75% vs 63%, 73% vs 83% were current or former smokers, 99% were white in both groups, 93% vs 92% had receive first-line chemotherapy and 6% vs 8% had received adjuvant chemotherapy, and best response to first-line chemotherapy was complete response in 0% vs 1% and partial response in 35% vs 44%.

Survival Rates After a median follow up of 33 months, docetaxel was associated with a borderline significant improvement in median overall survival (8.2 vs 5.4 months, adjusted hazard ratio [HR] 0.73, 95% confidence interval 0.53-1.00, P = .05). Median progression-free survival was significantly prolonged with docetaxel treatment (2.9 vs 2.4 months, adjusted HR 0.71, P = .02). Objective response occurred in 15.5% of the docetaxel group vs 3.0% of the erlotinib group (P = .003). Overall survival and progression-free survival outcomes across subgroups appeared to be better with docetaxel than with erlotinib, although many of the differences between groups were not significant. KRAS mutational status had no prognostic effect. In multivariable analysis, only treatment and performance status were associated with overall and progression-free survival.

Post-progression treatment in 51

TAILOR Trial: Erlotinib vs Docetaxel in Second-line Treatment of Non-small Cell Lung Cancer ■ As second-line treatment for wild-type EGFR advanced NSCLC, docetaxel was associated with a borderline significant improvement in overall survival compared with erlotinib.

■ Docetaxel significantly prolonged progression-free survival.

■ The findings suggested that chemotherapy is a better option in secondline treatment of NSCLC in the absence of a clear therapeutic target.

patients in the docetaxel group consisted of pemetrexed in 18%, gemcitabine in 22%, vinorelbine in 35%, and, in violation of study protocol, erlotinib in 8%. Post-progression treatment in 53 patients in the erlotinib group consisted of pemetrexed in 42%, gemcitabine in 17%, vinorelbine in 26%, and in violation of study protocol, docetaxel in 15%.

Adverse Events Treatment-related adverse events led to dose modification in 22% of patients in the docetaxel group and 21% of erlotinib patients. Neutropenia, neurological toxic effects, alopecia, asthenia, and nausea were more common in the docetaxel group and most patients in the erlotinib group had skin toxic effects. The most common grade 3 or 4 toxic effects were low absolute neutrophil count (20% in the docetaxel group vs 0% in the erlotinib group), skin toxic effects (0% vs 14%), and asthenia (10% vs 6%).

The authors noted that skin toxic effects were not a significant predictor of erlotinib response in the trial.

One patient in each group died from treatment-related sequelae (grade 4 diarrhea in an erlotinib patient and febrile neutropenia in a docetaxel patient).

As stated by the investigators: “In conclusion, our results unequivocally show that—although neither docetaxel nor erlotinib are magic bullets for second-line treatment of NSCLC—a cytotoxic approach to treatment of patients with NSCLC is still the best option in the absence of a clear therapeutic target.” n Reference 1. Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. July 22, 2013 (early release online).

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The ASCO Post | AUGUST 15, 2013

PAGE 86

JCO Spotlight Gastrointestinal Oncology

Link between Red Meat Consumption and Mortality Clarified in Patients with Nonmetastatic Colorectal Cancer

By Matthew Stenger

E

vidence shows that diets high in red and processed meat are associated with an increased risk of colorectal cancer. In a study reported in Journal of Clinical Oncology, Marjorie L. McCullough, ScD, Strategic Director of Nutritional Epidemiology, and colleagues from the Epidemiology Research Program of the American Cancer Society examined the association between pre- and postdiagnosis red/processed meat consumption and all-cause and colorectal cancer–specific mortality.1 They found that high prediagnosis consumption was associated with increased all-cause mortality and mortality from cardiovascular disease but not colorectal cancer mortality and that high postdiagnosis consumption was not associated with all-cause or cause-specific mortality.

Study Details Participants in the Cancer Prevention Study II Nutrition Cohort reported information on diet and other factors at baseline in 1992 to 1993, 1999, and 2003. Participants with a colorectal cancer diagnosis after baseline and up to June 30, 2009, were observed for mortality through December 31, 2010.

A total of 2,315 participants were diagnosed with invasive nonmetastatic colorectal cancer. Subjects had a mean age of 73 years at diagnosis and approximately 55% were male. Red/processed meat intake by quartile at baseline was a mean of 1.5 servings per week in the 1st (bottom) quartile, 3.8 per week in the 2nd quartile, 6.0 per week in the 3rd quartile, and 10.4 per week in the 4th (top) quartile.

Effect of Prediagnosis Diet In the analysis of prediagnosis diet, a total of 966 patients with colorectal cancer died during an average followup of 7.5 years, including 413 from colorectal cancer, 176 from cardiovascular disease, and 377 from all other causes combined. In multivariable analysis adjusting for age at diagnosis, sex, tumor stage, prediagnosis energy intake, body mass index, history of diabetes, and history of myocardial infarction, greater red/processed meat intake before colorectal cancer diagnosis

death from all other causes (RR = 1.39, 95% CI = 1.00–1.92, P = .08 for trend), but not death from colorectal cancer (RR = 1.09, 95% CI = 0.79–1.51, P = .54 for trend).

Effect of Postdiagnosis Diet In the analysis of postdiagnosis diet, 472 deaths occurred during a mean follow-up of 7.6 years, including 146 from colorectal cancer, 110 from cardiovascular disease, and 216 from other causes. Quartiles of red/ processed meat intake varied accord-

Our findings, which underscore the importance of a long-term healthy diet with limited red and processed meat intake, are relevant because cancer survivors in general are at greater risk of chronic diseases such as heart disease compared with the general population.

—Marjorie L. McCullough, ScD, and colleagues

was associated with greater risk (top vs bottom quartile) of death from all causes (relative risk [RR] = 1.29, 95% confidence interval [CI] = 1.05–1.59, P = .03 for trend).

The multivariable analysis also revealed greater prediagnosis red/processed meat intake to be associated with higher risks of death from cardiovascular disease (RR = 1.63, 95% CI = 1.00–2.67, P = .08 for trend) and

Diet and Death in Patients with Colorectal Cancer ■ High prediagnosis intake of red/processed meat was associated with

increased risk of all-cause and cardiovascular disease mortality but not colorectal cancer–specific mortality.

■ High postdiagnosis intake was not associated with all-cause or causespecific mortality.

■ Median or higher intake of red/processed meat both before and after

diagnosis was not associated with increased risk of colorectal cancer– specific mortality.

ing to year of survey.

On multivariate analysis adjusting for age at diagnosis, sex, tumor stage, and postdiagnosis energy intake, greater red/processed meat consumption (top vs bottom quartile) after colorectal cancer diagnosis was not independently associated with allcause mortality (RR = 1.02, 95% CI = 0.761.38, P = .90 for trend), colorectal cancer–specific mortality (RR = 1.28, 95% CI = 0.74–2.21, P = .46 for trend), cardiovascular disease mortality (RR = 0.88, 95% CI = 0.47–1.64, P = .48 for trend), or mortality from all other causes (RR = 0.94, 95% CI = 0.60–1.46, P = .76 for trend).

Effect of Change in Intake In multivariate analyses of changes in intake before and after diagnosis, patients with high intake (median or above) both before and after

diagnosis had increased risk of death from colorectal cancer (RR = 1.79, 95% CI = 1.11–2.89) compared with those with low intake before and after. Patients with low intake before and high intake after diagnosis had increased risk of death from other causes (RR = 1.62, 95% CI = 1.06–2.48). Patients with high intake before and low intake after diagnosis had increased risk of all-cause mortality (RR = 1.37, 95% CI = 1.02–1.85).

A low intake after diagnosis may have been due to illness.

No significant interactions were found between prediagnosis or postdiagnosis red/processed meat intake and total mortality (top vs bottom quartile) stratified by sex, tumor stage, colon or rectum site of disease, or body mass index. A borderline significant interaction was observed for prediagnosis intake and family history of colorectal cancer (RR = 2.87 for family history, 95% CI 1.28-6.43, P = .05). A post hoc analysis showed no association between intake and survival among patients with metastatic disease.

The investigators concluded: “[H] igh red and processed meat intake before a diagnosis of [colorectal cancer] was associated with a greater risk of death, a finding driven mainly by death as a result of causes other than [colorectal cancer]. Our findings, which underscore the importance of a long-term healthy diet with limited red and processed meat intake, are relevant because cancer survivors in general are at greater risk of chronic diseases such as heart disease compared with the general population.” n

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

Reference 1. McCullough ML, Gapstur SM, Shah R, et al: Association between red and processed meat intake and mortality among colorectal cancer survivors.

J Clin Oncol. July 1, 2013 (early release online).

STRENGTHEN HER DEFENSE

FDA-approved HER2* dimerization inhibitor (HDI) for the first-line treatment of HER2+ metastatic breast cancer (MBC)1,2

Indication

PERJETA速 (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin速 (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Boxed WARNING: Embryo-Fetal Toxicity

Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death.

Advise patients of these risks and the need for effective contraception.

Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. *HER2 = human epidermal growth factor receptor.

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly improve progression-free survival PERJETA-based regimen extended median progression-free survival (PFS) to 18.5 months (from 12.4 months)1 6.1-Month Improvement in Median IRF-assessed PFS1* Placebo + Herceptin + docetaxel

100

PERJETA + Herceptin + docetaxel

90

HR=0.62† 95% CI [0.51-0.75] P<0.0001

80 70

18.5

PFS (%)

60

MONTHS

50

12.4

40

MONTHS

30 20 10 0

P+H+D Pl+H+D

0

5

10

15

20 MONTHS

25

30

35

40

402 406

345 311

267 209

139 93

83 42

32 17

10 7

0 0

0 0

Patients at risk

• At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

IRF = independent review facility; CI = confidence interval; HR = hazard ratio. *At the time of the final PFS analysis, OS was not mature and first interim OS analysis results did not meet the prespecified stopping boundary for statistical significance.1 † Stratified by prior treatment status and geographic region.1 The CLEOPATRA trial was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of patients with HER2+ locally recurrent, unresectable or metastatic breast cancer (HER2+ status was defined as IHC 3+ or FISH amplification ratio ≥2.0 as determined at a central laboratory) (N=808); patients were randomized in a 1:1 ratio to either PERJETA + Herceptin + docetaxel (n=402) or placebo + Herceptin + docetaxel (n=406).1

Important Safety Information Boxed WARNING: Embryo-Fetal Toxicity

• Exposure to PERJETA can result in embryo-fetal death and birth defects.

Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety Information Left Ventricular Dysfunction

• In the randomized trial, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel

• Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis

• PERJETA has been associated with infusion and hypersensitivity reactions • On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group, with the majority being mild to moderate.

The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting • In the randomized trial, the overall frequency of hypersensitivity reactions/ anaphylaxis was 10.8% in the PERJETA-treated group and 9.1% in the placebotreated group

Significantly prolong overall survival 34% reduction in risk of death with PERJETA1 Second Interim Overall Survival (OS) Results1 Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR=0.66 95% CI [0.52-0.84] P=0.0008‡

80

OS (%)

70

MEDIAN NOT YET REACHED

60 50

37.6

40

20 10 0

P+H+D PI+H+D

0

5

10

15

20

402 406

387 383

371 350

342 324

317 285

25 30 MONTHS 230 143 198 128

• More than 50% of patients in the PERJETA + Herceptin + docetaxel arm were alive at the time of the second interim analysis, thereby indicating that the median OS for this arm has not yet been reached1 • At the time of analysis, there were 113 (28.1%) and 154 (37.9%) deaths in the PERJETA + Herceptin + docetaxel arm and the placebo + Herceptin + docetaxel arm, respectively1

MONTHS

30

• Median follow-up was 30 months (1 year following the first interim analysis) for both the PERJETAbased regimen and the placebo + Herceptin + docetaxel arms (Kaplan-Meier estimate)1-3

35

40

45

50

55

84 67

33 22

9 4

0 0

0 0

• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

Patients at risk

OS = overall survival. ‡ The HR and P-value for the second interim analysis of OS crossed the predefined efficacy stopping boundary (HR≤0.739, P≤0.0138).1

• Consistent PFS and OS benefit demonstrated across several HER2+ MBC patient subgroups1,3 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])1 • The incidence of Grade 3-4 hypersensitivity reactions/anaphylaxis was 2% in the PERJETA-treated group and 2.5% in the placebo-treated group according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE) (version 3). Overall, 4 patients in the PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression, defined as 3+ IHC by Dako HercepTest™ or FISH amplification ratio ≥2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC • Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

© 2013 Genentech USA, Inc.

All rights reserved.

PER0001010503

Printed in USA.

06/13

Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages.

References: 1. PERJETA Prescribing Information. Genentech, Inc. April 2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119. 3. Swain SM, Kim S-B, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471.

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning.

Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known.

5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.

Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)].

5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.

During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.

In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)].

5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 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.

In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents.

The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group.

The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions.

Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial PERJETA Placebo Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the

PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).

6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555.

Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)].

8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab.

10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman.

The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555.

Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.

8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients.

8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients.

Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175).

8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA.

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

PERJETA is a registered trademark of Genentech, Inc. 01/13 PER0000999401 © 2013 Genentech, Inc. 10139000

ASCOPost.com | AUGUST 15, 2013

PAGE 91

Journal Spotlight Thoracic Oncology

Intercalated Chemotherapy/Erlotinib Improves Progression-free Survival in Advanced NSCLC

By Matthew Stenger

E

GFR mutation status may not be known at the time treatment is started in patients with advanced non–small cell lung cancer (NSCLC).

Further, some data suggest that the efficacy of concurrent treatment with an EGFR tyrosine kinase inhibitor and chemotherapy is reduced because the G1 cell-cycle arrest caused by the tyrosine kinase inhibitor reduces the cell-cycle phase–dependent activity of chemotherapy.

In a phase III trial (FASTACT-2) conducted in 28 centers in seven Asian countries, Yi-Long Wu, MD, of the Guangdong Academy of Medical Sciences and colleagues found that the intercalated combination of erlotinib (Tarceva) and chemotherapy improved progression-free survival vs chemotherapy alone as first-line treatment in a population of advanced NSCLC patients with known and unknown EGFR mutation status.

The trial, reported in Lancet Oncology,1 showed that benefit was primarily limited to patients known to have activating EGFR mutations, but suggests that a proportion of those with unknown mutation status also benefit. Activating EGFR mutations are more common in Asian patients and in never-smokers, the latter of whom were also highly represented in the trial.

Study Details In the trial, patients with untreated stage IIIB/IV NSCLC were randomly assigned to six cycles of gemcitabine (1,250 mg/m2 on days 1 and 8) plus platinum (carboplatin 5 × AUC or cisplatin at 75 mg/m2 on day 1) with intercalated erlotinib (150 mg/d on days 15–28; n = 226) or placebo (n = 225) every 4 weeks. All patients in the placebo group were offered second-line erlotinib at the time of disease progression.

The erlotinib and chemotherapy groups were well-matched for age (median, 59 and 57 years), sex (58% and 62% male), smoking status (50% and 48% never-smokers), disease stage (IV in 91% and 89%), histology (adenocarcinoma in 77% and 75%), and ECOG performance status (0 or 1 in all patents). EGFR

mutation status was wild-type in 31% and 30%, single resistance mutation in � 1% and 3%, activating EGFR mutation in 22%and 21%, and unknown in 47% and 46%.

Survival Prolonged Progression-free survival was significantly prolonged with chemotherapy plus erlotinib (median, 7.6 vs 6.0 months, hazard ratio [HR] = 0.57, P � .0001). Analysis of progressionfree survival by patient characteristics showed that hazard ratios favored erlotinib in all subgroups, with the greatest benefit observed in female patients, never-smokers, and adenocarcinoma cases.

Median overall survival was also prolonged in the erlotinib group (18.3 vs 15.2 months, HR = 0.79, P = .0420). On investigator assess-

First-line Chemotherapy/Erlotinib in Lung Cancer ■ Intercalated chemotherapy and erlotinib improved progression-free

survival compared with chemotherapy alone in Asian patients with known and unknown EGFR mutation status.

■ Benefit of intercalated therapy was generally limited to patients with

activating EGFR mutations, but a progression-free survival benefit was also observed among patients with unknown mutation status.

response was observed in 84% of erlotinib patients and in 15% of chemotherapy patients (P � .0001).

Among patients with wild-type EGFR, there were no significant differences between erlotinib patients and chemotherapy patients in progression-free survival (6.7 vs 5.9 months, HR = 0.97, P = .8467) or overall survival (14.9 vs 12.2 months, HR = 0.77, P = .1612). Objective response was observed in 26% vs 19% (P = .35).

Intercalated chemotherapy and erlotinib is a viable first-line option for patients with NSCLC with EGFR mutation–positive disease or selected patients with unknown EGFR mutation status.

—Yi-Long Wu, MD, and colleagues

ment, objective response was observed in 43% of patients in the erlotinib group and in 18% of patients in the chemotherapy group (P � .0001).

On disease progression, 79% of the patients in the chemotherapy group received an EGFR tyrosine kinase inhibitor as second-line treatment and 6% as third-line treatment. Only 6% of patients in the erlotinib group received platinum-based chemotherapy as second-line treatment and 6% as third-line treatment.

Analysis by EGFR Mutation Status On subgroup analysis by EGFR mutation status, erlotinib benefit was observed primarily in patients with an activating EGFR gene mutation, with both progression-free survival (16.8 vs 6.9 months, HR = 0.25, P � .0001) and overall survival (31.4 vs 20.6 months, HR 0.48, P = .0092) being significantly prolonged in this subgroup. In this subgroup, objective

Among patients with unknown EGFR status, progression-free survival was significantly prolonged in the erlotinib group (7.1 vs 6.0 months, HR = 0.61, P = .0009), suggesting that a proportion of these patients had activating EGFR mutations. No difference in overall survival (18.1 vs 16.2, HR = 0.93, P = .64) was observed in this subgroup.

More EGFR tyrosine kinase inhibitor–type toxicity, including skin rash (5% grade 3) and diarrhea, was observed in the erlotinib group. The most commonly reported adverse events of any grade included neutropenia, anemia, nausea, and rash. Serious adverse events occurred in 31% of patients in the erlotinib group and 34% of chemotherapy group patients.

The most common grade 3 or higher adverse events were neutropenia (25% and 29%), thrombocytopenia (14% in both groups), and anemia (9% and 12%). Death occurred in 12 patients in the erlotinib group and in

7 in the chemotherapy group, and was considered treatment-related in 3 patients in each group.

The investigators noted that the good outcomes among patients with known EGFR mutation receiving intercalated erlotinib and chemotherapy suggest that such patients may benefit from this strategy in first-line treatment. They recommended that a randomized trial be conducted to compare intercalated therapy with an EGFR tyrosine kinase inhibitor plus pemetrexed (Alimta) or cisplatin vs EGFR tyrosine kinase inhibitor monotherapy as the control treatment.

Conclusions The investigators concluded, “Intercalated chemotherapy and erlotinib is a viable first-line option for patients with NSCLC with EGFR mutation–positive disease or selected patients with unknown EGFR mutation status.” Noting that use of the intercalated combination might provide better outcomes in patients with unknown EGFR status than the standard chemotherapy that such patients might otherwise receive, they stated, “We would suggest that the regimen be considered for patients with an unknown mutation status in whom clinical parameters are suggestive of a high incidence of EGFR mutations.” n

Disclosure: The trial was funded by F. Hoffman-La Roche. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Wu Y-L, Lee JS, Thongprasert S, et al: Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): A randomised, double-blind trial. Lancet Oncol 14:777-786, 2013.

The ASCO Post | AUGUST 15, 2013

PAGE 92

Journal Spotlight Thoracic Oncology

Significant Improvement in Overall Survival Seen with Pemetrexed Maintenance after Pemetrexed/Cisplatin Induction in Patients with Advanced NSCLC

By Matthew Stenger

I

n the phase III PARAMOUNT trial, pemetrexed (Alimta) continuation maintenance therapy significantly reduced the risk of disease progression by 38% compared with placebo after pemetrexed/cisplatin induction in patients with advanced nonsquamous non–small cell lung cancer (NSCLC).

Final overall survival results were recently reported in Journal of Clinical Oncology by Luis G. Paz-Ares, MD, of University Hospital Virgen del Rocío in Seville and colleagues, with pemetrexed maintenance being associated with a significant 22% reduction in risk of death.1 Updated safety results yielded no new findings, with drug-related grade 3 or 4 anemia, fatigue, and neutropenia being relatively infrequent but more common with pemetrexed.

13.9 months in the pemetrexed group and 11.0 months in the placebo group (hazard ratio [HR] = 0.78, P = .0195).

One- and 2-year overall survival rates were 58% vs 32% and 45% vs 21%, respectively (both P � .05). Median overall survival from the time of induction was 16.9 vs 14.0 months (HR = 0.78, P = .0191).

Hazard ratios for overall survival consistently favored pemetrexed for all patient subgroups (disease stage IIIB

of therapy being well matched between groups except for the more frequent use of docetaxel in the placebo group (43% vs 32%). The majority of patients received an approved secondline treatment (either docetaxel or erlotinib [Tarceva]).

Toxicity Pemetrexed maintenance was associated with significantly greater frequency of drug-related grade 3 or

The results of the PARAMOUNT study ... support the use of continuation maintenance pemetrexed for patients with advanced nonsquamous NSCLC. — Luis G. Paz-Ares, MD

Trial Outcomes In the PARAMOUNT trial, 939 patients with advanced nonsquamous NSCLC received four cycles of pemetrexed/cisplatin induction therapy; 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were then randomly assigned to maintenance pemetrexed (500 mg/m2 on day 1 of 21-day cycles, n = 359) or placebo (n = 180).

The mean number of maintenance cycles was 7.9 (range 1–44) for pemetrexed patients and 5.0 (range, 1–38) for placebo patients. After a median follow-up of 12.5 months for all patients and 24.3 months for surviving patients, median overall survival was

or IV, performance status at randomization, male or female, smoker or nonsmoker, age, and adenocarcinoma or other histology). Overall survival was numerically improved among patients with response on induction therapy (HR = 0.81, 95% confidence interval [CI] = 0.59–1.11) and those with stable disease on induction therapy (HR = 0.76, 95% CI = 0.57–1.01); the study was not powered to detect differences between these subgroups.

In total, 64% of pemetrexed patients and 72% of placebo patients received additional therapy, with types

Pemetrexed Maintenance in NSCLC ■ Pemetrexed maintenance reduced mortality risk by 22% compared with

placebo in patients with no progression and performance status of 0 or 1 after pemetrexed/cisplatin induction therapy.

■ Drug-related grade 3 or 4 anemia, neutropenia, and fatigue were

significantly more common with pemetrexed, although each had an incidence of < 7%.

4 anemia (6.4% vs 0.6%), neutropenia (5.8% vs 0%), and fatigue (4.7% vs 1.1%). The most frequent drugrelated grade 1 or 2 adverse events in the pemetrexed group were fatigue (17.5%), nausea (13.4%), and anemia (11.7%); grade 1 or 2 adverse events that were significantly more common with pemetrexed were anemia, neutropenia, leukopenia, increased AST, fatigue, nausea, vomiting, mucositis/ stomatitis in oral cavity, anorexia, eye watering, and fever.

Treatment was discontinued due to potentially drug-related adverse events in 12.0% of pemetrexed patients and 4.4% of placebo patients. Three deaths considered potentially drug-related occurred during maintenance treatment, due to pneumonia in one pemetrexed patient and sudden death–not otherwise specified and respiratory arrest in two placebo patients.

There were no significant differences between patients receiving more

than six cycles of pemetrexed and those receiving fewer cycles with regard to toxicity of any grade or drugrelated grade 3 or 4 laboratory toxicity; longer exposure was associated with a numeric increase in grade 3 or 4 neutropenia (9% vs 4%, P = .062). Grade 3 or 4 infections occurred in 1.5% of patients receiving more than six cycles and 1.5% of those receiving six or fewer.

The authors emphasized that since not all patients require maintenance therapy, as is shown by patients receiving placebo for multiple cycles without showing disease progression, additional studies are needed to identify patients who would benefit most from such treatment.

They concluded, “Certainly, our understanding of optimal use of maintenance therapy will be furthered when several ongoing clinical trials are completed over the next few years. Then and now, the decision to use maintenance therapy should be based on an individualized approach that includes patient-specific factors and wishes.

The results of the PARAMOUNT study provide evidence to direct those choices by providing new data on the benefits/risks of maintenance pemetrexed, supporting the use of continuation maintenance pemetrexed for patients with advanced nonsquamous NSCLC.” The study was supported by Eli Lilly. n Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Paz-Ares LG, de Marinis F, Dediu M, et al: PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non–small-cell lung cancer. J Clin Oncol.

July 8, 2013 (early release online).

DECODE metastatic melanoma.

EXTEND survival.

The first BRAF inhibitor shown to significantly extend overall survival (OS) 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速 (vemurafenib) tablets 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

EXTEND SURVIVAL Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)†‡ 100

HR=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60 Not reached

7.9

40 20 0

0

2

4

ZELBORAF (n=337)

6 8 OS (months)

10

12

14

Dacarbazine (n=338)

HR=hazard ratio CI=confidence interval *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. Results were 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.1,2 † At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine. ‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001) 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.

© 2013 Genentech USA, Inc. All rights reserved. BRF0000653204

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 or hypotension.

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 sub-study 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.

Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated.

Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

Learn more at Zelboraf.com/SURVIVAL

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 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

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) 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.

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

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 June 24, 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.

The ASCO Post | AUGUST 15, 2013

PAGE 96

ASCO State Affiliates Focus on the West Virginia Oncology Society

By Jo Cavallo

N

ow in its fifth year, the West Virginia Oncology Society (WVOS) is already having a major impact on cancer care in the state. In

2010, a joint initiative to develop a statewide cancer clinical trials network was launched Safety:7"

by WVOS and the West Virginia University Cancer Center.

ZELBORAF ® (vemurafenib) tablet, oral 6 ADVERSE REACTIONS Initial U.S. Approval: 2011 6.1 Clinical Trials Experience This is a brief summary of information about ZELBORAF. Before Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot prescribing, please refer to the full Prescribing Information. 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 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable clinical practice. or metastatic melanoma with BRAF V600E mutation as detected by an This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 FDA-approved test. randomized (1:1) 675 treatment-naive patients with unresectable or Limitation of Use: ZELBORAF is not indicated for treatment of patients metastatic melanoma to receive ZELBORAF 960 mg orally twice daily with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior 5 WARNINGS AND PRECAUTIONS systemic therapy received treatment with ZELBORAF 960 mg orally 5.1 New Primary Malignancies twice daily.

Cutaneous Malignancies Table 1 presents adverse reactions reported in at least 10% of patients Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma treated with ZELBORAF. The most common adverse reactions of any occurred at a higher incidence in patients receiving ZELBORAF compared grade (≥ 30% in either study) in ZELBORAF-treated patients were to those in the control arm in Trial 1. The incidence of cutaneous squamous arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse 24% compared to <1% in the dacarbazine arm [see Adverse Reactions reactions were cuSCC and rash. The incidence of Grade 4 adverse (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; reactions was ≤ 4% in both studies. approximately 33% of patients who developed a cuSCC while receiving The incidence of adverse events resulting in permanent discontinuation ZELBORAF experienced at least one additional occurrence with median of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% time between occurrences of 6 weeks. Potential risk factors associated for the dacarbazine arm. In Trial 2, the incidence of adverse events with cuSCC observed in clinical studies using ZELBORAF included age resulting in permanent discontinuation of study medication was 3% in (≥ 65 years), prior skin cancer, and chronic sun exposure.

ZELBORAF-treated patients. The median duration of study treatment In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial patients receiving ZELBORAF compared to none of the patients receiving 1, and 5.7 months for ZELBORAF in Trial 2. dacarbazine.

Reactions Reported in ≥ 10% of Patients Treated Perform dermatologic evaluations prior to initiation of therapy and every Table 1 Adverse with ZELBORAF* 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for Trial 2: Patients Trial 1: Treatment Naïve Patients 6 months following discontinuation of ZELBORAF. with Failure of at Non-Cutaneous Squamous Cell Carcinoma Least One Prior Systemic Therapy Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)].

ZELBORAF Dacarbazine ZELBORAF ADRs Monitor patients receiving ZELBORAF closely for signs or symptoms of n= 336 n= 287 n= 132 new non-cutaneous SCC. Grade Grade All Grade All All Other Malignancies Grades 3a Grades 3 Grades 3a (%) (%) (%) (%) (%) (%) Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms Skin and subcutaneous [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF tissue disorders closely for signs or symptoms of other malignancies.

Rash 37 8 2 0 52 7 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) and Dosage and Administration (2.1)].

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.

Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation.

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) [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.2)].

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)].

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.

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 [see Clinical Pharmacology (12.3)]. 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.

33 45 23 24 9 8 19 5 14

3 <1 1 1 2 0 0 <1 0

4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0

49 36 30 28 21 17 16 13 8

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

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 [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

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

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.

8.7 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 [see Clinical Pharmacology (12.3)]. 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.

for the most advanced care, said James N. Frame, MD, FACP, Immediate Past President of WVOS, Chair-elect of ASCO’s State Affiliate Council, and a leader in organizing the development and implementation of the West Virginia Cancer Clinical Trials Network.

With 250 members, WVOS is active in addressing the issues confronting oncologists and patients in West Virginia, including oncology drug shortages and physician reimbursement by the Centers for Medicare & Medicaid Services (CMS), as well as participating in legislative efforts to ensure the comprehensive establishment of the state’s health insurance exchanges, which will go into effect in 2014 as part of the Patient Protection and Affordable Care Act. The ASCO Post talked with Dr. Frame about WVOS’ accomplishments since its founding and its future goals.

Origins of the West Virginia Oncology Society

*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, VIIth 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

work, plans for the development of the network are nearing completion this year, with 15 academic institutions, community hospitals, and private practices joining the program so far.

The clinical trials network will enable residents of West Virginia to receive state-of-the-art oncology treatment in the communities where they live, rather than having to leave the state

Safety:10"

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 or hypotension. Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

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

With funding support from ASCO’s State Affiliate Grant Program to help build the infrastructure for the West Virginia Cancer Clinical Trials Net-

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422003 Initial U.S. Approval: August 2011 © 2013 Genentech, Inc

Why was it important for West Virginia to become an ASCO State Affiliate and have its own oncology society?

We wanted West Virginia to have a voice in matters that related to patient care, research, and legislative advocacy.

The reason we established a new society in 2008 is largely due to changes in the jurisdictions of Medicare Admin-

ASCOPost.com | AUGUST 15, 2013

PAGE 97

ASCO State Affiliates istrative Contractors. West Virginia used to be part of the Ohio/West Virginia Oncology Society, but with the changes in Medicare Administrative Contractor jurisdictions, West Virginia was assigned to the J11 region, which includes Virginia, North Carolina, and South Carolina. Thus, we were no longer part of Ohio’s jurisdiction, which meant that we would no longer have a society to represent our state.

The changes mandated by the Medicare Administrative Contractor realignment got us thinking about forming our own society, and oncologists from academia, community hospitals, and private practice developed an informal coalition. We especially wanted to develop a clinical trials network to better serve West Virginians.

There were only 18 medical sites in the state where cancer care is delivered, and maybe just 4 or 5 sites that offered clinical trials. We are a population of nearly 2�� million, geographically separated by mountains and valleys. Before we formed the West Virginia Oncology Society, it was difficult for oncologists to meet each other and establish a collegiality that would enable us to form relationships and collaborate on patient care.

So launching the West Virginia Cancer Clinical Trials Network provided a means to bring us together, and then we created our mission statement and

articulated our vision for what we wanted to accomplish.

Strength of a Coalition I read that more than 85% of West Virginia’s cancer specialists had already joined your society within its first year of existence.1 Why is WVOS so successful in attracting new members?

I think it’s our team spirit and the fact that we respect all oncology prac-

We want to increase our membership to include everyone involved in oncology care, such as nurse practitioners and physician assistants, because they are critical to our future.

—James N. Frame, MD, FACP

The West Virginia Oncology Society was founded in 2008.

The current President is Arvind B. Shah, MD. The Immediate Past President is James N. Frame, MD, FACP. The Society has 250 members.

The Society’s mission is to engender and promote improvements in patient care, education, clinical trial accrual, and oncology-related economic and legislative issues. To achieve those goals, WVOS has launched the West Virginia Clinical Trials Network; is engaged in advocacy efforts with Medicare, managed care companies, and state and federal policymakers to address the issues of drug shortages, reimbursement and practice management, and off-label drug use; and hosts educational programs for members to increase their knowledge of issues related to the practice of oncology.

■ The Society holds two membership meetings each year, one in the spring and one in the fall.

Visit

of WVOS President Arvind Shah, MD, we have taken a position on H.R. 1416, a bill introduced in Congress to exempt cancer drugs from the 2% Medicare sequester cut, and have asked our members to take action by contacting their Congressional representative about this issue.

The West Virginia Oncology Society has also submitted comments on the proposed rules for the establishment of the state’s health insurance exchanges under the Patient Protection and Affordable Care Act, and has asked for more direct guidance from the Department of Health and Human Services to ensure that patients with cancer have access to chemotherapies.

In addition, WVOS submitted comments on the 2013 Proposed Physician Fee Schedule to CMS. So as a society, we are starting to mature in our advocacy mission.

Future Goals tice settings, from university and community hospitals to private practices.

We’ve also aligned ourselves behind goals that are important for improved patient care, and we’ve delivered results.

For example—and this is the result of the efforts of former WVOS President John Azar, MD—when we were putting together our bylaws in 2008, the West Virginia Employees Insurance Agency, one of the state’s larg-

Fast Facts ■ ■ ■ ■ ■

est health-care payers, didn’t cover BRCA1 and BRACA2 gene testing for patients with breast cancer on Medicaid. Through Dr. Azar’s and WVOS’ advocacy efforts, we were able to get coverage for the test.

The strength of a coalition of physicians, nurses, pharmacists, and educational sponsors gave us the voice to lobby for coverage of the test, and it showed that we can get things done.

Our other great effort, of course, is the formation of the West Virginia Cancer Clinical Trials Network.

Drug Shortages How are you able to confront the oncology drug shortage problem affecting your state?

The problem is much better now.

But in 2011, agents like leucovorin, anthracyclines, and cytarabine were in short supply. We established a policy whereby if any practice in West Virginia was running into a drug shortage problem, we would post the information on our website and ask members for suggestions or remedies. It was a way for us to help each other in a transparent way and ensure that our patients had the treatment they needed.

Unique Challenges What challenges do you face that are unique to your society?

We are a small state with a big heart, and we want to make sure that our voices are heard and that problems can be solved to provide the best oncology care for our patients. That requires us to have a strong legislative advocacy effort. For example, under the leadership

What are your future goals?

We want to increase our membership to include everyone involved in oncology care, such as nurse practitioners and physician assistants, because they are critical to our future.

We want to bring them into the fold and provide them with educational opportunities.

Our other great challenge as a state society is helping bring down the high cancer mortality rate in West Virginia, which is the highest in the nation, due in large part to smoking, obesity, and having an older population. We are hoping that with the full implementation of the West Virginia Oncology Trials Network throughout the state, providers will have the training and infrastructure to offer clinical trials to more patients with cancer and provide improved access to cutting-edge therapies. n

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

Reference 1. Manchin J: Straight from the Governor’s Desk: Governor Joe Manchin on WVOS. Oncology Review. West Virginia Oncology Society, September 2009.

website at ASCOPost.com

The ASCO Post | AUGUST 15, 2013

PAGE 98

Health-care Policy

The Sunshine Act Calls for Greater Transparency in Industry-Doctor Relationships

By Ronald Piana

S

igned into law on March 23, 2010, the Patient Protection and Affordable Care Act represents the most significant overhaul of the U.S. healthcare system since the passage of Medicare and Medicaid in 1965. Because of the law’s sheer scope, parts of it still remain obfuscated by its 2,400 or so pages. Along with creating universal access to care, the legislation is also designed to deter overutilization of services and perverse incentives that adversely af-

Like most government programs, the wellintentioned Sunshine Act will have some bumps along the way as it is fully implemented. fect the delivery of care. One such part is the Physician Payments Sunshine Act, which will require pharmaceutical and medical device manufacturers to report most payments or gifts to physicians and teaching hospitals on a national level.

How will the sunshine act affect relationships?

The history of Sunshine Acts dates back to the Government in the Sunshine Act enacted September 13, 1976, which is one of a number of Freedom of Information Acts that are intended to create greater transparency in government. The obvious intent is to “shine a light” on the entities that abuse the system for financial gain.

Key Dates

A

pplicable manufacturers and group purchasing organizations must begin data collection in connection with the requirements of the Sunshine Act on August 1, 2013. The first reports must be filed with the Centers for Medicare & Medicaid Services (CMS)

by March 31, 2014. CMS will release the responsive data to the public through a CMS website by September 30, 2014. n

The Physician Payments Sunshine Act released its final rule in February, but the first reports are not due until March 31, 2014. In general, the Sunshine Act requires applicable manufacturers of drugs, devices, biologicals, or medical supplies to report annually to the Secretary of Health & Human Services certain payments or other transfers of value to physicians and teaching hospitals. It also obliges applicable manufacturers and applicable group purchasing organizations to report certain information regarding the ownership or investment interests held by physicians or the immediate family members of physicians in such entities.

How will the Sunshine Act affect working relationships between oncologists and members of the pharmaceutical industry? According to the Centers for Medicare & Medicaid Services (CMS), sales representatives can still visit oncologists in their practices, and they can still provide small snacks at conferences. However, given the relatively low spending cap, representatives from industry will have to publically report business dinners when a doctor is present.

Many leading oncologists have written agreements with pharmaceutical companies to serve as consultants on scientific advisory boards.

Although these agreements fall within the purview of the Sunshine Act, reasonable compensation and reimbursement for serving on bona fide advisory boards is still permitted as long as they are reported. This also holds true for payments related to clinical trials, but a provision in the Sunshine Act delays the public disclosure of clinical trial payments for up to 4 years.

Just how restrictive are the new regulations?

The Sunshine Act requires manufacturers to report individual expenses of $10 or more, and if the total of all payments or gifts to a health-care provider exceeds $100 in a given year, then all outlays to that provider must be reported, regardless of the value. It’s worth noting that reporting responsibility falls solely to the pharmaceutical or device manufacturer, not the individual health-care provider.

However, one part of the CMS final rule that has raised eyebrows among

Required Reporting

A ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

pplicable manufacturers are required to report to the Centers for Medicare & Medicaid Services the following types of payment: Consulting fees Compensation for services other than consulting, including serving as faculty or as a speaker at an event other than a continuing education program Honoraria Gifts Entertainment Food and beverage Travel and lodging Charitable contributions Royalty or license Current or prospective ownership or investment interest Compensation for serving as faculty or as a speaker for an unaccredited and noncertified continuing education program Compensation for serving as faculty or as a speaker for an accredited or certified continuing education program Grants Space rental or facility fees (teaching hospital only)

some health-care policy experts is an exception in payments made to physicians speaking at Continuing Medical Education (CME) programs. According to the final rule, companies will not be required to report payments to speakers at accredited CME meetings, as long as the pharmaceutical companies do not personally select the speakers.

In short, that means that accredited third-party CME providers will be exempt from reporting payment to speakers. Some policy experts point out that speakers at CME programs rarely give talks that are critical of the sponsors drugs or therapies, and for many “key opinion leaders,” paid speaking engagements constitute a good portion of their income.

‘Covered Recipients’

T

he Sunshine Act calls for disclosure by manufacturers of payments to “covered recipients.”

A covered recipient is a teaching hospital or any physician who is currently licensed and legally authorized to practice, except for a physician who is an employee of the applicable manufacturer that is reporting the payment. Medical residents are not covered recipients. n

Data concerning financial relationships between industry and healthcare providers have been collected for years. A 2007 study in The New England Journal of Medicine1 found that 94% of U.S. physicians had a relationship with the drug and device industries; 83% received gifts, and 28% received payments for services such as consulting or research participation. The study also found that commercial funding for CME has increased; industry currently pays for more than one-third of all CME offerings.

Critics of the Sunshine Act and other government oversight efforts are quick to point out that interaction between industry and healthcare providers is a central part of the working relationships that are part of our bench-to-bedside process. In other words, industry-doctor relationships are a seamless way to provide overworked physicians with the latest clinical data and upcoming developments in the pipeline. Naturally, like most government programs, the wellintentioned Sunshine Act will have some bumps along the way as it is fully implemented. n Reference 1. Campbell EG, Gruen RL, Mountford J, et al: A national survey of physician-industry relationships. N Engl J Med 356:1742-1750, 2007.

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To learn more, visit www.xofigo-us.com 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 • 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 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%) was similar for patients treated with Xofigo and placebo.

Myelosuppression—notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

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 • 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 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 • 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 • 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 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%)

Please see following pages for brief summary of full Prescribing Information.

© 2013 Bayer HealthCare Pharmaceuticals and Algeta ASA. All rights reserved.

BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer. ALGETA is a trademark of Algeta ASA.

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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 Renal and urinary disorders As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is 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, 2013

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News

Adolescents, Young Adults with Cancer Often Challenged By Unmet Needs Following Treatment Institute of Medicine and Livestrong Foundation urge more research.

By Margot J. Fromer

A

bout 70,000 adolescents and young adults (AYAs) between the ages of 15 and 39 are diagnosed with cancer each year, and in the past 30 years, there has been little or no improvement in survival in this population. In addition to the disease itself, they face many other challenges: reentry into school or the workforce, infertility as a result of treatment, shortand long-term neurocognitive effects, and cardiopulmonary conditions. And they are at high risk for post-traumatic stress disorder, depression, and suicide.

In July, the Institute of Medicine’s National Cancer Policy Forum and the Livestrong Foundation held a workshop in Washington, DC, to discuss these issues.

Scope of the Situation Archie Bleyer, MD, Clinical Research Professor, Knight Cancer Institute, Oregon Health and Science University, said that leukemia, lymphoma, and germ cell testicular cancer are the

Archie Bleyer, MD

most common among adolescents and young adults under 24. Between ages 25 and 39, they decrease in frequency, whereas metastatic breast, cervical, kidney, and colorectal cancers increase.

On the “plus side,” 12% to 16% of cancers in AYAs are noninvasive. In addition, Dr. Bleyer offered the following particulars on current incidence data in adolescents and young adults: • Thyroid and kidney carcinomas are increasing dramatically, the latter more in AYAs than any other age group. This is partly due to better detection.

• Colorectal and testis cancers also are increasing but not as rapidly.

• Acute lymphocytic leukemia (ALL)

is increasing in and only in adolescents and young adults.

• Breast cancer has increased during the past decade.

• Lung cancer has declined in older AYAs, probably because fewer smoke. Melanoma and cervical cancer also have declined because of increased use of sunscreen and human papillomavirus vaccine, respectively.

Only accidents, suicide, and homicide claim more AYA lives than cancer. In females, cancer is the leading disease-related death; in males it is second only to heart disease. White patients with cancer have the best 5-year survival, but they also have the highest incidence. Black patients have the lowest survival rates.

Dr. Bleyer said that AYA cancers are still relatively poorly understood and may be one reason for poor survival. “Disease biology is different in this age group, not only among the cancers themselves but also within individual types and individual patients.

Thus, there is an urgent need for more research into the molecular and epidemiologic nature of these diseases, as well as specific treatment strategies.”

Other factors for poor survival include delayed diagnosis, inadequate access to and participation in clinical trials, inadequate treatment, and unmet psychosocial and supportive care needs.

AYA HOPE Study Few data exist about clinical care and psychosocial problems, and there are few tools to measure them. For these reasons, in 2006, the National Cancer Institute (NCI) undertook the Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) study in 524 patients.

Linda Harlan, PhD, Epidemiologist in the NCI Division of Cancer Control and Population Sciences, explained that this feasibility study was designed to obtain data on consent and to conduct a patient survey.

The patients had germ cell (n = 205), Hodgkin (n = 142) and nonHodgkin (n = 131) lymphoma, ALL (n = 21), and sarcoma (Ewing sarcoma, osteosarcoma, and rhabdomyo-

young adults and provide education and training to improve awareness, prevention, access, and quality of care.

What Cancer Can Mean for AYAs

Karen Fasciano, PsyD

sarcoma, n = 25). They were asked to complete the survey at 6 to 14 months after diagnosis, as well as 1 to 2 years after diagnosis.

The survey focused on financial and other barriers to care, social and physical function, the effect of cancer on health-related quality of life, patterns of care delivery, and clinical trial participation. The follow-up contained questions about fertility preservation, school and job adjustment, and new primary cancers.

Approximately 43% of eligible patients responded to the survey, more than one-third of whom reported health-related quality of life problems.

Survey findings included: • Of patients who had worked or been in school full-time before diagnosis, 72% returned to full-time work or school. Only 34% who had been part-timers returned full-time.

• Those who had been full-time students or workers but who had no health insurance or who had quit working directly after diagnosis were least likely to return to work or school.

• Patients who had very intensive treatment and quit work or school as a result believed that the cancer negatively affected plans for the future.

• More than half said that cancer had a negative effect on their financial situation and body image, and slightly less than half had negative feelings about sexual function, control of their lives, and plans for having children.

• Surprisingly, more than half found that having had cancer improved their relationship with parents and siblings.

Dr. Harlan said that the study established a need to identify aspects of the cancer burden in adolescents and

Karen Fasciano, PsyD, Psychologist, Dana-Farber Cancer Institute, described developmental problems in AYAs with cancer. “At diagnosis, they might have difficulty comprehending information and dealing with their emotions, and they are probably devastated by what the disease will do to their lives. During treatment, they face challenges to their coping skills and are uncomfortable with returning to the dependence they thought they had left behind. When treatment is finished, they see that their lives are irrevocably changed, they need to reevaluate life choices, and, most difficult—they must cope with the uncertainty of the future.”

Eric Tai, MD, Medical Officer in the Centers for Disease Control (CDC) Division of Cancer Prevention and Control, described CDC’s Behav-

Eric Tai, MD

ioral Risk Factor Surveillance System, established in 1984 and the largest continuously conducted telephone health survey in the world. “AYA cancer survivors commonly reported behavioral, medical, and health-care access problems, many of which cause poor long-term medical and psychosocial outcomes.”

Preserving Fertility Ruth Rechis, PhD, Director of Evaluation and Research, Livestrong Foundation, said that in a Livestrong survey, 24% of AYAs took steps to preserve their fertility before treatment began. Among those who did not, 40%

ASCOPost.com | AUGUST 15, 2013

PAGE 103

News

Ruth Rechis, PhD

said they weren’t interested in having more children, 15% believed they would not be infertile, 22% didn’t have enough time, 17% did not receive appropriate information, and 13% said it was too expensive.

In many cases fertility can be preserved, said Jennifer Levine, MD, MSW, MS, Assistant Professor of Clinical Pediatrics, Columbia University

Preserving female fertility is more problematic but not impossible. Infertility in women can result from surgical removal of or damage to the uterus or ovaries (acute ovarian failure or premature menopause), hormonal dysfunction, and germ cell loss.

Embryo cryopreservation is the easiest and most common way to preserve fertility in women, but it has limitations, including age of the patient, religious beliefs, and the need for a partner or sperm donor. Moreover, it is expensive and can delay the start of treatment. Oocyte cryopreservation is possible, but oocytes are more susceptible to injury than embryos. It too is expensive and time-consuming. If the tumor is limited to the cervix, a radical trachelectomy can preserve fertility. Ovarian tissue cryopreservation is experimental and expensive.

Dr. Levine recommended that all AYA patients discuss fertility at diagnosis, and those who want to preserve it should be referred to a reproductive endocrinologist. If not, fertility should certainly be assessed after treatment.

Lifelong Consequences Jennifer Levine, MD, MSW, MS

Medical Center. In males, radiation, surgery, and chemotherapy can deplete germ cells temporarily or permanently.

They also can damage the ductal system, nerves, and the pituitary gland.

Prevention measures include sperm banking and cryopreservation prior to treatment. This is the most common and effective way to ensure postcancer fertility and should be done before treatment begins. After treatment, men should undergo semen analysis to determine whether stored sperm needs to be saved. Testicular sperm extraction and testicular tissue freezing are available, but both are experimental and expensive.

For AYA cancer survivors, the consequences of the disease stay with them forever. Patricia Ganz, MD, Distinguished University Professor, Jonsson Comprehensive Cancer Center, UCLA Schools of Medicine and Public Health, believes that lifelong surveillance is critical. “There is broad heterogeneity of cancer types as well as a wide age range,” she said. “Therefore, if a recurrence or second cancer is detected early, we can save a life.”

Factors that should be taken into consideration include rapid vs slowgrowing cancers and the implications for frequency and intensity of monitoring, especially for diseases that can be cured at the time of recurrence, and the paucity of evidence-based surveillance guidelines despite disease-spe-

cific strategies. For solid tumors and sarcomas, surveillance needs differ for local vs metastatic disease. In hematologic malignancies, the focus should be on imaging, blood markers, and bone marrow exams, Dr. Ganz noted.

There are few competing causes of death in adolescent and young adult patients, she pointed out. Treatment varies, but it tends to be highly successful in germ cell tumors, Hodgkin lymphoma, thyroid, and high-grade non-Hodgkin lymphoma.

Patricia Ganz, MD

Dr. Ganz stressed the importance of awareness that some cancers in the AYA population are associated with a hereditary predisposition gene. These include Li-Fraumeni syndrome, hereditary nonpolyposis colorectal cancer/ Lynch syndrome, familial adenomatous polyposis, and BRCA1/2-mutated breast cancers. If you are able to determine that an AYA patient carries a mutated gene that puts him at risk for additional second cancers, then appropriate screening and prevention strategies can be followed. She also addressed the predilection of some treatments, such as radiation and chemotherapy, to cause recurrence and/or second primaries, sometimes 10 to 20 years after initial exposure.

Nevertheless, Dr. Ganz used breast cancer surveillance to illustrate the limitations of some monitoring approaches: “Adjuvant clinical trials called for abandonment of routine monitoring with chest films and various scans in

the 1990s because recurrence detection was rare prior to clinical symptoms. In fact, there was no difference in survival outcome for women who had routine office visits and mammograms compared to those who had blood work, chest films, scans, and ultrasounds,” she pointed out.

“Moreover, no data support use of tumor markers, and the rate of false-negatives and false-positives is unknown,” she continued. “In fact, tumor marker results can contribute to further—and unnecessary—medical testing. Nor is there evidence to support the use of routine imaging such as chest and abdominal [computed tomography] scans or whole-body [positron-emission tomography] scans.”

After describing a study in Ontario, Canada, where many AYA patients were found to have excessive imaging studies, exposing them to unnecessary radiation, Dr. Ganz raised several questions about surveillance monitoring with imaging tests: • Why are disease-free long-term survivors receiving so many imaging studies, and how can their number, as well as other unnecessary procedures, be reduced?

• How effective will guidelines be in reducing unnecessary testing?

• How do we educate and empower AYA survivors?

• How do we identify high-risk groups and educate primary care providers?

She believes we urgently need an evidence base for surveillance to increase the rationality of testing. “We also need standardized approaches to screening for second malignancies, as well as chemical and surgical prophylaxis. And not least of all, we must implement behavioral and lifestyle risk-reduction strategies to prevent recurrences and second cancers.” n

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

Don’t Miss These Important Reports in This Issue of The ASCO Post Judy Garber, MD, MPH, on Triple-negative Breast Cancer see page 3

Ranjana Advani, MD, on B-cell Receptor Signaling Inhibitors in Lymphoma see page 18

Visit The ASCO Post online at ASCOPost.com

Fred R. Hirsch, MD, PhD, on ALK Inhibition in Lung Cancer see page 31

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ASCOPost.com | AUGUST 15, 2013

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News

Professional Societies Endorse 2015 Standard for Cancer Center Accreditation by Commission on Cancer American Psychosocial Oncology Society to Provide Support for Required Cancer Center Distress Screening

I

n 2015, the American College of Surgeons (ACoS) Commission on Cancer (CoC) will require cancer centers to implement screening programs for psychosocial distress as a new criterion for accreditation. The American Psychosocial Oncology Society (APOS) recently announced recommendations to support a new criterion for cancer center accreditation.

APOS, along with the Association of Oncology Social Workers (AOSW) and Oncology Nursing Society (ONS) endorse the new Commission on Cancer standard of psychosocial distress screening. “This is a landmark in our work to provide cancer care for the whole patient,” said Jimmie C. Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan-Kettering Cancer Center, New York, and founder of APOS. “This mandatory screening will help

address unmet psychosocial needs throughout oncology care. Our organization exists, in part, to provide educational support to meet the new CoC standards,” Dr. Holland said.

Vast Impact Anticipated This requirement will have a vast impact on patient care. There are currently over 1,500 CoC-accredited facilities in the United States serving 70% of newly diagnosed cancer patients. “The Cancer Support Community is pleased to join APOS, AOSW, and ONS in supporting the adoption of required distress screening in cancer care,” said Kim Thiboldeaux, President and CEO of the Cancer Support Community.

“Integrating routine distress screening and helping patients develop a care plan to address their social, emotional, and financial needs are essential to quality cancer care.”

Jimmie C. Holland, MD

APOS, together with AOSW and ONS, has published a joint statement, identifying eight key issues (see sidebar) that must be addressed before cancer centers can adhere to the new guidelines and provide quality patient care.

“We’re pleased that the CoC has taken this step,” said William F. Pirl, MD, MPH, Director of the Center for Psychiatric Oncology and Behavioral Sciences at Massachusetts General Hospital Cancer Center, Boston, and

Kim Thiboldeaux

William F. Pirl, MD, MPH

President of APOS. “Our organizations, representing over 36,000 professionals involved in care for patients with cancer, recommend that cancer centers to explore resources to help them adopt a universal definition of distress, use validated tools for distress screening, conduct screening more than once during a patient’s period of treatment, and establish a process for clear communication of results to the patient’s treatment team.” continued on page 106

Key Issues in Joint Commission Statement by American Psychosocial Oncology Society, Association of Oncology Social Work, and Oncology Nursing Society • It is imperative that [Commission on Cancer]-accredited programs adopt a universal definition of distress. We concur with the National Comprehensive Cancer Network definition of distress as an “unpleasant emotional experience of a psychological (cognitive, behavioral, emotional), social, and/or spiritual nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment.”1 • A variety of tools exist for distress screening,2 and programs should select and use validated instruments, following published threshold values and ranges to identify distressed patients.

• Given that distress has multiple dimensions, instruments should screen broadly and not focus solely on one particular symptom.

• Distress can occur at multiple time points from a cancer diagnosis onward and may go unrecognized if screening is conducted at only one time.

• Processes need to be established for the results of every screen to be communicated to and reviewed by the patient’s treatment team in a timely manner. Similar to measuring vital signs, a medical assistant could administer a screening instrument, but clinicians trained in distress screening must interpret the results.

• If the score exceeds the distress threshold, a trained clinician should differentiate the cause of distress (i.e., depression, lack of transportation, shortness of breath, etc.) and ensure that an assessment by or referral to an appropriate qualified clinician is completed. Programs should follow the NCCN guidelines for the management of distress. 1 • Referrals for the assessment and management of distress should be considered part of a patient’s routine medical care, and presented to the patient as such. Because the risk of suicide is elevated in individuals with cancer, patients whose screens

suggest suicide risk should be asked about suicidal ideation as part of their clinical evaluation.3-5 • The required psychosocial representative on the cancer committee who oversees the screening program should have training in the identification and management of distress in patients with cancer. Programs without such a person should consider educating a current staff member. Information about training opportunities can be found through APOS (www.apos-society. org), AOSW (www.aosw.org) and ONS (www.ons.org/CourseDetail. aspx?course_id=87 and www.ons. org/Research/PEP/).

• In the event that a cancer program does not have licensed mental health professionals on staff, we strongly encourage contracting with a professional psychosocial oncology expert or qualified community organization for referral and follow-up. n

References 1. National Comprehensive Cancer Network. Distress Management Clinical Practice Guidelines in Oncology.

Version 3.2012. Available at http:// www.nccn.org/professionals/physician_gls/pdf/distress.pdf.

Accessed August 1, 2012.

2. Carlson LE, Waller A, Mitchell AJ: Screening for distress and unmet needs in patients with cancer: Review and recommendations. J Clin Oncol 30(11):1160-1177, 2012.

3. Misono S, Weiss NS, Fann JR, Redman M, Yueh B. (2008) Incidence of suicide in persons with cancer. J Clin Oncol 26: 4731-4738, 2008.

4. Anguaino L, Mayer DK, Piven ML, Rosenstein D. (2011) A literature review of suicide in cancer patients.

Cancer Nurs 35: E14-E26.

5. Cooke L, Gotto J, Mayorga L, Grant M, Lynn R. (2013) What do I say? Suicide assessment and management. Clin J Oncol Nurs 17: E1-E7.

Used with permission from APOS. © 2013 American Psychosocial Oncology Society

The ASCO Post | AUGUST 15, 2013

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Awards

David Penson, MD, MPH, Receives $2 Million Research Award to Study Prostate Cancer

D

avid Penson, MD, MPH, Professor of Urologic Surgery, Vanderbilt University Medical Center, Nashville, has received a $2 million

David Penson, MD, MPH

research award from the Patient-Centered Outcomes Research Institute to study localized prostate cancer. Dr. Penson is also Director of the Vanderbilt Center for Surgical Quality and Outcomes Research.

Patient-reported Outcomes in Prostate Cancer Over the next 3 years, Dr. Penson will study patient-reported outcomes and compare the effectiveness of treatment of prostate cancer in 3,691 men diagnosed with prostate cancer in five

states in 2011. Working with Tatsuki Koyama, PhD, Assistant Professor of Biostatistics, and Daniel Barocas, MD, MPH, Assistant Professor of Urologic Surgery, Dr. Penson hopes to better educate men on the types of treatment available, known complications, and overall quality of life following treatment of prostate cancer.

“This is very important work focused on understanding the expectations of patients and improving outcomes in men who have prostate cancer,” said R. Daniel Beauchamp, MD, Chair of the Section of Surgical Sciences, at Vanderbilt.

Network of Tumor Registries The $2 million study builds on Dr. Penson’s recent success in developing a network of tumor registries that collect patient data that may hold the key to more scientifically proven treatment plans that make the most sense for each patient.

Vanderbilt started this network in 2010 through a $7.6 million Agency for Healthcare Research and Quality grant. Dr. Penson’s Comparative Effectiveness Analysis of Surgery and Ra-

diation (CEASAR) study continues to collect critically important data such as treatment complications and shortterm cancer rates by following nearly 4,000 men diagnosed with prostate cancer.

Though men diagnosed with prostate cancer have a variety of treatment options, including surgery, radiation, and active surveillance, each of these comes with its own risks, side effects, and impacts on overall quality of life.

What isn’t clear is how to take this information and personalize it for individual patients in a way that helps them make clinical decisions consistent with their own personal preferences and values.

“No one wants to tackle cancer by guessing,” said Dr. Penson. “For the first time, we really have an opportunity to give patients the tools and information they need to lead a healthier, fuller life.”

Collaboration with Patient Advocates To ensure key findings from the study are made widely available to men with prostate cancer, Dr. Penson has

Save

Commission on Cancer continued from page 105

Part of Routine Care The joint statement emphasizes that referrals for the assessment and management of distress should be considered part of a patient’s routine medical care, and presented to the patient as such. Because the risk of suicide is elevated in individuals with cancer, patients whose screens suggest suicide risk should be asked about suicidal ideation as part of their clinical evaluation.

To prepare for 2015 and the implementation of the screening program, APOS recommends that the required psychosocial representative on the cancer committee who oversees the screening program should have training in the identification and management of distress in patients with cancer. Online training opportunities are available through APOS (www.apossociety.org), AOSW, and ONS. n

partnered with patient advocacy leaders at Vanderbilt and nationally.

Dan McCollum, Health Information Specialist at the Eskind Biomedical Library and a prostate cancer survivor, will lead patient stakeholder communications.

He will work with the VanderbiltIngram Cancer Center’s Office of Patient and Community Education to identify interested prostate cancer survivors to serve on a patient advisory council.

The Tennessee chapter of the Men’s Health Network, a patient advocacy group focused on men’s health issues, including prostate cancer, will assist in engaging patients from outside of Vanderbilt.

And the Health Ratings Center of Consumer Reports will assist with study design and future dissemination of information to the public.

“I’m really excited about this award because it will generate rich information that patients can use to make personalized decisions on both how and where to treat their prostate cancer, based on hard science and actual patient outcomes,” Dr. Penson said. n

the date !

images courtesy of visittampabay.com

APOS

2014 T A M P A Implementing Quality Care Standards for Psychosocial Oncology and Supportive Care

APOS 11th Annual Conference 13 –15 February 2014

Tampa Convention Center • Tampa, Florida, USA

Featuring Keynote Speakers: Philip A. Pizzo, M.D.

Former Dean and Professor of Pediatrics and of Microbiology and Immunology Stanford University School of Medicine

Carolyn D. Runowicz, M.D.

Executive Associate Dean for Academic Affairs Professor of Obstetrics and Gynecology Florida International University, Herbert Wetheim College of Medicine

Visit www.apos-society.org/apos2014 for details!

NOW ENROLLING – A RANDOMIZED PHASE lll STUDY

A Phase III study of the pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in patients with HR+/HER2−, aromatase inhibitor-treated, locally advanced or metastatic breast cancer who progressed on or after mTOR inhibitor Postmenopausal women with HR+/HER2–, inoperable, locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor (N≈615) Evidence of progression on or after mTOR inhibitor-based therapy No more than one prior line of chemotherapy for metastatic disease Archival tumor tissue for analysis of PI3K pathway activation

Molecular pre-screening*

ECOG Performance Status ≤2

Randomization (2:1)

Additional inclusion/exclusion criteria apply.

Buparlisib + fulvestrant

Placebo + fulvestrant

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival *Molecular pre-screening for PI3K activation status can occur at any time prior to randomization after obtaining pre-screening informed consent.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established.

There is no guarantee that buparlisib will become commercially available.

For more information Contact your local Novartis representative.

Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (USA only).

Visit www.clinicaltrials.gov (NCT01633060).

Visit the PRI3M program website at www.pri3m.com or scan the QR code.

Pioneering Research of PI3K inhibitors in Malignancies

www.pri3m.com Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080

© 2013 Novartis

February 2013

G-BKE-1061803

Novartis Pharma AG CH-4002, Basel, Switzerland

The ASCO Post | AUGUST 15, 2013

PAGE 108

Integrative Oncology Acupuncture May Reduce Arm Lymphedema in Patients with Breast Cancer

By Matthew Stenger

A

rm lymphedema affects approximately 30% of breast cancer survivors, with rates increasing with longer follow-up and cases of lymphedema presenting well beyond the active treatment period. Lymphedema is observed even with the use of less-invasive surgical techniques for staging, and risk is further increased by such factors as radiation therapy, positive lymph node status, increased tumor burden, postoperative seroma or infection, obesity, and increased age.

Current treatments for lymphedema after breast cancer treatment are expensive and require ongoing intervention. As reported by Barrie R. Cassileth, MS, PhD, of the Integrative Medicine Service at Memorial SloanKettering Cancer Center and colleagues in Cancer,1 acupuncture may be an effective treatment.

Study Details In a pilot study, women with breast cancer who had undergone axillary surgery and had unilateral arm lymphedema for 6 months to 5 years and an affected arm circumference ≥ 2 cm greater than the unaffected arm received acupuncture treatment twice weekly for 30 minutes for 4 weeks. Arm circumference was measured before and after each acupuncture treatment, with response defined as a ≥�� 30% reduction in circumference difference.

After the 4-week treatment period, follow-up calls were made monthly for 6 months to document complications and self-reported lymphedema status.

Women with previous acupuncture treatment for lymphedema or currently using diuretics were excluded from the study, as were those with metastatic disease, history of autoimmune or

fibroproliferative disorders, history of primary lymphedema or bone marrow transplantation, or current treatment with corticosteroids or myelosuppressive or myelostimulatory drugs.

Patients had a median age of 55 years and most were white (76%) and had lymphedema of the left arm (64%). Primary surgery was mastectomy in 67% and breast-conserving surgery in 33%. Most patients had received chemotherapy (88%) and radiation therapy (85%) and had been on standard lymphedema treatment (88%) prior to the study. The median time from axillary surgery to start of acupuncture was 3.9 years.

Significant Improvement Patients had a total of 255 acupuncture treatment sessions, with 25 (76%) receiving all eight sessions, 7 (21%) missing one session, and 1 (3%) missing two sessions. A 30% or greater reduction in circumference difference was observed in 11 patients (33%), and 18 (55%) had a reduction of ≥�20%. �20%.

20%. Th Thee mean reduction in circumference difference was 0.90 cm (P < .0005), and reduction in circumference was observed across the full range of severity of lymphedema.

Thirty-one patients (94%) used other standard therapies during the study, with 28 (93%) of 30 reporting no change to their standard regimens during acupuncture treatment. Four of 11 responders reported sustained improvement for 4 months during the follow-up period. Three additional responders reported sustained improvement for at least 4 weeks after treatment.

During the treatment period, 14 (43%) of the 33 patients reported minor complaints, including mild local bruising or pain/tingling. There were

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 SloanKettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc.

Barrie R. Cassileth, MS, PhD org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 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, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. no serious adverse events and no infections or severe exacerbations during the treatment period or during 6 months of follow-up.

The study authors concluded, “Acupuncture for breast cancer-related lymphedema appears safe and may reduce arm circumference. Although these results await confirmation in a randomized trial, acupuncture can be considered for women with no other options for sustained arm circumference reduction.”

The investigators are currently conducting a randomized trial of acupuncture in this setting. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Cassileth BR, Van Zee KJ, Yeung KS, et al: Acupuncture in the treatment of upper-limb lymphedema. Cancer 119:24552461, 2013.

See commentary on page 110

Acupuncture for Lymphedema ■ Acupuncture was associated with a ≥ 30% reduction in arm circumference difference in 33% of patients and a ≥ 20% reduction in 55%.

■ No serious adverse events and no infections or severe exacerbations were observed during the treatment period or during 6 months of follow-up.

■ A randomized trial of acupuncture in this setting is currently underway.

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs www.mskcc.

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REFERENCES: 1. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. 2. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. 3. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358-2364.

Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2013 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved.

Printed in USA USP/COR/2013/0001(1)

The ASCO Post | AUGUST 15, 2013

PAGE 110

Integrative Oncology Continued from page 108

Western Science Catching Up with Traditional Chinese Medicine

By Donald I. Abrams, MD

S

ince the National Institutes of Health Consensus Statement in 1997 concluded that the evidence to date suggests acupuncture is effective in the treatment of chemotherapy-induced nausea and vomiting,1 numerous additional indications for its use in relieving symptoms related to cancer or its treatment have been confirmed.

There are data to support the use of acupuncture for relief of hot flashes related to hormonal manipulation in women with breast cancer,2 as well as in men on androgen-deprivation therapy.3 The musculoskeletal symptoms related to aromatase inhibitor therapy have also been found to improve with acupuncture in a sham-controlled trial.4 Recently, radiation-induced xerostomia in the treatment of head and neck cancer has also been ameliorated by the intervention.5 The National Comprehensive Cancer Network Adult Cancer Pain Guideline recommends acupuncture or acupressure as a useful integrative intervention to be considered.6 Many patients receive acupuncture in an attempt to decrease chemotherapy-associated peripheral neuropathy, with some evidence of success in clinical trials.

Now, the troublesome problem of lymphedema secondary to axillary lymph node dissection in women with breast cancer also appears to be responsive to acupuncture, on the basis of this well-conducted pilot from the Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center.

Former Taboos Dispelled One of the underlying features that make this report exciting is that lymphedematous limbs were previously considered to be off limits for acupuncture needle insertion, given a fear of the risk of infection or other potential complications. Although prior retrospective analyses questioned the need for this concern by showing no evidence of ill effects, this prospective trial reports no infections among the 34 women who were analyzed. Despite some reports of mild Dr. Abrams is Chief, Hematology-Oncology, San Francisco General Hospital; Integrative Oncology, UCSF Osher Center for Integrative Medicine; Professor of Clinical Medicine, University of California, San Francisco.

local bruising or pain and tingling, the investigators found no serious adverse events or exacerbations of the lymphedema in 255 treatment sessions with 6 months of follow-up.

Similarly, the fear of doing acupuncture in patients with cancer who have low platelet counts had already been put to rest by a study from the Integrative Medicine group in the Division of Pediatric Oncology at Colum-

trastuzumab (Herceptin) without more information about the particular patient’s pathology, a traditional Chinese medicine practitioner would not treat all women with treatment-related lymphedema with the same acupoints.

The young, thin, anxious woman with triple-negative breast cancer and lymphedema may warrant different acupuncture points than an overweight, postmenopausal, depressed,

The authors strongly signal that acupuncture helped a significant proportion of their participants with few minor complaints and no serious adverse effects. Why, then, would one suggest limiting this benign and seemingly effective intervention only to women with no other options?

—Donald I. Abrams, MD

bia University Medical Center when they reported no bleeding episodes in 32 patients being needled with mild to severe therapy-related thrombocytopenia.7 So, as more data accumulate, some of the former taboos against the procedure are being dispelled.

The Original Personalized Medicine Acupuncture is just one intervention used in the practice of traditional Chinese medicine, which usually also involves nutrition, movement, and herbal therapies. Traditional Chinese medicine practitioners use a whole different system to diagnose from the one we learn in Western medical practice. Treatment is usually individualized for each patient based on the traditional Chinese medicine diagnosis—think of it as the original personalized medicine.

This study, like virtually all studies in the Western literature, utilized a fixed set of acupuncture treatment points for all patients, regardless of their underlying traditional Chinese medicine diagnosis—hence, a deviation from the norm of practice and one that would, if anything, likely bias against the intervention. Just as an oncologist would not treat all women with breast cancer with docetaxel and

estrogen-receptor–positive counterpart in the eyes of the traditional Chinese medicine practitioner. However, to make the results more interpretable within the context of our Western scientific paradigms, only acupuncture is studied rather than the whole system of traditional Chinese medicine, and standardized acupuncture points for all study participants are the norm.

Two Concerns The investigators conclude that “although these results await confirmation in a randomized trial, acupuncture can be considered for women with no other options for sustained arm circumference reduction.” This summary statement presents two concerns.

First, the choice of an appropriate control intervention in acupuncture studies is very difficult. Inserting needles into what are not considered to be “true” acupuncture points could possibly exert similar effects to those obtained using the traditional sites.

Inserting specialized needles that do not puncture but are still along the active meridian and, in fact, sitting on a known acupuncture point may in and of itself cause a similar effect, since we know that burning the perennial plant mugwort over acupoints (moxibus-

tion) and applying manual pressure (acupressure) are therapeutic. So, deciding what constitutes a valid control for active acupuncture in the follow-on randomized trial could be a challenge.

Second, the authors strongly signal that acupuncture helped a significant proportion of their participants with few minor complaints and no serious adverse effects. Why, then, would one suggest limiting this benign and seemingly effective intervention only to women with no other options? Could this perhaps be one of the initial interventions one might consider? If it works for established lymphedema, could there be a role for prophylactic acupuncture to prevent lymphedema in patients at risk?

Many integrative oncologists generally manage all patients receiving active conventional cancer treatment interventions with a collaborating traditional Chinese medicine practitioner in hopes of minimizing side effects and optimizing clinical outcomes. Fortunately, it appears as if the science is catching up! n

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

Reference 1. Acupuncture. NIH Consensus Statement 15(5):1-34, November 3-5, 1997.

2. Walker EM, Rodriguez AI, Kohn B, et al: Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor-positive breast cancer: A randomized controlled trial.

28:634-640, 2010.

3. Beer TM, Benavides M, Emmons SL, et al: Acupuncture for hot flashes in patients with prostate cancer. Urology 76:1182-1188, 2010.

4. Crew KD, Capodice JL, Greenlee H, et al: Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer.

J Clin Oncol 28:1154-1160, 2010.

5. Simcock R, Fallowfield L, Monson K, et al: ARIX: A randomised trial of acupuncture v oral care sessions in patients with chronic xerostomia following treatment of head and neck cancer. Ann Oncol 24:776-783, 2013.

6. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Adult cancer pain. Version 2.2013. Available at www.nccn.org. Accessed July 18, 2013.

7. Ladas EJ, Rooney D, Taromina K, et al: The safety of acupuncture in children and adolescents with cancer therapy-related thrombocytopenia. Support Care Cancer 18:1487-1490, 2010.

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The ASCO Post | AUGUST 15, 2013

PAGE 112

Expert’s Corner Survivorship

Living and Working with Cancer A Conversation with Alan Astrow, MD

By Jo Cavallo

Alan Astrow, MD

T

he most recent figures from the National Cancer Institute put the number of cancer survivors in the United States at nearly 14 million—by 2022, that number is expected to top 18 million. And for the vast majority of those survivors—more than 80%— returning to work after treatment is a top priority and aids in their recovery, according to the results of a survey conducted by Cancer and Careers, an organization serving the needs of working cancer survivors. In addition, fully 60% of survey respondents said they did not take any time off or took only a few days off from their job after receiving a cancer diagnosis.1 With so many cancer survivors remaining in the workforce or returning to the workforce soon after a diagnosis, part of patient-centered oncology care has to address patients’ employment concerns, which may include adjusting treatment plans whenever possible to reduce side effects, that might inhibit job performance, said Alan Astrow, MD, Director of Hematology and Medical Oncology at Maimonides Medical Center in Brooklyn, New York.

Recently, Dr. Astrow addressed the issues of work and cancer during Cancer and Careers’ National Conference in New York. The ASCO Post talked with Dr. Astrow about the impact a cancer diagnosis may have on patients’ professional lives and what oncologists can do to help patients in their decisionmaking process about when to return to work after cancer treatment.

Patient Priorities What is important for patients to know about their treatment side effects and their potential impact on work?

Every patient’s response to treatment

is different. Also, the type of treatment often determines how soon a patient can return to work. Patients needing surgery may require time to recover from the acute effects of surgery before returning to work. Radiation and/or chemotherapy cycles, on the other hand, may last for months and may cause acute or gradually cumulative side effects.

Some patients prefer to continue working or may feel that they need to because of limited sick leave, whereas others will find that treatment toxicities hinder their job performance and they are unable to work. For the minority of patients who receive highly intensive chemotherapy, there may be some work environments that need to be avoided until blood counts recover because of the risk of developing an infection.

The patient’s type of cancer, treatment options, general health, and type of job are all factors in determining whether a patient should continue working while undergoing treatment and how soon after treatment she or he can return to work.

might want to take side effects such as peripheral neuropathy into account, to the extent that you have flexibility in designing the treatment plan.

Although you have to prescribe the most effective treatment for a specific cancer, often there are choices, and when there are choices, you try to consider the patient’s needs. The only way to learn the patient’s needs is by asking.

Encouraging Patient Participation You encourage patients to speak up about their career concerns with their medical team. Patients might be reluctant to do that for a variety of reasons.

How can oncologists broach the subject with their patients?

In New York—Brooklyn especially—patients tend not to be shy, which is a good thing. Wellness requires partnership, and I tell patients that there is no such thing as a bad or stupid question.

It is part of the job of the doctor and nurse to elicit the patient’s fears

Part of patient-centered care includes being aware of who the patient is and considering that what a patient does for a living is crucial information in devising a treatment plan.

—Alan Astrow, MD

Impact on Treatment How might a patient’s work concerns alter an oncologist’s treatment plan for that patient?

Part of being a good doctor is understanding what is important to the patient. Family, career, and friendships are all key parts of a person’s life.

We have a fellowship program at Maimonides Medical Center where we train our fellows to be aware of those aspects of the person’s life. Part of patient-centered care includes being aware of who the patient is and considering that what a patient does for a living is crucial information in devising a treatment plan.

For example, a patient might be a dancer, a pianist, or a construction worker for whom balance or fine motor coordination is crucial. If that patient needed chemotherapy, you

and concerns. For example, they can simply ask the patient, “How are things going at work?” The patient is free to answer or to let it go.

Paying attention to changes in a patient’s demeanor is part of the physician’s relationship with the patient. While the oncologist’s first responsibility is to treat the cancer, cancer is always happening within a person. If the patient seems out of sorts but doesn’t volunteer information, you might say, “You look worried today” and wait for a response. Or you could ask, “What’s on your mind today?

Tell me what you are thinking.”

Personal Experience Please talk about your own prostate cancer diagnosis and your concerns about telling colleagues about the diagnosis.

Three years ago, when I found out that I had prostate cancer, I knew I was

going to have to be away from the hospital for a number of weeks after surgery, and I wasn’t sure what to do. Should I tell my colleagues or keep that information private? I had to speak to some of the leadership in the hospital about taking a temporary medical leave, and they were very supportive. They left it up to me about how much I wanted to tell colleagues, or whether I wanted to say anything at all about the cancer.

I thought about it for a while and reasoned that if I were away for a few weeks without saying why, it might lead to wild speculation. Since prostate cancer is very common and a number of prominent individuals have been public about their cancer, I decided that the simplest thing would be to be straightforward and tell the doctors in my group. All my colleagues were understanding and encouraging, and I was glad I told them.

Has having cancer changed the way you relate to your patients?

I’ve always had an empathic style.

Naturally, I wish I didn’t have to personally experience a cancer diagnosis to add to my appreciation of what patients go through. Still, conveying a healing presence to patients requires that you give something of yourself. You can use your life experiences as a resource to help others—it is the gift of being, or becoming, a physician. Patients with cancer can be anxious—I certainly have been—and I may have a better sense of how that feels and what it means to patients as a result.

Life Changes How else has having had cancer changed your life?

You are more aware of the passage of time. We don’t live forever, and anything can happen at any moment. A cancer diagnosis can cut through one’s denial in a useful way, and having had cancer has been a reminder to me that if there are things that I’d like to do, enjoy, or accomplish, I should do them.

I don’t know if having cancer had anything to do with it, but since I had prostate surgery 3 years ago, I’ve been unusually productive. I gave one of the keynote talks at the Conference on Religion and Medicine,2 I am involved in several interesting research projects, and I have had papers published in The New England continued on page 113

ASCOPost.com | AUGUST 15, 2013

PAGE 113

Announcements

NIH Commits $24 Million Annually for Big Data Centers of Excellence

T

he National Institutes of Health will fund up to $24 million per year for 4 years to establish six to eight investigator-initiated Big Data to Knowledge Centers of Excellence. The centers will improve the ability of the research community to use increasingly large and complex datasets through the development and distribution of innovative approaches, methods, software, and tools for data sharing, integration, analysis and management. The centers will also provide training for students and researchers to use and develop data science methods.

Big Data to Knowledge Initiative Biomedical research is increasingly data-intensive, with researchers routinely generating and using large, diverse datasets. Yet the ability to manage, integrate and analyze such data, and to locate and use data generated by others, is often limited due to a lack of tools, accessibility, and training. In response, NIH launched the Big Data

Alan Astrow, MD continued from page 112

Journal of Medicine3 and the Journal of the American Medical Association.4 I take my time with my children more seriously than ever and I started playing golf again.

I certainly wouldn’t recommend prostate cancer as a form of life therapy, but having the experience has been strangely liberating. It was a reminder that there is no better time to get moving than now. n References 1. Cancer and Careers: Newly released survey reveals the majority of cancer patients and survivors want to continue working.

Available at http://www.cancerandcareers. org/en/2012-survey/2012-survey-pressrelease. Accessed July 25, 2013.

2. Astrow AB: Is medicine a spiritual vocation? Society 50:101-105, March/April 2013.

3. Astrow AB, Popp B: The Palliative Care Information Act in real life. N Engl J Med 364:1885-1887, 2011.

4. Astrow AB: Cancer survivorship and beyond. JAMA 30:1639-1640, 2012.

to Knowledge (BD2K) initiative in December. This initiative supports research, implementation, and training in data science that will enable biomedical scientists to capitalize on the transformative opportunities that large datasets provide.

The investigator-initiated Big Data to Knowledge Center of Excellence funding opportunity is the first of several funding opportunities to be announced in coming months.

“BD2K aims to enable a quantum leap in the ability of the biomedical research enterprise to maximize the value of the growing volume and complexity of biomedical data,” says Eric Green, MD, PhD, NIH Acting Associate Director for Data Science and Director of the National Human Genome Research Institute. “The Centers of Excellence will provide a key component of the overall initiative.”

By encouraging the formation of interdisciplinary teams in a collaborative environment the BD2K Centers of Excellence also seek to increase the

involvement of investigators outside of traditional biomedical areas who are experienced with data science.

“This funding opportunity represents a concerted effort to leverage the power of NIH in developing cutting-edge systems to address data science challenges,” said NIH Director Francis S. Collins, MD, PhD. “The goal is to help researchers translate data into knowledge that will advance discoveries and improve health, while reducing costs and redundancy.”

How To Apply Applicants responding to the BD2K Center of Excellence funding opportunity announcement should identify a research topic and propose research in data science. They should develop approaches, methods, software, and tools for data integration, analysis, database development and management, and visualization and

Eric Green, MD, PhD

Francis S. Collins, MD, PhD

modeling to address important research questions. The products from this research and development will be shared and distributed broadly to the research community. The centers are expected to interact as a consortium that cooperatively builds on individual research efforts.

An information webinar for prospective applicants will be held on Thursday, September 12, 2013, from 3 p.m. to 5 p.m. EDT. More details about this event and the overall BD2K initiative can be found at http://bd2k.nih. gov. Applications will be due on Nov. 20, 2013. n

Johns Hopkins Kimmel Cancer Center Announces New Leadership Appointment

M

ichael A. Carducci, MD, Professor of Oncology and Urology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore was recently

Michael A. Carducci, MD

selected as Associate Director for Clinical Research. In this role, Dr. Carducci will facilitate clinical research activities as well as oversee

the Clinical Research Office and other clinical research Cores.

Translational Research Experience Dr. Carducci brings considerable translational research experience to the role, directing a laboratory program and a portfolio of clinical trials targeted at introducing small molecules into cancer treatment. A translational researcher, Dr. Carducci directs a laboratory program focused on the re-expression of epigenetically silenced genes in cancer cells via the use of small molecules targeting DNA methyltransferases and histone deacetylases, and he manages a portfolio of clinical trials targeted at introducing these small molecules into cancer treatment. Overall, his laboratory and clinical research focus is on the devel-

opment and evaluation of new therapies for urologic cancers.

Dr. Carducci also is the AEGON Professor in Prostate Cancer Research and regional research director for the National Capital Region. As he takes on these new responsibilities, Dr. Carducci will relinquish the role of co-leader of the Prostate Cancer Program.

A graduate of Georgetown University, Dr. Carducci received his medical degree from Wayne State University School of Medicine. He completed an internal medicine internship, residency and chief residency at the University of Colorado Health Sciences Center. He went on to complete medical oncology and research fellowships at the Johns Hopkins Oncology Center at Johns Hopkins Hospital. n

The ASCO Post | AUGUST 15, 2013

PAGE 114

Announcements Society for Integrative Oncology

10th International Conference of the Society for Integrative Oncology Will Explore Translational Science Topics

T

his October for 3 full days (October 20–22) in Vancouver, Canada, oncologists, scientists, and other oncology health professionals will gather for the Society for Integrative Oncology Annual Meeting. This year’s conference theme is Translational Science in Integrative Oncology: From Bedside, to Bench, to Best Practices.

Keynote speakers include Frank Meyskens, Jr, MD, Professor of Medicine and Director of Chao Family Comprehensive Cancer Center at the University of California Irvine discussing chemoprevention through natural health products, and Kerry S. Courneya, PhD, Professor and Canada Research Chair in Physical Activity and Cancer presenting the role of physical activity in cancer prevention and survivorship.

The program will cover a variety of common topics that practicing oncologists frequently confront in their daily practice. Attendees will learn about the results of clinical trials including acupuncture, meditation, physical activity, and ginseng for patients with cancer, to address several common side effects and symptoms.

A number of sessions will also focus on basic science mechanisms of natural products and mind-body approaches and their potential implications for clinical practice.

Additionally, the conference includes several plenaries and workshops that aim to provide the audience with new skills and knowledge that can be immediately utilized in practice. Subjects covered include: evidence-based approaches to symp-

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tom management, introducing integrative therapies into your practice, nutrition and cancer, clinic and business models of integrative oncology,

and integrative oncology practice guidelines for lung cancer patients.

The conference offers AMA PRA Category 1 Credits. For fur-

ther information, visit the Society of Integrative Oncology website at www.IntegrativeOnc.org or call 347.676.1SIO. n

Simulated image based on patient with locally advanced BCC at Week 24.

Simulated image based on patient with locally advanced BCC at Week 24.

Boxed Warning And Additional Important Safety Information Boxed Warning And Additional Embryo-Fetal Death and Severe Birth Defects Important Safety Information

• Immediately report exposure to Erivedge during pregnancy and encourage women who may have been • exposed Immediately report exposure to Erivedgeeither during to Erivedge during pregnancy, directly pregnancy and encourage women who may have been or through seminal fl uid, to participate in the Erivedge •Embryo-Fetal Erivedge capsule can cause fetal harm when exposed to Erivedge during pregnancy, either directly Death and Severe Birth Defects pregnancy pharmacovigilance program by contacting administered to a pregnant woman based on its or through seminal fluid,Event to participate in the835-2555 Erivedge • Erivedge capsule can cause fetal harm when the Genentech Adverse Line at (888) mechanism of action pregnancy pharmacovigilance program by contacting administered to a pregnant woman based on its Blood Donation Adverse Event Line at (888) 835-2555 the Genentech • Verify pregnancy status prior to the initiation of mechanism of action Advise patients not to donate blood or blood products Erivedge. Advise male and female patients of these •Blood Donation • Verify pregnancy status prior to of while receiving Erivedge and for at least 7 months risks. Advise female patients of the the initiation need • after Advise patients notoftoErivedge donate blood or blood products Erivedge.

Advise male and female the last dose for contraception during and after patients treatmentof these while receiving Erivedge and for at least 7 months risks.

Advise female patients of the need and advise male patients of the potential risk Nursing Mothers after the last dose of Erivedge for contraception during and after treatment of Erivedge exposure through semen • Inform female patients of the potential for serious and advise male patients of the potential risk Nursing Mothers • Advise patients to contact their healthcare provider adverse reactions in nursing infants from Erivedge, of Erivedge exposure through semen Inform into female patients the potential for drug serious immediately if they suspect they (or, for males, their • taking account the of importance of the to • Advise patients to contact their healthcare provider adverse reactions in nursing infants from Erivedge, female partner) may be pregnant the mother immediately if they suspect they (or, for males, their taking into account the importance of the drug to female partner) may be pregnant the mother

ASCOPost.com | AUGUST 15, 2013

PAGE 115

Announcements

Leukemia & Lymphoma Society Appoints New Administrative Officer

T

he Leukemia & Lymphoma Society recently announced the appointment of Rosemarie Loffredo as its new Chief Administrative Officer and Chief Financial Officer.

In this newly created role, Ms. Loffredo will help ensure the Society achieves the goals of its long-range strategic plan. She will lead all administrative and staff functions, including finance, information technology, and

Rosemarie Loffredo

TRANSFORM THE TREATMENT OF TRANSFORM THE TREATMENT OF DIFFICULT ADVANCED BASAL CELL DIFFICULT ADVANCED CARCINOMA ((aBCC) BASAL CELL CARCINOMA ((aBCC) (Not actual size)

ERIVEDGE IS A UNIQUE ORAL THERAPY ERIVEDGE IS A UNIQUE ORAL THERAPY

• Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, and invasiveness), some patients may not be candidates for surgery or radiation1,2 • Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, • Erivedge is an oral some treatment option dosed ascandidates a 150-mg capsule once until1,2 and invasiveness), patients may not be for surgery or daily radiation disease progression or unacceptable toxicity3 • Erivedge is an oral treatment option dosed as a1,3 150-mg capsule once daily until • Erivedge reduced lesions in patients with aBCC 3 disease progression or unacceptable toxicity

(Not actual size)

1,3 • Erivedge reduced lesions in patients withby aBCC Objective response rates (ORR) IR from ERIVANCE1,3*

(n=63) mBCC (n=33) Objective response rates (ORR) bylaBCC IR from ERIVANCE1,3* ORR 43% (n=27) 30% (n=10) laBCC (n=63) mBCC (n=33) (95% CI) (30.5-56.0) (15.6-48.2) ORR 43% (n=27) 30%0% (n=10) Complete response 21% (n=13) (95% CI) (30.5-56.0) (15.6-48.2) Partial response 22% (n=14) 30% (n=10) Complete response 21% (n=13) 0% 7.6 Median duration of response (months) Partial response 22% (n=14) 30%7.6 (n=10) (5.7-9.7) (5.6-NE) (95% CI) 7.6 7.6 Median duration of response (months) (5.7-9.7) (5.6-NE) (95% CI) Indication ® Erivedge (vismodegib) capsule is a hedgehog pathway inhibitor indicated for the treatment Indication of adults®with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma Erivedge (vismodegib) capsule is aorhedgehog pathway inhibitor for the that has recurred following surgery who are not candidates forindicated surgery, and whotreatment are not of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma candidates for radiation. that has recurred following surgery or who are not candidates for surgery, and who are not *Patients received least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: candidates forat radiation.

absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target radiography or in externally visible with dimension (including scar tissue); or complete resolution ulcerationininlaBCC: all *lesions Patientsbyreceived at least 1 dose of Erivedge independent pathologist-confi rmed diagnosis of BCC.ofResponse target lesions.

Complete responders also had no residual BCC on sampling biopsy andlongest partial diameter) responders hadbaseline residualinBCC on absence of disease progression and either ≥30% reduction in lesion size (sum of the from target sampling Response mBCC: assessed by the Response Evaluation Criteria in Solid resolution Tumors (RECIST) version lesions bybiopsy. radiography or in in externally visible dimension (including scar tissue); or complete of ulceration in1.0. all target lesions. Complete alsoadvanced had no residual BCC on sampling biopsyrate; and CI=confi partial responders had residual IR=Independent Review; responders laBCC=locally BCC; ORR=objective response dence interval; NE=not BCC on sampling biopsy.

Response in BCC. mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. estimable; mBCC=metastatic IR=Independent Review; laBCC=locally advanced BCC; ORR=objective response rate; CI=confidence interval; NE=not estimable; mBCC=metastatic BCC.

Adverse Reactions •Adverse The most common adverse reactions (≥10%) were Reactions muscle spasms, alopecia, dysgeusia, weight loss, • fatigue, The most common adversedecreased reactions appetite, (≥10%) were nausea, diarrhea, muscle spasms, alopecia, dysgeusia, weight loss, constipation, arthralgias, vomiting, and ageusia fatigue, nausea, diarrhea, decreased appetite, • In clinical trials, a total ofvomiting, 3 of 10 premenopausal constipation, arthralgias, and ageusia women developed amenorrhea while receiving Erivedge • In clinical trials, a total of 3 of 10 premenopausal • Treatment-emergent grade 3 laboratory abnormalities women developed amenorrhea while receiving Erivedge observed in clinical trials were hyponatremia in •6 Treatment-emergent grade 3 laboratory abnormalities patients (4%), hypokalemia in 2 patients (1%), observed in clinical trials were hyponatremia in and azotemia in 3 patients (2%) 6 patients (4%), hypokalemia in 2 patients (1%), You may report side the FDA at and azotemia in 3 effects patientsto(2%) (800) FDA-1088 or www.fda.gov/medwatch.

You may may also report side side effects to thetoFDA at You report effects Genentech (800) FDA-1088 or www.fda.gov/medwatch. at (888) 835-2555.

You may also report side effects to Genentech Please Brief Summary of Prescribing Information on at (888)see 835-2555. following page.

Please see Brief Summary of Prescribing Information on following page.

See what you can offer your patients with aBCC at www.Erivedge.com See what you can offer your patients with References: 1. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. aBCC at www.Erivedge.com

2012;366:2171-2179. 2. Walling HW, et al. Cancer Metastasis Rev. ® 2004;23:389-402.

3. A, Erivedge capsule Prescribing References: 1. Sekulic Migden (vismodegib) MR, Oro AE, et al. N Engl J Med. Information. Genentech,2.Inc. January 2012;366:2171-2179.

Walling HW,2012. et al. Cancer Metastasis Rev. ® 2004;23:389-402. 3. Erivedge (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012.

© 2013 Genentech USA, Inc. All rights reserved.

HED0001655400 Printed in USA. © 2013 Genentech USA, Inc. All rights reserved.

HED0001655400 Printed in USA.

human resources. She will be responsible for enhancing the Leukemia & Lymphoma Society organizational efficiency and effectiveness in partnership with the organization’s executive team. n

The ASCO Post | AUGUST 15, 2013

PAGE 116

FDA Update

FDA Issues Warning on Rare but Serious Skin Reactions with Acetaminophen

T

he FDA recently issued a warning that acetaminophen has been associated with a risk of rare but serious skin reactions. These skin reactions, known as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and acute

generalized exanthematous pustulosis, can be fatal.

Serious Adverse Reactions FDA has warned that reddening of the skin, rash, blisters, and detachment

of the upper surface of the skin can occur with the use of drug products that contain acetaminophen. These reactions can occur with first-time use of acetaminophen or at any time while it is being taken. Non-steroidal anti-in-

flammatory drugs, such as ibuprofen and naproxen, also carry the risk of causing serious skin reactions, which is already described in the warnings section of their drug labels.

Safety:7" Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term

Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information.

WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations.

Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

-

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

-

All aBCC1 Patients (N = 138) Grade 3 Grade 4 All Grades 3 (%) (%) (%)

35 (25.4%)

3 (2.2%)

-

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

-

76 (55.1%) 15 (10.9%)

-

-

88 (63.8%)

-

-

aBCC = Advanced Basal Cell Carcinoma.

2 MedDRA = Medical Dictionary for Regulatory Activities.

3 Grading according to NCI-CTCAE v3.0.

Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)].

Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%).

1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole).

Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased.

Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown.

7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib.

In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits.

Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE 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 embryo or fetus.

Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)].

In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws).

8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555.

Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus.

Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)].

Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib.

8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

• Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects.

• Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555.

• Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother.

• Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2013 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832301

Health-care professionals should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions.

Adverse Event Reporting System

Safety:10"

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)].

ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules.

If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed.

Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)].

5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 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 clinical practice.

ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer.

The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1).

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients

2

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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 ERIVEDGE capsule have not been established in pediatric patients.

In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose).

8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)]

This new information resulted from the Agency’s review of the FDA Adverse Event Reporting System database and the medical literature to evaluate cases of serious skin reactions associated with acetaminophen.

FDA will require that a warning be added to the labels of prescription drug products containing acetaminophen to address the risk of serious skin reactions. FDA will also request that manufacturers add a warning about serious skin reactions to the product labels of over-the-counter acetaminophen drug products marketed under a new drug application and will encourage manufacturers of drug products marketed under the over-the-counter monograph do the same.

For more information, visit http:// www.fda.gov/Drugs. n

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PAGE 117

Announcements

Richard I. Fisher, MD, Named President and CEO of Fox Chase Cancer Center

R

ichard I. Fisher, MD, has been appointed President and Chief Executive Officer of Fox Chase Cancer Center in Philadelphia. Dr. Fisher will

fortunate to be able to draw on Dr. Fisher’s clear capabilities as a cancer center administrator, clinician, and research investigator to lead Fox Chase Cancer Center,” said Larry R. Kaiser, MD, FACS, Senior Executive

and sure-handed leadership and administrative ability, working closely with leaders at Fox Chase and across Temple Health. He has helped to advance a positive and forward-looking perspective that will help to reinvigo-

The Health System as a whole is fortunate to be able to draw on Dr. Fisher’s clear capabilities as a cancer center administrator, clinician, and research investigator to lead Fox Chase Cancer Center.

—Larry R. Kaiser, MD, FACS Richard I. Fisher, MD

also hold the title of Cancer Center Director of Fox Chase, serving as the Principal Investigator on the Cancer Center Support Grant from the National Cancer Institute. He will retain the title of Senior Associate Dean for Cancer Programs at Temple University School of Medicine. Dr. Fisher joined Temple Health on March 1 of this year.

Forward Momentum “The Health System as a whole is

Vice President for Health Sciences at Temple University, Dean of Temple University School of Medicine, and President and CEO of Temple University Health System. “In his new roles, he will play a vital part in sustaining our forward momentum and help us maximize the opportunities offered by the affiliation of Fox Chase with Temple University Health System,” Dr. Kaiser said.

Since his arrival, Dr. Kaiser noted, Dr. Fisher has demonstrated adroit

rate clinical and scientific cancer programs and to launch vital faculty recruitment efforts.

Career Highlights Before joining Fox Chase and Temple Health, Dr. Fisher was Vice President for Strategic and Program Development at the University of Rochester Medical Center and the Samuel E. Durand Professor of Medicine. For the previous 11 years, he served as Director of the James P. Wilmot Cancer

Center at the University of Rochester School of Medicine and Dentistry (URSMD) and Director of Cancer Services for the Strong Health System in Rochester, New York.

Over his career, Dr. Fisher has held a number of important leadership positions in oncology at the national level—including Chair of the Lymphoma Committee of the Southwest Oncology Group (SWOG) (1985-2013); Deputy Group Chair of SWOG (2005-present); and Chair of the Lymphoma Research Foundation Scientific Advisory Board (20082010). He also has served as a member of the Board of Scientific Advisors for the V Foundation (2003-present), a member of the NCI Lymphoma Steering Committee (2009-present), and Chair of the NCI SPORE review committee (2010).

Dr. Fisher earned his undergraduate degree in chemistry and physics at Harvard University before obtaining his MD degree from Harvard Medical School in 1970. He completed his internship and residency at Massachusetts General Hospital. n

Cedars-Sinai Medical Physicist Honored by American Association of Physicists in Medicine

B

enedick Fraass, PhD, FAAPM, FASTRO, FACR, has received the William D. Coolidge Award from the American Association of Physicists in Medicine for his distinguished career achievements in medical physics, including his pioneering work in radiation oncology.

“The William D. Coolidge Award credits those whose innovation and creativity have revolutionized the field of medical physics,” said Steven Piantadosi, MD, PhD, Director of the Samuel Oschin Comprehensive Cancer Institute and the Phase ONE Foundation Distinguished Chair. “Dr. Fraass has dedicated both his mind and talent to radiation oncology — providing more efficient treatment to thousands of patients across the world,” Dr. Piantadosi said.

Dr. Fraass is Vice Chair for Research and Professor and Director of Medical Physics in the Department of Radiation Oncology at Cedars-Sinai’s Samuel Oschin Comprehensive Cancer Institute.

He is a medical physicist specializing in

radiation oncology, imaging-based treatment planning, computer-controlled treatment delivery, and clinical studies of radiation oncology treatment for cancer.

Benedick Fraass, PhD, FAAPM, FASTRO, FACR

Dr. Fraass was instrumental in the creation of 3D treatment planning in the 1980s and early 1990s and helped pioneer the development of 3D conformal therapy, a technique in which beams of radiation are shaped to match a tumor during treatment, sparing nearby normal tissue.

Additionally, Dr. Fraass led the team

that implemented the first routine clinical use of 3D treatment planning.

Dr, Fraass and colleagues also created the first radiation oncology clinical dose escalation trials using conformal therapy in 1987, as well as doing pioneering work in computer-controlled treatment delivery. Fraass continues his efforts to improve patient safety.

“It is an honor to join the elite group of past Coolidge award recipients,” said Dr. Fraass. “The innovations our group developed have changed the field of radiation oncology, and have improved the cancer treatment for a great many patients. These improvements were only possible due to the teamwork of a dedicated collaboration of medical physicists, physicians, computer scientists, therapists and engineers, and I’m honored to represent all these people in accepting the award.”

Dr. Fraass has been principal investigator of many National Cancer Institute grants, including the NCI-funded program project grant “Optimization of

High Dose Conformal Therapy,” which was funded from 1993 to 2011 and has authored more than 205 publications.

Fraass serves as Co-Chair of the American Association of Physicists in Medicine Research Committee, the National Radiation Oncology Registry, the Integrating the Healthcare Enterprise-Radiation Oncology effort and the Radiation Oncology Safety Stakeholders Initiative.

He is a Fellow of the American Association of Physicists in Medicine, the American Society of Radiation Oncology and the American College of Radiology. In 2011, Dr. Fraass was named Professor Emeritus of the University of Michigan, where he served as director of the Radiation Oncology Physics Division from 1984 to 2011.

Past recipients of the William D. Coolidge Award include medical physicists William Coolidge, the inventor of the modern x-ray tube, and Harold Johns, who led the development and clinical use of the first Cobalt machines for radiotherapy. n

The ASCO Post | AUGUST 15, 2013

PAGE 118

2013

2013 Oncology Meetings August

For more information: www.tops-tennessee.com

Hematology and Medical Oncology Best Practices August 15-22 • Arlington, Virginia For more information: www.gwumc.edu/cehp/ hemoncbestpractices/

Michigan Society of Hematology and Oncology Annual Meeting September 20-21 • Traverse City, Michigan For more information: www.msho.org

Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org North Carolina Oncology Association Fall Membership Conference August 24 • Greensboro, North Carolina For more information: www.ncoa-northcarolina.com 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September Georgia Society of Clinical Oncology 2013 GASCO Annual Meeting September 6 • Atlanta, Georgia For more information: www.gasco.us SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

Minnesota Society of Clinical Oncology - MSCO Fall Membership Conference September 10 • Minneapolis, Minnesota For more information: www.msco-minnesota.com

NCCN 8th Annual Congress: Hematologic Malignancies September 20-21, 2013 New York, New York For more information: www.nccn.org

2013 Interscience Conference on Antimicrobial Agents and Chemotherapy September 10-13 • Denver, Colorado For more informaton: www.icaac.org Rocky Mountain Oncology Society Fall Membership Conference September 12 • Denver, Colorado For more information: www.rmos-colorado.com 9th Scientific Meeting of the Australasian Society for Breast Disease September 12-14 • Cairns, Queensland, Australia For more information: www.asbd.org.au International Liver Cancer Association Seventh Annual Conference September 13-15 • Washington, DC For more information: www.ilca2013.org/ Inflammation, Microbiota, and Cancer September 19-20 • Bethesda, Maryland For more information: ncifrederick.cancer.gov/events/ microbiota/agenda.asp Continuum Cancer Centers of New York Conference on Quality of Care in Oncology September 20 • New York, New York For more information: www.chpnet.org/cme Tennessee Oncology Practice Society 2013 Membership Conference September 20 • Nashville, Tennessee

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences ASH Consultative Hematology Course September 27 • Chicago, Illinois For more information: www.hematology.org Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences 2013 ASH State-of-the-Art Symposium September 27-28 • Chicago, Illinois For more information: www.hematology.org ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston,

Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

October The 2nd International Multidisciplinary Forum on Palliative Care (IMFPC 2013) October 3-6 • Sofia, Bulgaria For more information: www.imfpc.org Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences Second Annual Conference Global Biomarkers Consortium October 4-6 • Boston, Massachusetts For more information: www.globalbiomarkersconsortium. com Virginia Association of Hematologists and Oncologists Fall Membership Conference October 11 • Virginia Beach, Virginia For more information: www.vah-o.org 17th Annual Interdisciplinary Conference on Supportive Care, Hospice, and Palliative Medicine October 11-12 • Houston, Texas For more information: www. mdanderson.org/conferences 4th International Breast Cancer Prevention Symposium: Genes, the Environment, and Breast Cancer Risks October 11-13 • Beirut, Lebanon For more information: www.purdue.edu/breastcancer/ Merrill J. Egorin Workshop in Cancer Therapeutics and Drug Development October 11-14 • Leesburg, Virginia For more information: www.cancereducationconsortium. org/programs_paaw.html 9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/ continued on page 126

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2013

2013 Oncology Meetings continued from page 118

International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Clin ical+Trials+Workshops International Stereotactic Radiotherapy Conference October 19-20 • Houston, Texas For more information: www. mdanderson.org/conferences

2013 International Society of Geriatric Oncology Congress October 24-26 • Copenhagen, Denmark For more information: www.siog.org 51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/

4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in

Illinois Medical Oncology Society 2013 Membership Conference October 25 • Itasca, Illinois For more information: www.imos-illinois.com

18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 19-23, 2013 • Boston, Massachusetts For more information: www.aacr.org 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas

11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences

For more information: www.mdanderson.org/conferences

Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

November Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences

EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de

Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro

9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/

New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences

Diagnostic Development Tutorial November 5-7 • Brussels, Belgium For more information: www.markersincancer.eu

Academy of Oncology Nurse Navigators 4th Annual Navigation and Survivorship Conference November 14-17 • Memphis, Tennessee For more information: aonnonline.org/conference

SITC Workshop on Personalized Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013 SITC Primer on Tumor Immunology and Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013 Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information: www.abc-lisbon.org/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw

JANUARY 24–26, 2014

Renaissance Vinoy St. Petersburg • St. Petersburg, FL

Chair: Pamela Hallquist Viale • Co-Chairs: Sandra E. Kurtin and Wendy H. Vogel

advancedpractitioner.com/jadprolive

African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org 36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

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PAGE 127

Pioneers in Oncology Dr. Joseph Bertino’s Breakthrough Work in Methotrexate Resistance Led to Understanding Why Cancer Drugs Work or Fail

By Jo Cavallo

“Clem Finch was really forwardthinking and allowed his fellows to work with basic scientists in the laboratory, something that really wasn’t done back then. And to be under the mentorship of Dr. Huennekens, who was one of the great enzymologists of his day, was a big start for me,” said Dr. Bertino.

Understanding Drug Resistance Joseph R. Bertino, MD

L

ooking over his 5 decades in clinical oncology and research, Joseph R. Bertino, MD, says his greatest professional satisfaction comes from seeing his former students and oncology fellows go on to achieve great success in their own medical and research careers. It is a fitting sentiment since Dr. Bertino credits his early mentors, including Clement A. Finch, MD, the first Chief of Hematology at the University of Washington School of Medicine, with helping launch his career in oncology, a career that remains dedicated to improving the lives of patients suffering from hematologic cancers.

First Physician in the Family Born in Port Chester, New York, on August 16, 1930, Dr. Bertino was the youngest of three sons born to Joseph and Mamie Bertino. Having emigrated from Italy to the United States just before World War I, it was important for his parents to see their son go to medical school and become the first physician in the family, said Dr. Bertino. Although interested in chemistry and biology in high school, it was not until he was accepted to Cornell University that he decided to pursue a career in medicine.

During medical school, Dr. Bertino became determined to understand the causes leading to the development of hematologic cancers, especially leukemia and lymphoma. In 1958, 4 years after graduating from SUNY Downstate Medical School in Brooklyn, New York, he moved to Seattle, where he began his fellowship training with Dr. Finch, who was an expert on red cell and iron metabolism, and Frank M. Huennekens, PhD, an Assistant Professor of Biochemistry.

It was Dr. Huennekens’ pioneering work in folate metabolism that led to Dr. Bertino’s understanding of how the chemotherapy drug methotrexate worked and would later contribute to his breakthrough research in cancer drug resistance. Three years later, Dr. Bertino was offered a joint appointment in the Departments of Pharmacology and Medicine at Yale University School of Medicine. Under the leadership of Arnold Welch, MD, PhD,

tion was a mechanism of methotrexate resistance, which ushered in a new era in drug resistance research.

“It was an exciting time because DNA was thought to be stable and we didn’t expect to see a change in DHFR gene copy number in the resistant cells. The fact that multiple DHFR genes popped up as a mechanism of overproducing dihydrofolate reductase was groundbreaking at that time,” said Dr. Bertino.

Finding New Targets in Rare Lymphomas Dr. Bertino left Yale in 1987 to become Head of Developmental Therapy and Clinical Investigation at Memorial Sloan-Kettering Cancer Center, where his research on drug resistance in leukemia and soft-tissue sarcomas found that defective uptake of methotrexate and low-level amplification of the dihy-

If you look at our medical journals, half the papers now come from scientists in other countries. It’s good to see countries other than the U.S. participating in scientific research and contributing to the welfare of cancer patients, but we don’t want to lose our leadership in the field.

—Joseph R. Bertino, MD

at the Rutgers Robert Wood Johnson Medical School, where the focus of his research is centered on new drug development for solid tumors, especially prostate cancer and small cell lung cancer. He is also working to find new targets for T-cell lymphomas and for a rare subtype of B-cell lymphoma called double-hit lymphoma.

“Double-hit lymphoma is a subset of large B-cell lymphomas that overexpress both Myc and Bcl-2 and has a very bad prognosis,” said Dr. Bertino.

Dr. Bertino and his colleague Alexei Vazquez, PhD, and his graduate student Philip Tedeschi, recently showed that Myc stimulates growth by increasing expression of serine and glycine metabolism and folate mitochondrial enzymes, providing an explanation for methotrexate sensitivity in tumor cells that are rapidly proliferating. Myc also stimulates proliferation of double-hit lymphomas, and while initially sensitive to methotrexate and other drugs, Bcl-2 and family members protect the malignant cells from dying, explained Dr. Bertino.

“Treating this disease is very difficult, and we are now studying the tumors and trying to understand how best to treat them by attacking cell proliferation and inhibiting the antiapoptotic proteins,” said Dr. Bertino.

Stellar Career the Department of Pharmacology at Yale was outstanding, with many exceptional faculty members who were interested in cancer pharmacology.

Dr. Bertino served as the first Director of the Yale Cancer Center from 1973 to 1975 but relinquished his post when he was named an American Cancer Society Research Professor.

At Yale, his studies in chemotherapy drug resistance began in earnest, and he discovered that methotrexate exposure led to an increase in dihydrofolate reductase (DHFR).

In 1976, Dr. Bertino took a yearlong sabbatical to work with Robert N. Schimke, MD, in the Department of Biological Sciences at Stanford University. During that time, he and his colleagues Dr. Schimke, Rodney E. Kellems, PhD, and Frederick W. Alt, PhD, discovered that gene amplifica-

drofolate reductase gene were causes of resistance. It was the result from this and other studies that have led to the development of new therapies for leukemia and lymphoma, earning Dr. Bertino international recognition for his accomplishments.

In 2002, one of Dr. Bertino’s former fellows at Yale, William N. Hait, MD, PhD, who was the founding Director of the Cancer Institute of New Jersey at the Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, asked Dr. Bertino to join the institute as Associate Director.

Today, Dr. Bertino is the Chief Scientific Officer of the institution (which is now known as Rutgers Cancer Institute of New Jersey) and the American Cancer Society Professor of Medicine and Pharmacology

In 1975, Dr. Bertino was named President of ASCO, and in 1983, was the founding Editor-in-Chief of the Journal of Clinical Oncology. In 1995, he served as President of the American Association for Cancer Research (AACR). He is also the recipient of numerous awards, including ASCO’s David A. Karnofsky Memorial Award, the AACR-Joseph H. Burchenal Memorial Award, the American Cancer Society Medal of Honor for Research, and the Jeffrey A. Gottlieb Memorial Award.

In addition to a stellar career in medicine, Dr. Bertino has had a rich personal life. He and his wife Mary Patricia, who passed away in 2011, raised four children and saw their family grow to include eight grandchildren and two great-grandchildren. continued on page 128

The ASCO Post | AUGUST 15, 2013

PAGE 128

Awards Young Scientists of Note

Cedars-Sinai Names Award Recipient in Gifted Scholars Program

C

edars-Sinai in Los Angeles, California, recently named Christine R. Carico the 2013 recipient of the Medical Center’s Pauletta and Denzel Washington Family Gifted Scholars Program in Neuroscience award. Ms. Carico will spend the next year researching brain disorders like the one that took the life of her father.

disease, I have made it my ultimate goal to find a cure for brain cancer.

This scholarship will help propel me toward this goal by allowing me to learn from some of the most talented and renowned scientists in the field.”

Award Provides Support and Opportunity Washington Scholars receive financial support and participate in cuttingedge scientific projects in CedarsSinai’s research labs. The Department

of Neurosurgery began funding the scholarships in 2004 to support students who demonstrated the desire, initiative, and aptitude to make significant contributions in the sciences.

Pauletta and Denzel Washington glad-

Calling in Academic Medicine “My interest in neuroscience started when my father was diagnosed [with anaplastic astrocytoma], but it wasn’t until his death in 2007 that I realized academic medicine was my calling,” said Ms. Carico, who was 12 years old when her father’s cancer was diagnosed in 2003. “After witnessing the horrific course of the

Joseph R. Bertino, MD continued from page 127

The Future of Research Although Dr. Bertino has had the satisfaction of witnessing the discovery of many effective treatments in both solid tumor and hematologic cancers over the past 60 years—a time that saw an increase in the number of cancer survivors jump from just 3 million in the early 1970s to nearly 14 million today—federal cuts in research funding threaten further progress, he said.

“If you look at our medical journals, half the papers now come from scientists in other countries. It’s good to see countries other than the U.S. participating in scientific research and contributing to the welfare of cancer patients, but we don’t want to lose our leadership in the field. We have so many opportunities now to make advances in cancer research, but progress will be slowed because we won’t be able to take advantage of some opportunities due to lack of funding.” n

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.

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PAGE 129

Awards

ly lent their names and continue to take an active role in the program.

The scholarship has provided summertime positions for two students each year but recently was reconfigured to give one recipient more indepth exposure to research techniques, enabling the scholar to make more significant contributions, said Keith

L. Black, MD, Professor and Chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience. The year-long internship provides a stipend of $30,000 to $34,000, and the awardee is expected to submit a research paper or abstract to a national neuroscience, cancer or neurosurgery meeting.

Christine R. Carico

Keith L. Black, MD

Chirag Patil, MD

Path Forward

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Ms. Carico, who was born in Mountain View, California, and now lives in West Hollywood, soon will earn her Bachelor’s degree in Neuroscience at the University of California, Los Angeles. During her junior year of high school, Ms. Carico undertook an optional research project, working in Stanford University laboratories. She co-authored a journal article on cells and mechanisms involved in the development of leukemia and shadowed members of Stanford’s neurosurgical team to learn more about the field.

Ms. Carico was involved in basic research during a summer 2010 fellowship at UCLA through the Undergraduate Cancer Research Training Program sponsored by Charles R. Drew University of Medicine and Science. Starting in January 2011, she worked more than a year in a UCLA lab studying a signaling pathway involved in the transformation of normal tissue into abnormal masses. At the same time, and while carrying a full academic load, she started working at the Center for Neurosurgical Outcomes Research in the Department of Neurosurgery at Cedars-Sinai, where she continues today and has collaborated on six published studies.

Praise from Mentor Chirag Patil, MD, Director of the Center for Neurosurgical Outcomes Research, has known Ms. Carico for more than 6 years, beginning when she was a high school student and she shadowed him at Stanford University Medical Center, where Dr. Patil completed an internship in general surgery, a residency in neurosurgery, and a fellowship in stereotactic radiosurgery.

“Christine is the best and most dedicated undergraduate student I have ever mentored or come in contact with,” he said. “She is extremely bright and is very talented. Neuroscience and neurooncology have been a passion of hers since her father’s diagnosis with anaplastic astrocytoma. Her story of fortitude, discipline, and turning a big loss into a focused drive is inspirational. n

The ASCO Post | AUGUST 15, 2013

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Issues in Oncology

Cost of Cancer Drugs continued from page 1

(Avastin), which works through a similar molecular mechanism but costs about $5,000 a month—less than half of the $11,063 per month price of zivafilbercept. (A month after the Op-Ed appeared, Sanofi Aventis, maker of zivafilbercept, reduced the drug’s price by 50% for patients with previously treated colorectal cancer.)

They were taking this stand, explained the physicians, because “ignoring the cost of care is no longer tenable. Soaring spending has presented the medical community with a new obligation. When choosing treatments for a patient, we have to consider the financial strains they may cause alongside the benefits they might deliver.”

The sharp rise in the price of cancer therapies, the authors argued, means that much of the burden to pay for these expensive drugs falls to patients through higher health insurance and Medicare copayments, often driving them into bankruptcy.

(A recent study4 by researchers at the Fred Hutchinson Cancer Research Center in Seattle found that, in Washington State, people with cancer were twice as likely to file for bankruptcy as people without cancer. Cancer took the greatest financial toll on younger patients who had two- to fivefold higher bankruptcy rates compared to older patients.)

Taking an Active Role The Memorial Sloan-Kettering physicians are not the only ones now taking an active role in protesting high drug prices. In April, a group of 120 experts in chronic myeloid leukemia (CML) from around the world

afford them and to maintain “sound long-term health care policies.”

According to Hagop M. Kantarjian, MD, Department Chair and Professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, and the corresponding author of the Blood editorial, the impetus for the article came from the realization that two of the three drugs approved by the U.S. Food and Drug Administration (FDA) last year in the treatment of CML—bosutinib (Bosulif) and ponatinib (Iclusig)— came with an eye-popping price tag of over $100,000 per year. The third drug, omacetaxine (Synribo), costs $28,000 for induction and $14,000 per maintenance course, according to the Blood article.

“We were lucky in 2012 to have FDA approval of three CML drugs,” said Dr. Kantarjian. “But when I started looking into the price of these drugs, I noticed that of the 12 cancer drugs approved that year, 11 were priced above $100,000 per year,” he noted.

“Then I looked at the price of imatinib (Gleevec), a drug I use on a daily basis,” he continued. “When imatinib was approved in 2001, it cost between $25,000 and $30,000 a year. Now, it has gone up to $92,000 a year. If you consider that imatinib’s original price included the cost of development and profits to the company, there was no reason to increase the price except that it was something Novartis, the drug’s manufacturer, could do with impunity.” According to Dr. Kantarjian, the cost of a typical cancer drug has doubled over the past decade, from around $5,000 per

When I started looking into the price of these drugs, I noticed that of the 12 cancer drugs approved that year, 11 were priced above $100,000 per year.

—Hagop M. Kantarjian, MD

banded together to draw attention to the rising cost of cancer drugs, especially tyrosine kinase inhibitors for the treatment of CML. In an article in Blood,5 the authors argued that it was important to lower the prices of cancer drugs so more patients could

month to over $10,000 in 2010.

“And when you look at cost benefit in terms of prolonging life or improving quality of care or reducing toxicities, there is almost no correlation between the benefit and the price of the drug,” he added.

Cost vs Benefit Newton F. Crenshaw, Vice President of Lilly Oncology, agrees that while drug prices at times do not correlate with long-term benefit, drug breakthroughs happen in a step-bystep process.

“If people are saying that the value of a drug should be based solely on how long it improves overall survival, that really ignores the history of drug innovation, which is often incremen-

an oversight hearing to look into the “exorbitant cost of cancer drugs.”

Finding Solutions What everyone does agree on is that health-care costs in the United States are unsustainable at their current rate.

“ASCO’s viewpoint is that all parties—medical societies, government agencies, pharmaceutical companies, insurance companies, patient groups,

In a business like this where the risks are profound, you fail far, far, far many more times than you succeed.

You have to look at the total economic costs associated with finding those winners.

—Newton F. Crenshaw

tal and punctuated by an occasional breakthrough. And we need to reward all of those steps,” said Mr. Crenshaw.

“Two decades ago, the overall survival for metastatic lung or colon cancer was a matter of months. Today, people with those diseases are living as much as 2 years longer. It’s not a cure, but having that much more time matters to patients.”

Perhaps the biggest area of contention between the cancer experts who penned the Blood article and the pharmaceutical industry is how much it actually costs to bring a new drug to market. The figure often cited by drug manufacturers is about $1.3 billion, which is based on analysis by the Tufts Center for the Study of Drug Development. Mr. Crenshaw agrees that that figure is accurate.

“In a business like this where the risks are profound, you fail far, far, far many more times than you succeed.

You have to look at the total economic costs associated with finding those winners,” said Mr. Crenshaw. However, other studies6 put the cost of developing a new drug at between $60 and $90 million.

Publicity from the article in Blood is not just stirring debate among oncology specialists and drug manufacturers over the reasons for the increase in cancer therapy costs, but spiraling drug prices have also caught the attention of Congressman Stephen F. Lynch (D-MA), a senior member of the House Oversight and Government Reform Committee, who is calling for

and health-care policymakers—need to make a serious commitment to address this problem together,” said Clifford Hudis, MD, President of ASCO and Chief, Breast Cancer Medicine Service at Memorial Sloan-Kettering. “What we don’t want to do is remove the motivation for developing new therapies.”

To confront the rising cost of cancer care and its impact on patients, ASCO established a Value of Cancer Care task force, which issued a Guidance Statement on the Cost of Cancer Care7 in 2009. The Guidance Statement offered several recommendations, including that physicians discuss with patients the cost of care and the development of patient education materials on the high cost of cancer care to help guide their decision-making regarding treatment options (visit www.cancer.net/all-about-cancer/ managing-cost-cancer-care).

In the spring of 2012, as part of the American Board of Internal Medicine’s Choosing Wisely initiative, ASCO announced its list of the Top Five common costly tests, procedures, and treatments that are not supported by evidence to have a meaningful clinical benefit. The list includes the use of chemotherapy for patients with advanced cancers who are unlikely to benefit, costly imaging technologies for staging or early breast and prostate cancers, routine blood tests for biomarkers and advanced imaging tests for the deteccontinued on page 131

ASCOPost.com | AUGUST 15, 2013

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News Cancer Screening

Tomosynthesis Plus Digital Mammography Reduces Breast Cancer Screening Recall Rate Compared to Mammography Alone

T

he addition of tomosynthesis to standard digital mammography resulted in a 30% reduction in overall recall rates among women being screened for breast cancer, according to a new study published online in Radiology.1 The results demonstrate that digital tomosynthesis is an effective tool in reducing the recall rate in breast cancer screening.

Digital Breast Tomosynthesis Digital mammography is the gold standard for breast cancer screening, but may yield suspicious findings that turn out not to be cancer. These falsepositive findings are associated with a higher recall rate, or the rate at which women are called back for additional imaging or biopsy.

Digital breast tomosynthesis has shown promise at reducing recall rates, particularly in younger women and in those with dense breast tissue.

Tomosynthesis is similar to mammography in that it relies on ionizing radiation to generate images of the breast. However, unlike conventional mammography, tomosynthesis allows for three-dimensional reconstruction

of the breast tissue, which can then be viewed as sequential slices through the breast.

“Tomosynthesis increases the conspicuity of cancers by removing superimposed and overlapping tissue from the view,” said Brian M. Haas, MD, from Yale University School of Medicine in New Haven, Connecticut.

“All age groups and breast densities had reduced risk for recall in the tomosynthesis group,” Dr. Haas said.

“Women with dense breasts and those younger than age 50 particularly benefited from tomosynthesis.” Lower recall rates help reduce patient anxiety and also reduce costs from additional diagnostic examinations, Dr. Haas said.

Study Details

Higher Radiation Dose with Tomosynthesis

In the study, Dr. Haas and colleagues compared screening recall rates and cancer detection rates in two groups of women: those who received conventional digital mammography alone and those who had tomosynthesis in addition to mammography.

Of the 13,158 patients who underwent screening mammography, 6,100 received tomosynthesis. The cancer detection rate was 5.7 per 1,000 in patients receiving tomosynthesis, compared with 5.2 per 1,000 in patients receiving mammography alone. The addition of tomosynthesis to digital mammography resulted in a 30% reduction in the overall recall rate, from 12.0% for mammography alone to 8.4% in the tomosynthesis group.

Tomosynthesis has a radiation dose approximately double that of digital mammography alone. However, Dr. Haas noted that new technology approved by the U.S. Food and Drug Administration could reduce the dose.

“The technology involves taking the tomosynthesis data and collapsing it into planar imaging that resembles two-dimensional mammography,” Dr. Haas said. “It has the potential to eliminate the need for acquisition of the conventional two-dimensional images in addition to the tomosynthesis images.”

The research group is currently in the process of comparing the cancers found on tomosynthesis with those found on

Cost of Cancer Drugs continued from page 130

tion of breast cancer recurrence, and overuse of drugs to stimulate white blood cell production in patients receiving chemotherapy.

“What I have observed so far in my area of practice is that Choosing Wisely has allowed many, many oncologists to do what they know is right—for example, to not do screening blood tests for metastatic breast cancer,” said Dr. Hudis. “That may sound like a small thing on an individual patient level, but it is the kind of thing that can add up to a lot of savings.”

In the fall, ASCO will announce the next Top Five list of high-cost procedures and treatments with limited clinical benefit and will publish details of its evidence-based recommendations.

Starting a Dialogue While the full impact of the new stand against high drug prices some oncologists are taking is unknown, Dr. Kantarjian and Mr. Crenshaw agree that a meeting of the key stakehold-

What I have observed so far in my area of practice is that Choosing Wisely has allowed many, many oncologists to do what they know is right.

—Clifford Hudis, MD

ers to discuss the issue and develop solutions is vital. “We are working to reach out to Dr. Kantarjian and his colleagues because we think dialogue is important,” said Mr. Crenshaw. He added that several groups of stakeholders, including pharmaceutical companies and Dr. Kantarjian, are working on plans to hold a “summit” to discuss the economics of cancer research, possibly this fall.

“Keeping patients front and center in this discussion is really ASCO’s job,” said Dr. Hudis. “We have to figure out some way to continue and even accelerate the pace of drug

discovery and development while at the same time determining how to get those advances to the broadest array of people. And we do have to incentivize real breakthroughs, not just the smaller incremental advances that sometimes are all we get.” n

Disclosure: Drs. Kantjarian and Hudis reported no potential conflicts of interest.

Mr. Crenshaw is Vice President of Lilly Oncology.

References 1. Squires DA: Explaining high health care spending in the United States: An international comparison of supply, utilization, prices, and quality. Issues in Inter-

mammography. They are also tracking the study group for cancers that develop in the interval between screenings to make sure that the reduced recall rate associated with tomosynthesis is not resulting in missed cancers.

Tomosynthesis Plus Digital Mammography vs Mammography Alone The cancer detection rate was 5.7 per 1,000 in patients receiving tomosynthesis plus standard digital mammography, compared with 5.2 per 1,000 in patients receiving mammography alone.

The addition of tomosynthesis resulted in a 30% reduction in the overall recall rate, from 12.0% for mammography alone to 8.4% in the tomosynthesis group.

Tomosynthesis has a radiation dose approximately double that of digital mammography alone. n Reference 1. Haas BM, Kalra V, Geisel J, et al: Comparison of tomosynthesis plus digital mammography and digital mammography alone for breast cancer screening. Radiology. July 30, 2013 (early release online).

national Health Policy, May 2012. Available at www.commonwealthfund.org.

Accessed June 25, 2013.

2. Brill S: Why medical bills are killing us. Time, March 4, 2013.

3. Bach PB, Saltz LB, Wittes RE: In cancer care, cost matters, New York Times, October 14, 2012.

4. Ramsey S, Blough D, Kirchhoff A, et al: Washington State cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis.

Health Aff (Millwood). May 15, 2013 (early release online).

5. Experts in Chronic Myeloid Leukemia: The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: From the perspective of a large group of CML experts. Blood 121:4439-4442, 2013.

6. Light DW, Lexchin JR: Pharmaceutical research and development: What do we get for all that money? BMJ 345:e4348, 2012.

7. Meropol NJ, Schrag D, Smith TJ, et al: American Society of Clinical Oncology guidance statement: The cost of cancer care. J Clin Oncol 27:3868-3874, 2009.

The ASCO Post | AUGUST 15, 2013

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Perspective

Precision Medicine continued from page 1

Isolated Decision-makers The Palmetto declaration was a policy for Medicare Jurisdiction 1. The policy was focused on the reimbursement level and payment for the conduct of BRAF testing (and other tests).

In that policy statement, Palmetto proposed that the level of reimbursement for a BRAF test in 2013 drop to $57.51 from the reimbursement of $257.34 paid in 2012. The declaration set off howls of disapproval and disbelief from the laboratory testing companies and other entities concerned about the impact of the decision on the application of biomarkers in treatment strategies to achieve enhanced safety, effectiveness, and efficiency.

A more alarming part of this affair related to the apparent isolation of the Palmetto reimbursement decisionmakers for molecular tests from the role and integration of such tests along the continuum of cancer care. Indeed, the decision-makers tried to save $200 on a molecular test that guides the selection of agents targeting the BRAF mutation that cost upwards of $50,000 for a complete course of therapy.

In a world where health-care policy preachers have, for at least 20 years, espoused the need to consider the various components of a treatment episode in toto when deciding on coverage and reimbursement policy, the Medicare contractor had retreated to a reimbursement view and policy that was as isolationist as possible. In the minds of many, the decision on reimbursement levels for BRAF (as well as for EGFR) tests established a real threat to the financial viability of a successful and burgeoning scientific molecular testing industry.

Reimbursement Changes Further, the reimbursement world in both the public and private sectors is undergoing significant change. The traditional “code-stacking” method of billing for laboratory tests is giving way to assigned “molecular testing” current procedural terminology (CPT) codes that are further specified when linked with a “Z-Code” identi-

fier (an advanced diagnostic test identifier from the McKesson Diagnostics Exchange catalogue).

Payers have longed complained that the old code-stacking method only named specific testing steps, analytes, etc, or “stacks” in a testing procedure but did not identify the actual test and its identified biologic target.

be defined as the provision of sufficient information to actually change a clinician’s decision. More likely, clinical utility will be defined by the great plurality of health plans, public and private, as a demonstrated improvement in specified patient outcomes.

UnitedHealth has published a short dissertation on molecular testing that

A question for the future could be, to what extent might the FDA regulate the clinical logic embedded in software that interprets the results of a genomic panel—ie, will the agency seek to oversee algorithmic guides to molecular testing–directed treatment?

—William T. McGivney, PhD

Often, payers did not know what test they were paying for.

The Centers for Medicare & Medicaid Services (CMS) will use the 2013 reimbursement determinations of Medicare contractors, including Palmetto, and apply a “gap-fill” process to determine national reimbursement levels or “national limitation amounts” for 2014. Thus, what happens reimbursement-wise at the Medicare contractor level in 2013 truly has significant implications going forward.

Coverage Policy Palmetto may also be the de facto technology assessor and arbiter of coverage policy for all individual Medicare contractors (and, therefore, the Medicare program). Indeed, Palmetto has published details of its MolDx program, including what the contractor calls a “technical assessment” process for evaluating data on clinical validity and utility in order to determine whether to cover a specific molecular test and, if so, for what indications.

A major issue in the coverage process is how to define clinical utility and what data are dispositive in establishing clinical utility. The term might

includes a discussion of how coverage decisions are made. As expected (and consistent with Palmetto’s policy), it appears that scientific data will be required to demonstrate improved patient outcomes.

Setting the general threshold for improvement of patient outcomes is important. But, when policy-setting actually begins on a test-by-test basis, a multitude of questions will arise from the many clinical uses of molecular tests in prevention, screening, diagnosis, treatment (directive or predictive), prognosis, therapeutic monitoring, disease surveillance, and follow-up.

For example, to what extent will tests that provide important prognostic information to patients be covered?

Also, bear in mind that this discussion has focused on individual molecular tests and has not considered the panel of mutations, rearrangements, etc, that can be evaluated in panels assessed by high throughput genomic sequencing platforms.

Role of the FDA It is interesting to note that both the UnitedHealth and Palmetto pieces discuss the concept of coverage with evidence development—the Medicare mechanism used to provide

conditional coverage for new technologies with a requirement for the collection, analysis, and presentation of more data, to define the benefit derived by patients regarding specific outcomes. One potential target for the granting of coverage with evidence development might be the category of molecular tests known as laboratorydeveloped tests.

Some molecular tests have been approved by the FDA. However, a significant number of molecular tests have been marketed without specific FDA approval. Coverage with evidence development might be applied to generate more data about a specific laboratory-developed test as it is introduced and diffuses into cancer care.

Heretofore, laboratory-developed tests have not been regulated to any significant degree by the FDA. In a presentation at the 2013 ASCO Annual Meeting, FDA Commissioner Margaret Hamburg indicated that the FDA is again considering whether to enhance its oversight of so-called laboratory-developed tests, because there has been a proliferation of such tests and their results are clearly and often used to help direct patient care.

A question for the future could be, to what extent might the FDA regulate the clinical logic embedded in software that interprets the results of a genomic panel—ie, will the agency seek to oversee algorithmic guides to molecular testing–directed treatment?

Keeping Pace The scientific understanding of the human genome, its expression, and the effects of that expression is advancing rapidly. Such understanding is being efficiently translated into health-care technologies that should improve patient care and benefit.

I have touched on just some of the issues that are being addressed by federal regulators, public and private managed care companies, commercial entities, and leading research institutions.

All of these parties are striving to keep pace, or at least not be left behind! n Disclosure: Dr. McGivney is a consultant for several biopharmaceutical companies, including medical diagnostics firms.

This is the biologic medicine That the patient counts on That the nurse trusts That the pharmacist has confidence in That the doctor relies on Because it was manufactured knowing the patient’s treatment depends on it.

Building confidence in the quality and supply of biologic medicines starts with a deeper understanding of how these medicines are made.

After all, there’s so much at stake.

That’s why manufacturing matters.

Learn more at

buildingbiologics.com

An educational initiative from ©2013 Amgen Inc. All rights reserved. 71325-R1-V4

The ASCO Post | AUGUST 15, 2013

PAGE 134

In the News Dermatologic Oncology

‘Alarming Difference’ in Survival Outcomes for Young White Men with Melanoma

By Charlotte Bath

A

n “alarming difference” in survival outcomes between young, non-Hispanic white males and females with primary invasive melanoma “highlights the urgent need for both behavioral interventions to promote early detection strategies in young men and further investigation of the biological basis for the sex disparity in melanoma survival,” investigators from Stanford University Medical Center and Cancer Institute and the Cancer Prevention Institute of California concluded in a study published in JAMA Dermatology.1 Among 26,107 non-Hispanic white adolescents and young adults (AYAs), males accounted for 39.8% of overall cases of melanoma but 63.6% of melanoma-specific deaths.

Surveillance, Epidemiology, and End Results (SEER) data from 18 population-based registries across the United States were used to identify 10,378 males and 15,729 females between the ages of 15 and 39 with primary invasive melanoma of the skin diagnosed between 1989 and 2009. “Because approximately 95% of cutaneous melanoma cases occur in whites, the analysis was limited to non-Hispanic white patients,” the investigators explained A total of 1,561 deaths (993

among the males and 568 among the females) occurred during a mean follow-up of 7.5 years. “Adolescent and young adult males were 55% more likely to die of melanoma than agematched females after adjustment for tumor thickness, histologic subtype, anatomic location, presence and extent of metastasis, and anatomical location (hazard ratio = 1.55; 95% con-

We don’t think [the difference in survival outcomes] is just a matter of improved physician detection in young women compared to young men…Behavioral factors or different health surveillance patterns can’t be entirely ruled out, but I think that our data more strongly suggest that biology is at play.

—Susan M. Swetter, MD

fidence interval [CI] = 1.39–1.73),” the researchers reported. “Males were also more likely to die within each age range assessed (eg, 15–24, 25–29, 30–34, and 35–39 years), and even those with thin melanomas (≤ 1.00

NCAA Athletes as ‘SUNSPORT’ Ambassadors

C

mm) were twice as likely to die as agematched females (hazard ratio = 1.95; 95% CI = 1.57–2.42).”

“The findings are so consistent that they imply a fundamental biological difference in ‘male’ vs ‘female’ melanoma, at least for a significant fraction of patients,” according to an editorial2 accompanying the study report.

onsistent use of sunscreen is one of the key messages of SUNSPORT (Stanford University Network for Sun Protection, Organization, Research, and Teamwork). The program is geared towards reducing sun exposure among students playing in National Collegiate Athletics Association (NCAA) sports. “The typical NCAA outdoor athlete spends 4 hours per day and 10 months per year training or competing outdoors,” according to SUNSPORT data, but while 96% of these athletes agree that sunscreen helps prevent skin cancer, “over 50% never used sunscreen and 75% used sunscreen 3 or fewer days per week.”

The program also advises athletes to use protective clothing, hats, and sunglasses, to avoid sun exposure during peak hours, and to avoid tanning beds and other sources of ultraviolet light. “We are starting to really promote sun protection practices and awareness of skin cancer risk in college-age athletes and then hope that they can serve as ambassadors for younger age athletes and in high school and middle school because that adolescent population becomes more recalcitrant to sun protection messages in general,” according to Susan M. Swetter, MD. Dr. Swetter is Professor of Dermatology and Director of the Pigmented Lesion & Melanoma Program at Stanford University Medical Center and Cancer Institute in Palo Alto, California. SUNSPORT is a collaborative effort of the Stanford Department of Dermatology, the Stanford Cancer Institute, Stanford Athletics, and Stanford Hospital and Clinics. n

Tumor Thickness, Histology, Location Looking at tumor thickness, “which is the most important determinant of how patients do, we found across the board that the young men did worse than the young women, regardless of the thickness,” the study’s corresponding author, Susan M. Swetter, MD, said in an interview with The ASCO Post. Dr. Swetter is Professor of Dermatology and Director of the Pigmented Lesion & Melanoma Program at Stanford University Medical Center and Cancer Institute in Palo Alto, California.

Although tumors of the lower extremity are generally associated with better outcomes than those of the head or neck or trunk, a persistent survival disadvantage was observed in men with lower extremity tumors, Dr. Swetter added. Even after adjusting for tumor thickness, males were 67% more likely than the females to die of lower extremity melanomas.

In males and females, the most common histologic subtype was superficial spreading subtype, but males were more likely to be diagnosed with nodular melanoma, 6.8% vs 4.1% in females.

“Although males presented with more [nodular melanomas], which have been associated with rapid growth, the male survival disadvantage was not limited to this subtype. In fact, AYA males with [superficial spreading subtype]…had a 73% higher risk of melanoma death compared with females. This study provides evidence that the AYA male survival disadvantage is not explained simply by health screening differences, because one would then expect the sex disparity to be limited to thicker primary melanomas or to tumors located on the head and neck and trunk,” according to the study report.

“One thing that we would emphasize in our study.” Dr. Swetter said, “is that despite the fact that men are doing worse with all tumor thicknesses, it is still critical to enhance early detection strategies, because patients do better with a thinner melanoma than a thicker melanoma. So even though we are seeing men twice as likely to die with a very thin T1 melanoma (less or equal to a millimeter in depth), the chance of surviving those tumors is so great that we want to promote detection of these thin tumors in general in both young men and women.”

Biology vs Behavior The researchers proposed several possible biologic mechanisms for the higher male melanoma mortality, including differences in sex hormones, immune homeostasis, vitamin D metabolism, and oxidative stress, but firm evidence for these and other possible mechanisms is lacking. “There is not substantial evidence or understanding of what is driving this from a biologic standpoint,” Dr. Swetter stated. “The bottom line is we don’t really understand what is causing this biologic difference.”

Studies showing higher melanoma mortality among older men than women have reported that men “tend to be more resistant to screening practices—skin self-exams, seeing the doctor, navigating the health-care system effectively—than women,” Dr. Swetter noted, and that older men “may have a huge benefit” from physician intervention and skin exams. “But we are talking here about a younger population that doesn’t see the doctor as much, other

ASCOPost.com | AUGUST 15, 2013

PAGE 135

In the News

than women because of reproductive health issues in the childbearing years. This is also a population in whom the melanomas tend to be more self-detected, rather than physician detected,” Dr. Swetter said.

“In general, the patients in this age group are healthier compared to older individuals. They are seeing physicians less regularly, and just a very small percentage of melanomas in this young, less than 40 age group are discovered by physicians.

So we don’t think it is just a matter of improved physician detection in young women compared to young men.” Behavioral factors or different health surveillance patterns can’t be entirely ruled out, Dr. Swetter said, “but I think that our data more strongly suggest that biology is at play.”

Youth May Feel Impervious to Effects of UV Exposure The mean age at diagnosis was 31.9 years in males and 31.2 years in females, but 34.2% of the melanomas occurred before age 30. Dr. Swetter said that she didn’t think young people “are sufficiently aware” of their risk of melanoma. “I think it is analogous to the smoking argument. Younger individuals feel impervious to the longterm effects of ultraviolet [UV] exposure and assume, ‘Well I’ll get my skin cancer in my 50s, and it is curable,’” Dr. Swetter commented.

“I do think that we need to raise awareness of the dangers of excessive sun exposure, promote avoidance of tanning—particularly artificial tanning through tanning bed use—and enhance sun protection through regular sunscreen use and sun protection practices,” Dr. Swetter said. “A large, population-based study from Australia first published online in 20103 suggested that regular sunscreen use could reduce the incidence of melanoma by 50% compared to those who used it on a discretionary or optional fashion,” she noted.

The Food and Drug Administration (FDA) “is providing a great benefit to consumers,” Dr. Swetter said, through its efforts to relabel sunscreens so that the labels are easy to understand and make it clear that sunscreens do not provide a total sunblock but are instead sun protective agents that should provide broad-spectrum UV filtration of both UVB and UVA. “Traditionally UVA filtration has been less effective

A Hot Season for Skin Cancer News, So Expect More Questions

A

n “alarming difference” in survival outcomes between young, non-Hispanic white males and females with primary invasive melanoma (see accompanying article) is one of several skin cancer–related study findings in the news this summer.

Other studies have concerned the rising rates of melanoma among young people, the recurrence of melanoma decades after initial treatment, and recalcitrant individuals who go back to using tanning beds after a diagnosis of basal cell carcinoma.

In addition, the U.S. Food and Drug Administration (FDA) announced new rules on sunscreen labeling, and a Congressional Skin Cancer Caucus was established to address issues related to raising cancer awareness, promoting screening and early detection, and improving access to treatment. All this news may prompt more questions from patients.

‘All Is Not Lost’ Susan Swetter, MD, corresponding author of the study finding that white adolescent and adult males are more likely than their female counterparts to die of melanoma,1 said that the attention focused on the survival disadvantage among males has caused concern among some young male patients who feel doomed by DNA. “You have to tell them that all is not lost,” Dr. Swetter said in an interview with The ASCO Post. “The key is in understanding that with a thin melanoma, you still have a great likelihood of being cured. So trying to promote those behaviors that result in thinner melanoma detection are key, until we actually have some kind of biologic understanding and intervention that could be effective in preventing melanoma.” Dr. Swetter is Professor of Dermatology and Director of the Pigmented Lesion & Melanoma Program at Stanford University Medical Center and Cancer Institute in Palo Alto, California.

For the 15% of individuals who return to using tanning booths after in the U.S. sunscreens compared to other sunscreens worldwide. Hopefully, the FDA will expedite the approval of better UV filters that have been studied worldwide and are in

a diagnosis of basal cell carcinoma (as reported in a research letter published online in JAMA Dermatology2), “the message would be ‘Please, don’t,’” Dr. Swetter said.

“There has been some evidence that tanning is addictive, by producing endogenous opiates and giving people a natural feeling of well-being, and I think that is a major issue. It is not just the appearance of having

that risk is way down the line for many of them.”

A key message to adolescent and young men would be, “Keep your shirt on” while playing sports or working outside. “We consistently see more melanomas on the trunk in men. It has been reported for decades,” Dr. Swetter stated. In the current study, 46.2% of melanomas in males were on the trunk. Because

You have to tell [patients] that all is not lost. The key is in understanding that with a thin melanoma, you still have a great likelihood of being cured.

—Susan Swetter, MD

darker skin; it could actually have a biologic effect in producing an elevated mood,” she continued. “That’s a real problem in terms of trying to have effective primary prevention messages. Hopefully with the FDA becoming more stringent on tanning bed practices and regulations, we may be able to combat some of this excessive tanning use.”

A study in the Mayo Clinic Proceedings3 and recently reported in The New York Times4 found that between 1970 and 2009, melanoma had increased eightfold for women and fourfold for men aged 18 to 39.

“There have been clinics where I’m startled to see multiple young women in their early 20s with melanoma,” Dr. Swetter said.

Different Messages for Males and Females “There might be two different messages that physicians can impart for men and women,” Dr. Swetter said. “For women, who tend to use tanning beds more, the message could be focused on not doing so.”

In addition, “we have found that preventing photoaging and looking old tends to be a more effective message in young women and adolescents than preventing skin cancer because widespread use in Australia and the European Union,” Dr. Swetter said.

“We really do need better sunscreens to be readily available in the United States.”

most of those melanomas are on the back, she tells male patients to “think about having someone look at your back to see if there is anything that looks different than the rest.”

Male patients should also know “that if you do get melanoma, you tend to do worse than a woman with all the matched characteristics. So if you see something new or changing, go to the doctor and don’t wait, because early detection of melanoma can save lives.” n References 1. Gamba CS, Clarke CA, Keegan THM, et al: Melanoma survival disadvantage in young non-Hispanic white males compared with females. JAMA Dermatol.

June 26, 2013 (early release online).

2. Cartmel B, Ferrucci LM, Spain P, et al: Indoor tanning and tanning dependence in young people after a diagnosis of basal cell carcinoma. JAMA Dermatol. July 3, 2013 (early release online).

3. Reed KB, Brewer JD, Lohse CM, et al: Increasing incidence of melanoma among young adults: An epidemiological study in Olmsted County, Minnesota. Mayo Clinic Proceedings 87:328334, 2012.

4. Fitzsimmons EG: Skin cancer on the rise in women. New York Times, July 5, 2013. Available at www.nytimes.com.

Accessed July 26, 2013.

The ‘Ugly Duckling’ “We also need to promote awareness of changing lesions on the skin, whether they look like a classic melacontinued on page 136

The ASCO Post | AUGUST 15, 2013

PAGE 136

News

Height Significantly Linked to Cancer Risk in Postmenopausal Women

By Jo Cavallo

A

n analysis of data from the Women’s Health Initiative (WHI) of the height measurement at enrollment of 144,701 postmenopausal women and the risk of all cancers combined has found that 20,928 of the women had a diagnosis of one or more invasive cancers during a median followup of 12 years. The women’s height was significantly linked with the risk of all cancers (hazard ratio [HR] = 1.13; 95% confidence interval [CI] = 1.11–1.16), as well as with cancers of the thyroid, rectum, kidney, endometrium, colorectum, colon, ovary, and breast, and with multiple myeloma and melanoma (range of HRs: 1.13 for breast cancer to 1.29 for multiple myeloma and thyroid cancer). The study was published in Cancer Epidemiology, Biomarkers & Prevention.1

Study Background The women, representing all major racial/ethnic groups, were between the ages of 50 and 79 years, and enrolled in the study between 1993 and 1998. At the time of enrollment, the women were asked questions about their medical and reproductive history, diet, and lifestyle, including alcohol consumption, smoking habits, and level of physical activity. Height and weight measurements were recorded.

The researchers found that for every 10-cm increase in height, there

Melanoma Outcomes continued from page 135

noma, which tends to be the superficial spreading subtype with the ABCDE clinical warning signs, or an ‘ugly duckling’ lesion that just doesn’t look like a person’s other skin lesions,” Dr. Swetter told The ASCO Post. The ABCDE acronym, introduced in 1985 as ABCD and with the E added in 2004, stands for some key features of melanoma: Asymmetry, Border irregularity, Color variability, Diameter greater than 6 mm, and Evolution or change.

Named after the Hans Christen Anderson fairy tale, the ugly duckling concept is based on the prem-

was a 13% increase in risk of developing any cancer. Among specific types of cancers, there was a 13% to 17% increase in the risk of getting melanoma and cancers of the breast, ovary, endometrium, and colon, and a 23% to 29% increase in the risk of developing cancers of the kidney, rectum, thyroid, and blood.

Height May Be a Cause of Malignant Transformation “We were surprised by the number of cancer sites that were positively associated with height,” Geoffrey Kabat, PhD, Senior Epidemiologist in the Department of Epidemiology and Population Health at Albert Ein-

Height and Cancer Risk ■ For every 10-cm increase in height, there was a 13% increase in risk of developing any cancer.

■ Among specific cancers, there was a 13% to 17% increased risk of

developing melanoma and cancers of the breast, ovary, endometrium, and colon, and a 23% to 29% increased risk of developing cancers of the kidney, rectum, thyroid, and blood.

■ The findings support evidence that exposures in early life play a role in influencing a person’s risk of cancer.

Height is not a modifiable risk factor and is determined both by genetics and by early life exposures and environmental circumstances. The study authors noted that, like nutrition, height should be considered as

We were surprised by the number of cancer sites that were positively associated with height.

—Geoffrey Kabat, PhD

stein College of Medicine of Yeshiva University, and lead author of the study, said in a statement. “In this data set, more cancers are associated with height than were associated with body mass index. Ultimately, cancer is a result of processes having to do with growth, so it makes sense that hormones or other growth factors that influence height may also influence cancer risk.”

a marker that influences cancer risk rather than a risk for cancer itself.

“Of particular relevance are findings that adult height is associated with a higher energy intake in childhood and adolescence, higher intake of milk protein in premenarchic girls, and higher circulating levels of insulinlike growth factor (IGF-I),” wrote the authors. Higher levels of circulating IGF-I have been shown to promote

ise that nevi in the same individual tend to look alike, but a melanoma looks different. “Some of the nodular melanomas that we see, which tend to grow more rapidly and elude early detection, don’t have those typical ABCDE warning signs,” Dr. Swetter noted. “They tend to grow upward and may bleed. There may be no color variation, and the lesion may not have a large diameter.”

“Despite our study’s alarming findings in young men, we still tell both men and women of all ages, that they should see a health provider promptly for any changing mole or skin lesion that doesn’t match the

others,” Dr. Swetter said. “It could be a harmless finding, but it could also be early detection of melanoma, which could save their life.” n

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

References 1. Gamba CS, Clarke CA, Keegan THM, et al: Melanoma survival disadvantage in young non-Hispanic white males compared with females. JAMA Dermatol. June 26, 2013 (early release online).

2. Fisher DE, Geller AC: Disproportionate burden of melanoma mortality in young U.S. men: JAMA Dermatol.

cell proliferation and inhibit apoptosis and an increased risk of prostate, breast, and colorectal cancer. Because height is associated with greater organ size and skin surface area, more cells may be at risk of malignant transformation, according to the researchers.

Further studies examining the links between adult height and increased cancer risk are needed to identify the possible mechanisms, such as nutrition and diet, underlying the associations of height with specific cancers, concluded the researchers. n

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

Reference 1. Kabat GC, Anderson ML, Heo M, et al: Adult stature and risk of cancer at different anatomic sites in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. July 25, 2013 (early release online).

June 26, 2013 (early release online).

3. Green AC, Williams GM, Logan V, et al: Reduced melanoma after regular sunscreen use: Randomized trial follow-up. J Clin Oncol 29:257-263, 2010.

Key Features of Melanoma: ABCDE Assymetry Border irregularity Color variability Diameter greater than 6 mm Evolution or change in appearance

Up the AntiEGFR Start ERBITUX® (cetuximab) in 1st-Line I N D I C AT I O N S Head and Neck Cancer—ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck Colorectal Cancer—ERBITUX is indicated for the treatment of KRAS mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use, in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer EGFR=epidermal growth factor receptor.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Approximately 90% of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (5-FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks — Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS, on adjacent pages.

START WITH THE EXTREME

Regimen

EXTREME=ERBITUX® (cetuximab) in first-line Treatment of REcurrent or MEtastatic head and neck cancer.

EXTREME Regimen=EU-approved cetuximab combined with platinum-based therapy with 5-FU.

The First Regimen Approved in 30 Years With Extended Overall Survival for Recurrent Locoregional or Metastatic SCCHN EXTREME REGIMEN (n=222)1

vs

PLATINUM-BASED THERAPY WITH 5-FU (n=220)1

EXTENDED Median Overall Survival

(OS) (Primary Endpoint)

10.1 MONTHS

36% IMPROVEMENT IN OS*

7.4

MONTHS

HR=0.80 (95% CI: 0.64–0.98); p=0.034

IMPROVED Objective Response Rates (Reduced Tumor Size)†

20%

36%

PATIENTS

PATIENTS

OR=2.33 (95% CI: 1.50–3.60); p=0.0001

PROLONGED Median Progression-Free Survival

5.5

MONTHS

3.3

MONTHS

HR=0.57 (95% CI: 0.46–0.72); p<0.0001 * Relative improvement in median overall survival for the EXTREME regimen was ([10.1-7.4]/7.4) x 100%=36%.1 †

Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 CI=confidence interval; CT=platinum-based therapy with 5-FU; HR=hazard ratio; OR=odds ratio; SCCHN=squamous cell carcinoma of the head and neck.

The EXTREME Study was an open-label, randomized (1:1), multicenter, controlled clinical trial that compared EU-approved cetuximab + CT versus CT alone. Choice of platinum therapy (cisplatin or carboplatin) was up to the treating physician. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately 15% of the patients in the cisplatin-alone arm switched to carboplatin during the treatment period. In exploratory subgroup analyses of the EXTREME Study by initial platinum therapy (cisplatin or carboplatin), for patients (n=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 vs 7.3 months, respectively; HR=0.71 [95% CI: 0.54–0.93]). The difference in median progression-free survival was 2.1 months (5.6 vs 3.5 months, respectively; HR=0.55 [95% CI: 0.41–0.73]). The objective response rate was 39% and 23%, respectively (OR=2.18 [95% CI: 1.29–3.69]). For patients (n=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 vs 8.3 months; HR=0.99 [95% CI: 0.69–1.43]). The difference in median progression-free survival was 1.7 months (4.8 vs 3.1 months, respectively; HR=0.61 [95% CI: 0.42–0.89]). The objective response rate was 30% and 15%, respectively (OR=2.45 [95% CI: 1.10–5.46]).1 The EXTREME Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material.

ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in these studies; these pharmacokinetic data, together with the results of the EXTREME Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in SCCHN.1

IMPORTANT SAFETY INFORMATION (continued) Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection (44% vs 27%). The most common grade 3/4 adverse reactions for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11% vs 8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

START WITH THE CRYSTAL

Regimen

CRYSTAL=Cetuximab combined with iRinotecan in first-line therapY for metaSTatic colorectAL cancer.

CRYSTAL Regimen=EU-approved cetuximab + FOLFIRI; FOLFIRI=irinotecan, 5-fluorouracil, and leucovorin.

The First and Only Biomarker-Directed Therapy for Newly Diagnosed KRAS Mutation-Negative (Wild-Type) EGFR-Expressing mCRC1 ALL-RANDOMIZED PATIENT POPULATION1 CRYSTAL Regimen (n=608)

Median Overall Survival*

KRAS WILD-TYPE SUBPOPULATION1 P O S T- H O C A N A LY S I S

FOLFIRI alone (n=609)

CRYSTAL Regimen (n=320)

18.5

23.5

(95% CI: 18–21)

(95% CI: 17–20)

(95% CI: 21–26)

MONTHS

MONTHS

HR=0.88 (95% CI: 0.78–1.0)

Objective Response Rates (Reduced Tumor Size)‡

46%

19.5 MONTHS

(95% CI: 17–21)

HR=0.80 (95% CI: 0.67–0.94)†

38%

57%

IMPROVED

39%

PATIENTS

PATIENTS

PATIENTS

PATIENTS

(95% CI: 42–50)

(95% CI: 34–42)

(95% CI: 51–62)

(95% CI: 34–44)

PRIMARY ENDPOINT Median Progression-Free Survival

EXTENDED

19.6 MONTHS

FOLFIRI alone (n=356)

8.9

8.1

9.5

MONTHS

MONTHS

(95% CI: 8.0–9.4)

(95% CI: 7.6–8.8)

PROLONGED

8.1

MONTHS

MONTHS

(95% CI: 8.9–11.1)

(95% CI: 7.4–9.2)

HR=0.85 (95% CI: 0.74–0.99); p=0.0358

§

HR=0.70 (95% CI: 0.57–0.86)

In all randomized patients, overall survival was not significantly different at the planned, final analysis based on 838 events (HR=0.93 [95% CI: 0.8–1.1]; p=0.327).

Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer.

•The primary endpoint for the study was progression-free survival in the all-randomized patient population. * Post-hoc updated overall survival analysis based on an additional 162 events.1

Not significantly different.1 Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 § Based on the stratified log-rank test.1 CI=confidence interval; HR=hazard ratio; mCRC=metastatic colorectal cancer.

†

‡

The CRYSTAL Study was a Phase 3, open-label, randomized, multicenter study of 1217 patients with EGFR-expressing mCRC. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI (the CRYSTAL Regimen) or FOLFIRI alone as first-line treatment. KRAS mutational status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had KRAS mutation-negative (wild-type) tumors. Post-hoc analyses of efficacy data were performed on patient subgroups defined

by KRAS mutation status.1 The CRYSTAL Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in this study; these pharmacokinetic data, together with the results of the CRYSTAL Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in mCRC.1

IMPORTANT SAFETY INFORMATION (continued) Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS, on adjacent pages.

UP THE ANTI-EGFR

Dermatologic Toxicities ■ In clinical studies of ERBITUX (cetuximab), dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of patients —Acneiform rash usually developed within the first 2 weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae —Sun exposure may exacerbate these effects Electrolyte Depletion ■ Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs 6%) and of grade 3–4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy —Replete electrolytes as necessary Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX Adverse Reactions ■ The most serious adverse reactions associated with ERBITUX are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) across all studies were cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

CONTACT your sales representative or call 1-800-805-1058 (8 AM-8 PM EST, M-F) to receive patient education materials, enrollment information, and forms

Phone 1-800-861-0048 or Fax 1-888-776-2370 8 AM to 8 PM EST, M-F Please see enclosed Full Prescribing Information, including Boxed WARNINGS. References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2013. 2. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer. 1981;47(1):207-214. 3. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011-2019.

SCAN QR CODE for more information. By scanning the QR code, you are confirming you are a US Healthcare Professional.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2013 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved.

ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

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4/13

UP THE ANTI-EGFR

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing Information, Warnings and Precautions.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.]

INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

K-Ras Mutation-negative, EGFR-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]

• i n combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.]

Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient.

[See Clinical Studies (14.1, 14.2) in Full Prescribing Information.]

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1.

Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.]

Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients.

Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy.

[See Dosage and Administration (2.4) in Full Prescribing Information.]

Use of Erbitux in Combination With Radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%.

In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

K-Ras Testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information].

Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results.

Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux.

Epidermal Growth Factor Receptor (EGFR) Expression and Response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/ faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of 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.

The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 b 15 3 2 0 Infusion Reaction Infection 13 1 9 1 a 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 c 43 2 21 1 Alanine Transaminase, high Aspartate Transaminase, highc 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, highc Respiratory Pharyngitis 26 3 19 4 Skin/Appendages d 87 17 10 1 Acneiform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux (cetuximab) in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89).

Table 2:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU 5-FU Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona Infections and Infestations Infectionb 44 11 27 8 Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous Tissue Disorders c 70 9 2 0 Acneiform Rash Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”.

Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm.

Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab.

U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224).

Table 3:

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera EU-Approved Cetuximab plus FOLFIRI FOLFIRI Alone (n=317) (n=350) Grades Grades Grades Body System Grades b 1–4 1–4 3 and 4 3 and 4 Preferred Term % of Patients Blood and Lymphatic System Disorders Neutropenia 49 31 42 24 Eye Disorders Conjunctivitis 18 <1 3 0 Gastrointestinal Disorders Diarrhea 66 16 60 10 Stomatitis 31 3 19 1 Dyspepsia 16 0 9 0 General Disorders and Administration Site Conditions 14 2 <1 0 Infusion-related Reactionc Pyrexia 26 1 14 1 Infections and Infestations Paronychia 20 4 <1 0 Investigations Weight Decreased 15 1 9 1 Metabolism and Nutrition Disorders Anorexia 30 3 23 2 (Continued)

13646203_0084803_v3_UpTheAntiAd_10.5x14_Pgs1_6.indd 6

Table 3: (Continued)

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera EU-Approved Cetuximab plus FOLFIRI FOLFIRI Alone (n=317) (n=350) Grades Grades Grades Body System Grades 1–4b 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous Tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”.

Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51).

Table 4:

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic Colorectal Cancer Treated with Erbitux Monotherapya Erbitux plus BSC BSC alone (n=118) (n=124) Grades Grades Grades Body System Grades b 3 and 4 1–4 3 and 4 Preferred Term 1–4 % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 c 18 3 0 0 Infusion Reactions Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 Infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related.

Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

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The incidence 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 the incidence of antibodies to Erbitux (cetuximab) with the incidence of antibodies to other products may be misleading.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of Erbitux.

Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis • Mucosal inflammation DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, 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. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric Use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects.

OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2013 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

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Announcements

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Nazarbayev University Selects Pittsburgh School of Medicine as Strategic Partner to Establish Medical School in Kazakhstan

T

he University of Pittsburgh School of Medicine has been chosen to guide the Republic of Kazakhstan’s Nazarbayev University as it establishes its own medical school, which aims to educate physicianscientists to become the nation’s next leaders in health care, medical education and biomedical research.

“This is the School of Medicine’s most ambitious educational partnership undertaken to date and meets the university’s goal of building its presence on the global health stage,” said Arthur S. Levine, MD, University of Pittsburgh Senior Vice Chancellor for the Health Sciences and Dean, School of Medicine.

Strategic Partnership Nazarbayev University sought a strategic partner to provide consultation and technical assistance in developing its medical school, which

will be built in Kazakhstan’s capital, Astana. The site selected for the Nazarbayev University School of Medicine is near the school’s main campus and in close proximity to the hospitals of National Medical Holding, also part of Nazarbayev University, which will serve as clinical rotation sites for the students. “[University of Pittsburgh School of Medicine] will provide the knowledge and experience needed to institute a U.S.-style curriculum to train their Republic’s new doctors and biomedical researchers,” said Dr. Levine.

University of Pittsburgh School of Medicine experts will advise school officials on how to design and develop teaching facilities for a medical school curriculum; recruit and train school leadership and faculty; plan organizational and administrative structures, policies and procedures; and develop courses, syllabi and clinical experi-

ences with the participation of physician-educators from the hospitals of National Medical Holding.

New Model of Medical Education “In collaboration with the University of Pittsburgh School of Medicine, we will establish a new model of medical education that trains superb clinicians,” said Nazarbayev University President Shigeo Katsu. “Our aim is to establish Kazakhstan’s first integrated academic health system and, ultimately, to transfer this model to other regions of the country to improve the overall health care of the people of Kazakhstan.”

The medical school, which will use English as the language of instruction, is expected to open in fall 2015.

Applicants will be expected to meet admissions requirements similar to those of U.S.-style medical schools

that have been developed in other countries, such as an appropriate premedical foundation and completion of the Medical College Admissions Test.

Kazakhstan’s use of Pittsburgh’s biomedical expertise began in June 2011 with the short-term training of principal investigators and other research personnel from Nazarbayev University’s Center for Life Sciences and Center for Energy Research.

Collaborative activities expanded in July 2012 when University of Pittsburgh Medical Center, Pitt’s clinical partner, and one of the nation’s leading academic medical centers, announced that it was selected by Nazarbayev University to assist its development of a national oncology treatment and research center, which is expected to include a 300-bed hospital, outpatient care, a research facility and a hotel complex. n

The ASCO Post | AUGUST 15, 2013

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Expert’s Corner Patient Education

Making the Science of Cancer Understandable to a Broad Audience A Conversation with David Sadava, PhD

By Jo Cavallo

David Sadava, PhD

A

n educator and scientist for over 30 years, David Sadava, PhD, became interested in the science of cancer while on sabbatical from Claremont Colleges, where he was teaching courses in molecular biology and biotechnology, and went to the City of Hope Medical Center in Duarte, California, to study the mechanisms involved in the development of cancer.

“I found interesting scientific problems in the study of cancer, and I thought I could continue doing research on cancer and use what I learned to teach my courses, so it opened a new door for me. I’m still teaching science, but it’s within the context of cancer,” said Dr. Sadava, now Adjunct Professor of Cancer Cell Biology at City of Hope Medical Center in Duarte, California, and the Pritzker Family Foun-

dation Professor of Biology, Emeritus, at the Claremont Colleges. In addition to writing and teaching, Dr. Sadava is currently researching drug resistance in lung cancer.

Dr. Sadava’s transition to studying and teaching the science of cancer led to the development of a series of video lectures called “What Science Knows About Cancer” (available at thegreatcourses.com), aimed at a lay audience.

The ASCO Post talked with Dr. Sadava about how he is using the lectures to help cancer patients learn about their disease and become more proactive in their care, as well as educate the general public on science and cancer.

Rationale for the Series Why did you feel it was necessary to create the lecture series “What Science Knows About Cancer?”

Once the word got out that I was using cancer to teach science to my students, people with cancer would come up to me and say, “My doctor didn’t explain why I have to take this chemotherapy” or “Do you know where I can get a second opinion?”

They wanted to understand, in general, how chemotherapy works and the side effects, what it means if a tumor becomes drug-resistant, and where they could find clinical trials. So I put all that information in the lecture series.

The course does not try to secondguess what the patients’ oncologists are doing. It is meant to be informative

and the different types of therapy, including chemotherapy, surgery, and radiation.

My course presents the progress that has been made in cancer research, the current state of that research, and what advances may be possible in the future.

—David Sadava, PhD

and fill in the gaps in the public’s understanding of science, especially the science of cancer.

Content Accessibility The course is taught at college level.

How well is the information understood by people without a science background or college education?

The course material is appropriate for most people. I find that most of the families coping with cancer that I help, and friends who are not physicians or scientists, understand the material without a problem.

The course is divided into 24 lectures at a half-hour each, to make the information they are seeking easier to find and more palatable. For example, people can view lectures on cancer growth and development, tumor staging and grading, the difference between a case-control and cohort study,

I also bring the audience into cancer research laboratories to show how investigators approach the problems they are researching and the progress being made.

Goals of the Series What do you hope to accomplish with this course?

When I was approached to do this series I leapt at the opportunity, because I am both an educator and a scientist and I think there is a huge gap in the public’s knowledge about the science of cancer. My course presents the progress that has been made in cancer research, the current state of that research, and what advances may be possible in the future.

I’m doing this because I believe in public education, and this is my way of making a contribution to that effort. n

Disclosure: Dr. Sadava receives royalties from The Great Courses.

Pig Diagnosed With Lymphoma and Treated at Cornell University Hospital for Animals

D

octors at Cornell University Hospital for Animals in Ithaca, New York, reported what they believe may be the first case of a pig being treated for lymphoma. The animal was described as a 730-pound black-andwhite Hampshire pig that was diagnosed with presumptive B-cell lymphoma.

The 4-year-old pig, called “Nemo,” was brought to the Cornell Hospital for Animals by his owner after becoming ill earlier this year.

The pig became a teaching case for veterinary oncologists at the University Hospital for Animals, undergoing a novel care plan and paving the way to

combat cancer in large animals. Clinicians worked to prepare for intravenous medication delivery. In the first such procedure ever done to treat a sick pig, surgeon Jim Flanders, DVM, who had performed similar procedures in smaller animals, joined large-animal surgeon Susan Fubini, DVM, to surgically implant a vascular access port.

The two doctors ran a catheter up a vein in the pig’s neck to a port behind his ear, creating a route for delivering drugs where they would be most effective while minimizing harm. Resident Emily Barrell, DVM, selected and delivered the chemotherapeutic drugs.

“Although lymphoma has been

documented in swine, there aren’t any documented cases of pigs being treated for it,” said Cornell hospital oncologist Cheryl Balkman, DVM. “We adapted a treatment plan based on what we know is effective in dogs, cats, and humans with lymphoma,” Dr. Balkman said.

The pig’s clinical signs soon resolved, and he has continued to do well during long-term treatment. Though little is known about the prognosis for pigs with cancer, this one case has offered veterinarians valuable information for helping large animals. Nemo continues to reside at Cornell’s Hospital for Animals. n

Emily Barrell, DVM, with the 730-pound blackand-white Hampshire pig called “Nemo” at Cornell University Hospital for Animals.

ASCOPost.com | AUGUST 15, 2013

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Patient’s Corner Gynecologic Oncology

I Overcame Cervical Cancer but Not Its Long-term Effects Thirty-four years after being diagnosed with cervical cancer, I’m still coping with the consequences of treatment.

By Carol Goodrich, as told to Jo Cavallo

I

n 1979, when I was just 35 years old, I started experiencing abnormal vaginal bleeding and lower back pain. When a Pap test came back normal, the gynecologist I saw said not to worry about anything, that I was fine.

But I wasn’t fine. My symptoms quickly escalated, and I sought the opinion of another gynecologist. He gave me a physical examination and said that I had a large tumor on my cervix. He was sure it was malignant and that I needed to be admitted to the hospital the next morning for additional tests.

A pathology examination of the cervical tissue from a dilation-and-curettage procedure confirmed cervical cancer.

The news sent me reeling.

I was told that the cancer had not metastasized, but that the tumor was so big it was inoperable and that I would need external-beam radiation therapy, followed by high-dose brachytherapy, to dissolve the mass. I don’t remember exactly how many radiation treatments I had, but I know that it went on for 3 months and left me exhausted and also so nauseated that I had to stop the car along the side of the road on my way to work.

Although those early side effects gave me hints of the digestive troubles that would plague me 2 decades later, for the most part I was able to manage the therapy well. It was the mental anguish of having such a deadly cancer that caused me greater initial problems. I was so paralyzed with fear and depression and so certain I was going to die, I refused to buy Christmas pres-

ents, even though Christmas is my favorite holiday, or even shop for a new dress. Why buy a new dress if I’m not going to be around to wear it?

Escalating Health Problems My husband Don was so supportive. He would hold my hand and tell me that we would beat this cancer, and together we fought it. After 5 years with no cancer recurrence, my oncologist declared me cured, and

Since then, the problems have gotten worse. In 2008, I had a bowel resection that kept me hospitalized for 6 weeks yet has not completely healed. My general health has deteriorated. Because every diet I tried failed to remedy my extreme digestive pain and bouts of vomiting, a medication port was implanted so I could get total parenteral nutrition (TPN). Although the TPN was discontinued a few months ago, eating

What my 34-year-long health odyssey has taught me is the importance of having a good doctor/ patient relationship—one in which patients are treated as individuals, not as statistics, and are given as much information as possible about the potential consequences of specific treatments.

—Carol Goodrich

for much of the next 20 years I felt well. But in 2004, I started having episodes of vomiting that were so violent I would bring up green bile.

Three years later, the vomiting became more frequent and was often accompanied by severe abdominal pain caused by intestinal blockages.

This resulted in hospital stays to have my stomach pumped and receive intravenous nutrients and fluids.

and absorbing solid food is still a challenge for me.

Now, in addition to increasing abdominal pain, I have severe rectal bleeding and peripheral neuropathy in my feet, all of which have diminished my quality of life. Because digesting food and eliminating waste have become so excruciating, even the simple act of going out to dinner with friends is unthinkable.

Improving Survivors’ Quality of Life My doctors tell me that all these health issues are the result of late effects from the radiation therapy I received more than 3 decades ago, and the damage can’t be reversed.

I’m grateful that the treatment saved my life and has prevented the cancer from coming back. However, half my life has been spent battling the effects of the radiation I received in 1979, and I wish I had been warned about the potential long-term risks so I would have understood what was happening to me. I know advances have been made in the treatment of cervical cancer since I was diagnosed and that therapies—including radiation therapy—are now much more targeted, greatly reducing long-term complications, and that’s good news.

What my 34-year-long health odyssey has taught me is the importance of having a good doctor/patient relationship—one in which patients are treated as individuals, not as statistics, and are given as much information as possible about the potential consequences of specific treatments.

While the side effects from my treatment are permanent, my greatest hope is that the combination of more targeted therapies and more open communication between doctors and patients will result in greater longterm quality of life for the millions of cancer survivors living today. n Carol Goodrich lives in Naples, Florida.

Contact The ASCO Post Editorial Correspondence

Rates, reprints, or supplements

James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Women with Primary Breast Cancer Diagnosed During Pregnancy Have Overall Survival Similar to Nonpregnant Patients Results from an international collaborative study showed that women with primary breast cancer diagnosed during pregnancy had overall survival similar to nonpregnant patients. Reporting their findings in the Journal of Clinical Oncology, the authors concluded: “This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy.”

In a comparison of 311 women with breast cancer diagnosed during pregnancy and 865 women who were not pregnant, the hazard ratio of pregnancy was 1.19 (95% confidence interval [CI], 0.73–1.93; P = .51) for overall survival. Cox regression estimated that the 5-year overall survival rate would have increased from 78% to 81% if these patients had not been pregnant.

For disease-free survival, the hazard ratio of pregnancy was 1.34 (95% CI = 0.93–1.91; P = .14) and Cox regression estimated that the 5-year diseasefree survival rate would have increased from 65% to 71% if these patients had not been pregnant. “Regarding the [disease-free survival] analysis, the observed [hazard ratio] of 1.34 suggests

better outcome for the nonpregnant group; however, the CI shows that any distinct effect of pregnancy cannot be concluded,” the investigators stated.

The age limit was 45 years, with a median age of 33 years for pregnant and 41 years for nonpregnant patients. Women with in situ or primary metastatic disease and those relapsing during pregnancy were excluded from the analyses, as were women who became pregnant during treatment or received their diagnosis postpartum. Analysis adjusted for age, stage, grade, hormone receptor status, human epidermal growth factor receptor 2 status, histology, type of chemotherapy, use of trastuzumab (Herceptin) radiotherapy, and hormone therapy.

Median follow-up was 61 months.

“During follow-up, 42 pregnant patients (14%) and 103 nonpregnant patients (12%) died,” the researchers reported.

Maternal and Fetal Safety

Observations from this and other studies, “suggest that chemotherapy during pregnancy can be administered as it is in nonpregnant women (with chemotherapy dosing based on body surface area), despite the altered pharmacokinetics during pregnancy,” the authors noted.

“Apart from maternal safety, fetal safety is also considered when patients are counseled. Chemotherapy exposure during the second and third trimesters of pregnancy did not impair neonatal outcome,” the researchers added.

“Taken together, the available data confirm maternal and fetal safety when breast cancer is treated during pregnancy,” the investigators concluded. “Standard treatment during pregnancy, including chemotherapy, adds to an optimal maternal outcome.

This outcome now seems to be comparable to that of nonpregnant patients. In addition, the administration of chemotherapy during pregnancy contributes to fewer preterm deliveries and thus also to improved fetal outcome.”

“This study provides ©Edward Frascino/The New Yorker Collection/www.cartoonbank.com additional comfort for

women and physicians who must care for the pregnant patient with breast cancer,” according to an editorial that accompanied the article. “The cancer can be treated, the pregnancy can be maintained, labor and delivery can be successful, and the outcome for mother and neonate can be expected to be favorable.”

Amant F, et al: J Clin Oncol 31:25322539, 2013.

Theriault RL, Litton JK: J Clin Oncol 31:2521-2522, 2013.

Cisplatin plus Cetuximab vs Cisplatin-alone in Patients with Metastatic Triple-negative Disease Adding cetuximab (Erbitux) to cisplatin doubled the overall response rate and appeared to prolong progressionfree and overall survival in a randomized phase II study among patients with metastatic triple-negative breast cancer.

Although the trial did not meet its primary endpoint of overall response rate, the authors of the study, published in the Journal of Clinical Oncology, concluded that the results warranted further investigation of the combination in treating metastatic triple-negative breast cancer.

Triple-negative breast cancer, defined as estrogen receptor–negative, progesterone receptor–negative, and human epidermal growth factor receptor 2 (HER2)-negative disease, has been shown to overexpress epidermal growth factor receptor (EGFR). In addition, the authors noted that triplenegative breast cancer cell lines that overexpress EGFR are inhibited by the anti-EGFR monoclonal antibody cetuximab, which has also been shown to enhance the antitumor activity of cisplatin and carboplatin.

In this study, patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive up to six cycles of cisplatin plus cetuximab or cisplatin alone. “The full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy,” the investigators stated. The study was conducted in Europe, Israel, and Australia.

“The study groups were well balanced for performance status, line of

treatment, and median time to metastasis,” the authors noted. Overall, 86% of patients had infiltrating ductal carcinoma and the median age was 52 years.

Study Outcomes The best overall response rate was 20% (95% confidence interval [CI] = 13–29; 23 of 115) and 10% (95% CI = 4–21; 6 of 58) in the cisplatin plus cetuximab and cisplatin-alone groups, respectively (odds ratio = 2.13; 95% CI = 0.81–5.59; P = .11). “Thus, the primary endpoint was not met,” and the researchers stated, and it was a negative trial.

“However, it is possible that this may not accurately represent the true activity of this combination regimen as, unlike other randomized phase II studies, the primary endpoint was based on two null hypotheses; on the one hand, superiority of the cetuximab arm and, on the other, an [overall response rate] of greater than 20%,” the authors noted.

“Therefore, the observed doubling of the overall response rate with the addition of cetuximab to cisplatin should not be ignored when considering the potential of anti-EGFR agents in [metastatic triple-negative breast cancer].”

Median progression-free survival was significantly longer among patients receiving cisplatin plus cetuximab than among patients receiving cisplatin alone (3.7 vs 1.5 months; hazard ratio [HR] = 0.67; 95% CI = 0.47–0.97; P = .032).

Median overall survival among patients receiving cisplatin plus cetuximab was 12.9 vs 9.4 months among those receiving cisplatin alone (HR = 0.82; 95% CI = 0.56–1.20; P = .31).

“All 171 patients experienced at least one adverse event,” the researchers reported, with 61% of patients in the cisplatin plus cetuximab group and 42% of the patients in the cisplatin-alone group experiencing at least one grade 3 or 4 adverse event. “The more frequent grade 3 or 4 adverse events in the cisplatin plus cetuximab compared with the cisplatin-alone group are mainly owing to grade 3 acne-like rash associated with cetuximab, which was generally manageable. In addition, patients in the cisplatin plus cetuximab group had a slightly higher incidence of grade 3 or 4 neutropenia than patients in the cisplatin-alone group as well as some grade 3/4 infusion-related reactions.”

Baselga J, et al: J Clin Oncol 31:25862592, 2013.

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In the Literature

For Women ≥ 70 Years with Early Breast Cancer Adding Radiotherapy to Lumpectomy and Tamoxifen Does Not Increase Survival Long-term follow-up of Cancer and Leukemia Group B (CALGB) trial 9343 confirmed and extended 5-year results that in women age > 70 years with clinical stage I, estrogen receptor (ER)-positive breast cancer treated with lumpectomy followed by tamoxifen, “irradiation adds no significant benefit in terms of survival, time to distant metastasis, or ultimate breast preservation, even though it provides a small decrease” in ipsilateral breast recurrence.

Reporting their results in the Journal of Clinical Oncology, the CALGB investigators concluded that “depending on the value placed on local recurrence,” tamoxifen without radiation “remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer.”

A total of 636 women treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). The investigators found that at 10 years follow-up, 98% of patients receiving tamoxifen plus radiation therapy (95% confidence interval [CI] = 96%–99%) vs 90% of those receiving tamoxifen alone (95% CI = 85%–93%) were free from local and regional recurrences. This 8% difference was considered statistically significant.

Overall survival at 10 years was 67% (95% CI = 62%–72%) in the tamoxifen plus radiation therapy group and 66% (95% CI = 61%–71%) in the tamoxifen alone group.

“The addition of [radiation therapy] seems to provide no benefit in terms of [overall survival], distant disease-free survival, or ultimate breast preservation, with the proviso that the study lacked the power to definitively show noninferiority of either arm,” the authors noted.

“Importantly, the study also shows that the impact of breast cancer in this select group of older women is much smaller than that of comorbid conditions. Of the 636 women in this study, only 21 (3%) have died as a result of breast cancer, whereas 313 (49%) have died as a result of other causes (only 6% of deaths attributed to breast cancer).”

The investigators also pointed out that the definition of negative margin has changed since the study began in 1994, with the current trend being toward greater negative margins (usually 1–2 mm), They noted that the low rate

of ipsilateral breast recurrence without radiation therapy in this study “might further decrease with wider excision, suggesting that any benefit of [radiation therapy] over antiestrogen treatment alone in local recurrence may be of even less significance today.”

“We applaud the CALGB investigators for providing the oncology community with phase III data suggesting that selected elderly patients with ER-positive, early-stage disease being treated with hormonal therapy may not need breast radiation,” Benjamin D. Smith, MD, and Thomas A. Buccholz, MD, of The University of Texas MD Anderson Cancer Center in Houston, wrote in an accompanying editorial. “We support this conclusion for patients age 75 or older with low- to intermediate-grade disease and those with shorter life expectancies as a result of comorbidities. However, we feel that radiation use continues to be appropriate for patients younger than age 75 and those with high grade tumors.”

Hughes KS, et al: J Clin Oncol 31:2382-2387, 2013.

Smith BD, Buchholz TA: J Clin Oncol 31:2367-2368, 2013.

PROSTATE CANCER Androgen Deprivation Therapy Associated with Increased Risk of Acute Kidney Injury The use of androgen deprivation therapy was significantly associated with an increased risk of acute kidney injury among men with newly diagnosed nonmetastatic prostate cancer, according to a study published in JAMA. The study was motivated by the increasing use of androgen deprivation therapy in patients with earlier-stage disease and the high mortality rate (around 50%) in patients with acute kidney injury, the researchers noted. The testosterone suppression associated with androgen deprivation therapy “may lead to a hypogonadal condition that can have detrimental effects on renal function, thus raising the hypothesis that [androgen deprivation therapy]–induced hypogonadism could potentially lead to acute kidney injury,” they explained.

The United Kingdom Clinical Practice Research Datalink and the Hospital Episodes Statistics database were used to identify 10,250 patients.

During a mean follow-up of 4.1 years, 232 incident cases of acute kidney in-

jury were identified, an incidence rate of 5.5 per 1,000 person-years. These cases were randomly matched with up to 20 controls for age, calendar year of prostate cancer diagnosis, and duration of follow-up. “[Androgen deprivation therapy] was categorized into 1 of 6 mutually exclusive groups: gonadotropin-releasing hormone agonists, oral antiandrogens, combined androgen blockade, bilateral orchiectomy, estrogens, and combination of the above,” the investigators explained.

Key Data Patients who were currently using any androgen deprivation therapy had an increased risk of acute kidney injury compared to those who never used any androgen deprivation therapy. The odds ratio was 2.48 (95% confidence interval [CI] = 1.61– 3.82), “generating a rate difference of 4.43/1,000 persons per year (95% CI = 1.54-7.33),” the researchers reported. The odds ratio “was lower and not statistically significant” for former androgen deprivation therapy users (odds ratio [OR] = 1.25 [95% CI = 0.68–2.29]).

This association between use of androgen deprivation therapy and increased risk of acute kidney injury “was mainly driven by a combined androgen blockade consisting of gonadotropin-releasing hormone agonists with oral antiandrogens (OR = 4.50 [95% CI = 2.61–7.78]), estrogens (OR =4.00 [95% CI, 1.0615.03]), other combination therapies (OR = 4.04 [95% CI = 1.88–8.69]), and gonadotropin-releasing hormone agonists (OR = 1.93 [95% CI = 1.20– 3.10]),” the investigators noted.

The finding that the highest odds ratio was observed in patients taking combination therapies “suggests a possible additive effect exerted by [androgen deprivation therapy] on both receptor antagonism and reduction of testosterone excretion,” the researchers wrote. “Furthermore, the highest [odds ratio] of [acute kidney injury] was also observed in the earliest period of treatment, though the [odds ratio] remained continuously elevated with longer durations of use. The former might be related to an early and severe deteriorating effect of [androgen deprivation therapy] in susceptible patients who probably experience subtle reductions in kidney functions.”

Lapi F, et al: JAMA 310:289-296, 2013.

MELANOMA Anti-PD-1 Antibody Lambrolizumab Produces Durable Responses with Low Toxicity in Patients with Advanced Melanoma Lambrolizumab produced a high rate of sustained tumor regression when tested among 135 patients with advanced melanoma in a multiinstitutional, international, phase I expansion study reported in The New England Journal of Medicine. At a median follow-up of 11 months, responses were durable in the majority of patients. Toxic effects were mainly limited to grade 1 or 2.

Previously known as MK-3475, lambrolizumab is an antibody against the programmed death 1 (PD-1) receptor. Patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab (Yervoy) and those who had not, were given lambrolizumab intravenously at a dose of 10 mg/kg every 2 or 3 weeks or 2 mg/kg every 3 weeks.

The confirmed response rate across all dose cohorts was 38% (95% confidence interval [CI] = 25–44), with the highest confirmed response rate observed in the 10 mg/kg every 2 weeks cohort (52%; 95% CI = 38–66). “The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate = 38% [95% CI = 23–55] and 37% [95% CI = 26–49], respectively),” the investigators observed. Among the responders, 81% (42 of 52) were still receiving treatment at the time of analysis in March 2013.

Adverse Events Drug-related adverse events of any grade were reported by 79% of patients, with grade 3 or 4 adverse events reported by 13%. “Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade,” the authors reported.

“The cohort with the maximum administered dose of lambrolizumab [10 mg/kg every 2 weeks] showed the highest response rate of 52%.

This cohort also showed the highest rate of drug-related adverse events, continued on page 152

The ASCO Post | AUGUST 15, 2013

PAGE 152

In the Literature

Emerging Clinical Data continued from page 151

although this may be due in part to a longer duration of therapy,” the authors wrote.

“Although cross-study comparison of adverse event rates should be viewed with caution, it seems that in comparison to anti-CTLA-4 therapy,

lambrolizumab therapy was associated was associated with a lower incidence and a different spectrum of immune-related adverse events, possibly owing to a distinct mechanism of action with a more targeted effort on tumor-specific T cells,” the researchers noted.

“The study was sponsored by

Merck Sharpe and Dohme, which provided the study drug and worked closely jointly with the senior academic authors to design the study, collect the data, and interpret the study results,” the authors acknowledged.

Hamid O, et al: N Engl J Med 369:134-144, 2013.

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SARCOMAS Ridaforolimus Delayed Tumor Progression in Patients with Previously Treated Metastatic Sarcoma “Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy,” according to results of an international phase III trial. The large randomized placebo-controlled phase III trial evaluated the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas.

Aberrant mTOR signaling is common in sarcomas and other malignancies and ridaforolimus has demonstrated clinical activity against sarcomas and other solid tumors in phase I and II trials.

Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus at 40 mg (four 10-mg tablets) or matching placebo administered orally once per day for 5 days every week.

The mean age was 52.0 years for the 347 patients receiving ridaforolimus vs 50.6 years for the 364 patients receiving placebo arm. “Approximately 90% of patients had soft tissue sarcomas, with the other 10% having bone sarcomas, and approximately 73% of patients had high-grade tumors, with only 5% having low-grade tumors,” the researchers reported. “More than 60% of patients had lung metastases, followed by liver and bone metastases. Almost 40% of patients in the ridaforolimus and placebo arms had received > two lines of prior therapy.”

Study Results

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Independent review found that treatment with ridaforolimus “led to a modest, although significant, improvement” in progression-free survival, the primary endpoint of the study, compared with placebo (hazard ratio [HR] = 0.72; 95% confidence interval [CI] = 0.61–0.85; P = .001).

The median progression-free survival was 17.7 weeks for those receiving ridaforolimus vs 14.6 weeks for those receiving placebo. This represented a 28% reduction in the risk of progression or death. “Ridaforolimus incontinued on page 153

ASCOPost.com | AUGUST 15, 2013

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Letters to the Editor

Support Group Offers Resources for Patients with Oral/Head and Neck Cancer

I

am the Outreach Administrator/ Newsletter Editor at Support for People with Oral and Head and Neck Cancer (SPOHNC). SPOHNC is a national nonprofit organization involved in the development of support programs. As such, it can have an enormous positive impact on meeting the psychosocial needs of patients as well as preserving, restoring, and promoting physical and emotional health.

SPOHNC is dedicated to raising awareness and meeting the needs of oral and head and neck cancer patients.

We do this through more than 125 SPOHNC Chapter support groups in 39 states across the country, as well

as our National Survivor Volunteer Network; a survivor-to-patient matching program; our monthly newsletter, News from SPOHNC; two volumes of our cookbook and resource guide, Eat Well, Stay Nourished; our Meeting the Challenges of Oral and Head and Neck Cancer—A Survivors Guide; and We Have Walked In Your Shoes, A Guide to Living with Oral and Head and Neck Cancer. Information, resources and links concerning oral/head and neck cancer and its diagnosis, treatment, and side effects can be found on our website at www.spohnc.org. You can also find us on Facebook.

A member of our Medical Advisory

Board forwarded us a link to an article published in the June 10 issue of The ASCO Post (“Coping with Tongue Cancer: A Lonely Journey,” by Betsy Keller, as told to Jo Cavallo). It’s a shame that Betsy Keller was not aware of our organization, which has been in existence for more than 20 years, helping patients, survivors, caregivers, and family as they endure their cancer journey, through treatment and beyond.

SPOHNC was started 20 years ago

by Nancy Leupold, an oral cancer survivor, when she found that there was no support and very little information for patients who have been diagnosed with oral and head and neck cancer.

We have much to offer, and we’re here to fill the need that Ms. Keller spoke of in her editorial piece. In Florida alone, we have 10 SPOHNC Chapter support groups, and there is one in the Boca Raton area.

We encourage your readers to share information about SPOHNC with their patients and their colleagues.

Visit our website at www.spohnc.org, and contact us at 1-800-377-0928 or info@spohnc.org. n —Chris Leonardis Outreach Administrator Support for People with Oral and Head and Neck Cancer Locust Valley, New York

Emerging Clinical Data

those receiving placebo.

The investigators argued that combination therapy with ridaforolimus and inhibitors of other intracellular compensatory signaling pathways “may lead to even more substantial benefit by preventing compensatory cellular mechanisms, which likely minimized the inhibitory action of ridaforolimus.”

Demetri GD, et al: J Clin Oncol 31:2485-2492, 2013.

Leukemia Study Group and Study Alliance Leukemia to conclude, “ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediaterisk [ acute promyelocytic leukemia].”

Eligibility requirements for the study included age between 18 to 71 years and low-to-intermediate risk acute promyelocytic leukemia based on a white-cell count ≤ 10×109 per liter. “Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA,” the authors explained.

the log-rank test for the difference in event-free survival curves indicated the superiority of ATRA-arsenic trioxide (P = 0.02),” the authors explained.

The 2-year overall survival probability was 99% in the ATRA–arsenic trioxide vs 91% in the ATRA-chemotherapy group (P = 0.02). The median follow-up was 34.4 months.

ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections than ATRAchemotherapy, but more patients in the ATRA-arsenic trioxide group had grade 3 or 4 hepatic events. In addition, prolongation of the QTc interval occurred in 12 patients in the ATRAarsenic trioxide group, but no patients in the ATRA-chemotherapy group.

“The present study suggests that APL is curable without conventional chemotherapy. Although longer follow-up will be needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic trioxide act synergistically to eradicate [acute promyelocytic leukemia],” the authors averred.

“No pharmaceutical company was involved in the design of the study, data collection or analysis, or the writing of the manuscript,” the researchers noted. “Arsenic trioxide was donated for this investigation by Cephalon Europe and, since 2011, by Teva Pharmaceutical Industries.”n Lo-Coco F, et al: N Engl J Med 369:111-121, 2013.

continued from page 152

duced a mean 1.3% decrease in target lesion size vs a 10.3% increase with placebo (P < .001),” the researchers reported. The median overall survival was 90.6 weeks with ridaforolimus vs 85.3 weeks with placebo (HR = 0.93; 95% CI = 0.78–1.12; P = .46).

“Despite the proportional benefit, because of the faster rate of disease progression in this study population, the absolute magnitude of [progression-free survival] improvement with ridaforolimus was relatively modest,” the authors wrote. “This small, but nonetheless statistically significant, difference in [progression-free survival] with ridaforolimus did not translate into a significant difference in [overall survival]. It is important to note that this trial was not powered to detect differences in [overall survival]; additionally, the statistical plan was based on a predicted [overall survival] duration of 12 months in the placebo population, and the longer-than-expected survival in the placebo arm reduced the power of the study to detect any differences in [overall survival].”

The toxicities observed with ridaforolimus were “as expected with mTOR inhibition,” the investigators noted. Adverse events that occurred more commonly with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 adverse events were reported by 64.1% of patients receiving ridaforolimus vs 25.6% of

LEUKEMIA ATRA and Arsenic Trioxide May Be Even Better Than ATRA Alone in Treating Low to Intermediate Risk Acute Promyelocytic Leukemia All-trans retinoic acid (ATRA) plus arsenic trioxide bested the already high remission rates achieved

by ATRA with chemotherapy, the standard of care for acute promyelocytic leukemia, in a phase III multicenter trial among patients with low-to-intermediate risk acute promyelocytic leukemia. “Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P = .12),” according to the results published in The New England Journal of Medicine.

These results led researchers from the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) and the German–Austrian Acute Myeloid

Study Results The study “was designed to show that ATRA-arsenic trioxide was not inferior to ATRA-chemotherapy with respect to the event-free survival rate at 2 years,” the authors noted. Results showed that 2-year event-free survival rates were 97% in the ATRAarsenic trioxide group and 86% in the ATRA-chemotherapy group. This represented a difference of 11% (95% confidence interval [CI] = 2–22).

“Since the lower bound of the 95% confidence interval for the difference in event-free survival rates was not lower than -5%, the noninferiority of ATRA–arsenic trioxide was confirmed (P < .001). Furthermore,

Sandra M. Swain, MD

Immediate Past President ASCO MeMber SinCe 1986

Allen S. Lichter, MD

ASCO Chief Executive Officer

ASCO MeMber SinCe 1980 Clifford A. Hudis, MD ASCO President

ASCO MeMber SinCe 1991

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ASCOPost.com | AUGUST 15, 2013

PAGE 155

Letters to the Editor

Seeking Clarity on the PSA Story

M

y feature interview in the August 15, 2012, issue of The ASCO Post, entitled “Rethinking the Role of PSA Screening in Public Health”1 drew swift reaction from well-known figures in the prostate cancer field. The subsequent Letters to the Editor, three in all, constituted a two-pronged attack. They first cast doubt on my discovery of prostatespecific antigen (PSA) in 1970, and then leveraged that doubt to question my widely publicized view that PSA screening in asymptomatic men does far more harm than good.

I have already responded to the first letter, by Drs. James Mohler and Donald Trump,2 in the September 15, 2012, issue of this publication.3 For the sake of concision and to avoid redundancy, I will collectively address the final two letters, from Drs. T. Ming Chu4 and William J. Catalona.5 However, given the fairly recent rethinking about PSA screening—notably reflected in the new guidelines from the American Urological Association (AUA)6—I won’t redress the use of PSA, save to say that I’m glad my 3-decades-long mission against routine screening is beginning to see a flickering light at the end of the tunnel.

Recapping the Discussion The debate in brief: I discovered PSA in 1970, but the Chu and Catalona letters cited above argue that Dr. Chu, in 1979, was the true discoverer of PSA. As this is essentially a Roswell Park–centric feud, it is interesting to note that the late Dr. Gerald P. Murphy, former Director of the National Prostate Cancer Project and Roswell Park Memorial Institute (subsequently known as Roswell Park Cancer Institute) and coauthor with Dr. Chu on their 1979 paper, stated, “[W]e should not dwell on [when and by whom PSA was identified]. Rather, we should focus on the significance of the finding.”7 I could not agree more. Nonetheless, I’ll set the record straight once again, hopefully putting an end to this ongoing debate.

Different PSAs? The common thread in the letters is that the PSA I discovered in 1970 is not the same as what Dr. Chu purified and characterized 9 years later.

From a re-review of our results with three independent immunologists, it appears that this contention is rooted in biased interpretations of the two principal types of immunologic methods utilized, ie, precipitin and hemagglutinin assays.

Hemagglutinin studies—based on tanned cell hemagglutination and its inhibition—unequivocally demonstrated that PSA is present in human prostate extract, prostatic fluid, and seminal plasma. When viewed in context with precipitin data (gel-diffusion precipitation) for the reaction between antisera to human prostate extract and prostatic fluid, a very strong reaction of identity—designating a commonality of the content of each—was obtained. This showed that PSA was present in human prostate extract and prostatic fluid. In

and editorials, there has been nothing “new” on the scientific front for me to write about.

On the subject of my 1979 communication with Dr. Chu referred to in his letter, other than inviting him to contribute a chapter on enzyme markers for prostate cancer to a book I edited,11 our exchanges were as follows: On March 16, I informed him that I noted his Federation Proceedings abstract of 1979, sent him reprints of our recent studies and suggested, given our mutual interest, that we consider collaborating.

On October 2, I requested from him a reprint of Wang et al (Invest Urol, 17:159, 1979), inquired whether his nonprostatic acid phosphatase was identical to ours, and asked for a sample of his specific antigen and antiserum for comparison. On Oc-

I won’t redress the use of PSA, save to say that I’m glad my 3-decades-long mission against routine screening is beginning to see a flickering light at the end of the tunnel.

—Richard J. Ablin, PhD, DSc (Hon)

concert with subsequent studies by Wang et al,8 it was shown that PSA in seminal plasma originated from prostatic fluid.

In terms of biochemical and biophysical characteristics, I appreciate that Dr. Chu recognizes the limits of these techniques at the time of my team’s discovery. Nonetheless, my colleagues and I have subsequently been able to ascertain that the molecular weight of our PSA was in the range of 28 to 34 kDa (unpublished data). This molecular weight is commensurate with that subsequently established for PSA by Dr. Chu and others.

Other Points of Debate Considering Dr. Chu’s dispute over my discovery, I question the motive and relevance of his statement, “Dr. Ablin has not published a new peer-reviewed paper on PSA since the early 1970s….” To the contrary, I published peer-reviewed manuscripts on PSA in 19979 and 2011.10 Quite frankly, other than commenting on the futility of PSA screening in several commentaries

tober 11, Dr. Chu replied, “We are not prepared yet to distribute our antigen preparation, as the supply is still limited. However, if you have your antigen purified and wish to exchange a small quantity with ours, we shall be pleased to do so.” Certainly, in concert with his just-published paper, this was somewhat of a mixed message.

With regard to Dr. Chu’s statement, “to date, Dr. Ablin has not made his PSA accessible to the scientific community,” I would say this: When I left the University of Buffalo for another position in mid-1970, my research materials (save for very small selected aliquots) remained there. In fact, other than Roswell Park’s furtive request in 1979 (referred to above), I do not recall other requests, which in any event I could not have fulfilled, given my lack of an adequate sample.

Contrary to Dr. Chu’s assertion, my comments referring to his 1977 Federation Proceedings abstract12 were not “criticisms.” They merely stated that the information reported in that abstract was incorrect. Certainly, in

accord with Dr. Chu’s own remarks, “Readers should base their judgment … on science and evidence…,” That is exactly what I did. I believe, from a chronologic perspective, it is ironic that just when Doctor Chu was joining Roswell Park in 1970, I had already discovered PSA.

‘True’ History Reinterpreted As for Dr. Catalona’s “true” history of the discovery of PSA, he has omitted reference to the 2005 AUA presentation by Rao et al,13 wherein the authors state, “It is … misinterpreted in the literature that Wang et al were the first to identify PSA in the human body taking the credit away from Dr. Richard Albin.”

And permit me to further direct attention to the 2007 paper by Kundu et al,14 on which Dr. Catalona was the corresponding author. The opening sentence in the Discussion section read, “Prostate-specific antigen was first identified in prostate tissue in 1970, purified in 1979, identified in serum in 1980,” [at which point the authors cited these three references: Ablin et al: J Reprod Fert 22:573, 1970; Wang et al: Invest Urol 17:159, 1979; and Papsidero et al: Cancer Res 40:2428, 1980].

Circling Back On behalf of my earlier co-workers and the immunologists who kindly re-reviewed our initial studies, I do hope the foregoing account may provide further clarity and some degree of resolution to those who continue to question my discovery of PSA in 1970. Perhaps we all should pause in this continuing debate and remember the words of the late Dr. Murphy: “[W]e should not dwell on [when and by whom PSA was identified]. Rather, we should focus on the significance of the finding,”7 and, if I might add, its appropriate use. n Richard J. Ablin, PhD, DSc (Hon) Department of Pathology University of Arizona College of Medicine The Arizona Cancer Center and BIO5 Institute Tucson, Arizona References 1. Piana R: Rethinking the role of PSA screening in public health. ASCO continued on page 156

The ASCO Post | AUGUST 15, 2013

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Letters to the Editor

Clarity on PSA Story continued from page 155

Post 3(12):1, 10, 18, 2012.

2. Mohler J, Trump D: More thoughts on PSA (letter). ASCO Post 3(14):2, 2012.

3. Ablin RJ: Dr. Ablin’s reply (letter).

ASCO Post 3(14):83, 2012.

4. Chu TM: Origins of PSA testing: The conversation continues (letter).

ASCO Post 3(17):110, 2012.

5. Catalona WJ: The ‘true’ history of the discovery of prostate-specific antigen (letter). ASCO Post 3(18):95, 2012.

6. American Urological Association: Early Detection of Prostate Cancer: AUA Guideline. April 2013. Available at www.auanet.org. Accessed July 16, 2013.

7. Murphy GP: The Pannek/Partin

article reviewed. Re: Prostate-specific antigen: What’s new in 1997. Oncology 11:1279-1280, 1997.

8. Wang MC, Loor RM, Li SL, et al: Physicochemical characterization of prostate antigen purified from human prostate gland and seminal plasma. IRCS Med Sci 11:327-328, 1983.

9. Ablin RJ: A retrospective and prospective overview of prostate-specific an-

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tigen. J Cancer Res Clin Oncol 123:583594, 1997.

10. Haythorn MR, Ablin RJ: Prostate-specific antigen testing across the spectrum of prostate cancer. Biomark Med 5:515-526, 2011.

11. Ablin RJ (ed): Prostatic Cancer, p 321. New York, Marcel Dekker, 1981.

12. Wang MC, Valenzuela LA, Murphy GP, et al: Tissue specific and tumor specific antigens in human prostate.

Fed Proc 36:1254, 1977.

13. Rao AR, Sharma M, Shergill I, et al: History of the discovery of prostate specific antigen: Unravelling the controversy. American Urological Association Annual Meeting. Abstract 892.

Presented May 21-26 2005.

14. Kundu SD, Roehl KA, Yu X, et al: Prostate specific antigen density correlates with features of prostate cancer aggressiveness. J Urol 177:505-509, 2007.

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Letters to the Editor Hematology

Déjà Vu Redux: Lessons from the SWOG-8516 Study in Aggressive Lymphomas

J

oseph M. Connors, MD, authored a commentary in the June 25 issue of The ASCO Post inspired by a recent New England Journal of Medicine publication on dose-adjusted EPOCH-R chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) for primary mediastinal B-cell lymphoma. He summarized his reaction to the study as “It’s déjà vu all over again,” in reference to the pivotal Southwest Oncology Group (SWOG)-8516 trial, which compared CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) to the third-generation regimens—and which celebrated its 20-year anniversary on the publication date of the doseadjusted EPOCH-R study.1

Cautionary Tale For 20 years, SWOG-8516 has been heralded as the cautionary tale against clinically implementing results of phase II clinical trials in newly diagnosed diffuse large B-cell lymphoma.

Dr. Connors reminds us that “In the 1980s, several groups … reported remarkably better outcomes for patients with diffuse large cell lymphoma when they were treated with ProMACE-CytaBOM (cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and prednisone), m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), or MACOP-B (methotrexate, doxorubicin, cyclohosphamide, vincristine, prednisone, and bleomycin” compared to CHOP. He goes on to note that history (by way of SWOG-8516) proved them all wrong. This tale of misguided hope has been a battle cry by some against clinically embracing phase II results, while others have promoted inadequately tested ideas from arms of phase III trials, such as R-CHOP-14 in untreated diffuse large B-cell lymphoma.2 As in all matters, and especially in science, the devil is in the details. So let’s take a look at the landscape of the SWOG-8516 randomized study. The era was hampered by two significant issues: (1) the absence of a validated prognostic score to compare patients across trials, and (2) a crude understanding of histopathology as manifested by the Working Formulation.3

Both of these issues played roles in the perceived improvement in third-generation treatments during the 1980s.

Nuanced Picture A critical look paints a nuanced picture for the superiority of thirdgeneration regimens at the time. In 1984, Armitage et al published a study of CHOP in diffuse histiocytic lymphoma—for our younger colleagues, diffuse histiocytic lymphoma is the historical term for diffuse large B-cell lymphoma—that showed an (estimated) freedom from progression of 41.5% at approximately 3 years, setting a benchmark for CHOP.4 In 1991, Longo et al published an

randomized study, reported in 1993, where the treatment failure rates were 41% (CHOP), 46% (ProMACE-CytaBOM), 46% (m-BACOD), and 41% (MACOP-B) at 3 years.1

Historical Ironies What lessons should we take from SWOG-8516? Certainly not that all phase II trials are suspect. Indeed, the SWOG multicenter trials recapitulated the phase III results. While the singleinstitution trials suffered from patient selection bias, which appears to mostly account for the favorable results, this pitfall has been largely overcome by the International Prognostic Index (IPI). Perhaps the most important lesson is that the re-

When dealing with potentially curative diseases, the stakes are high. Thus, it is important to carefully weigh the risks and benefits of phase II results and give patients the benefit of the doubt when survival may be improved.

—Wyndham H. Wilson, MD, PhD

important randomized study of ProMACE-MOPP (prednisone, methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine) vs ProMACE-CytaBOM that showed an (estimated) freedom from progression of 63% at 5-years for ProMACE-CytaBOM.5 Like the other single-institution studies of mBACOD and MACOP-B, this result suggested a major advance in the cure of diffuse large B-cell lymphoma, or a “home run,” as Dr. Connors felt at the time.

What appears to have been forgotten is that SWOG performed a series of phase II trials of ProMACE-CytaBOM (SWOG-8503), m-BACOD (SWOG-8410) and MACOP-B (SWOG-8508) as a prelude to the SWOG-8516 randomized study and reported 3-year failure-free survivals of approximately 37%, 35%, and 42%, respectively—all no different from CHOP!6-8 Thus, it came as little surprise that all of these regimens performed similarly in the SWOG

sults of the SWOG multicenter phase II trials should have been heeded.

Dr. Connors wisely quotes George Santayana: “Those who cannot remember the past are condemned to repeat it.” When we began the development of EPOCH in 1989, we endeavored to remember history. We performed multiple studies of doseadjusted EPOCH with and without rituximab and showed consistently better results compared to multiple studies of CHOP with and without rituximab when analyzed by IPI risk groups and histology.9-12 These studies eventually led to two multicenter phase II studies of doseadjusted EPOCH-R performed by the Cancer and Leukemia Group B (CALGB) and AIDS Malignancies Consortium (AMC) cooperative groups that validated our results.13,14 Dose-adjusted EPOCH-R for primary mediastinal B-cell lymphoma followed a similar development path, with the patients having comparable prognostic characteristics to the patients in the studies of R-CHOP (which include radiation) for

the same disease, and confirmation in an independent validation cohort.

It is also important to consider the role of tumor biology in the conduct of clinical trials for diffuse large B-cell lymphoma. Unfortunately, most trials remain agnostic to the molecular subtypes of diffuse large B-cell lymphoma (germinal center B-cell, activated Bcell, and primary mediastinal B-cell), which are as different from one another as they are from Hodgkin and Burkitt lymphomas.15,16 The irony of this should not be lost on primary mediastinal B-cell lymphoma aficionados, who know that regimens like MACOP-B plus radiation may be a better platform than CHOP plus radiation.17 To add further irony, R-CHOP (with or without radiation) has never been prospectively studied in primary mediastinal B-cell lymphoma and yet is considered by many to be the de facto standard.

Clinical Implementation How should we clinically implement promising results of phase II trials in oncology? The Food and Drug Administration weighs the issue of risk-benefit for accelerated drug approval, which is typically based on single-arm phase II trials. The burden of proof is based on regulatory language that a drug is “reasonably likely to provide clinical benefit” and has a favorable risk profile.

When dealing with potentially curative diseases, the stakes are high. Thus, it is important to carefully weigh the risks and benefits of phase II results and give patients the benefit of the doubt when survival may be improved. n —Wyndham H. Wilson, MD, PhD Deputy Chief Lymphoid Malignancy Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda, Maryland References 1. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993.

2. Pfreundschuh M, Schubert J, Ziepert M, et al: Six versus eight cycles of bicontinued on page 158

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Letters to the Editor

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

occurs at a higher incidence in Avastin‑treated patients compared to controls.

The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Aggressive Lymphomas continued from page 157

weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: A randomised controlled trial (RICOVER-60). Lancet Oncol 9:105-116, 2008.

3. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage.

The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 49:21122135, 1982.

4. Armitage JO, Fyfe MA, Lewis J: Long-term remission durability and functional status of patients treated for diffuse histiocytic lymphoma with the CHOP regimen. J Clin Oncol 2:898-902, 1984.

5. Longo DL, DeVita VT Jr, Duffey PL, et al: Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: Results of a prospective randomized trial. J Clin Oncol 9:25-38, 1991.

6. Miller TP, Dahlberg S, Weick JK, et al: Unfavorable histologies of nonHodgkin’s lymphoma treated with ProMACE-CytaBOM: A groupwide Southwest Oncology Group study. J Clin Oncol 8:1951-1958, 1990.

7. Dana BW, Dahlberg S, Miller TP, et al: m-BACOD treatment for intermediateand high-grade malignant lymphomas: A Southwest Oncology Group phase II trial.

J Clin Oncol 8:1155-1162, 1990.

8. Weick JK, Dahlberg S, Fisher RI, et al: Combination chemotherapy of intermediate-grade and high-grade nonHodgkin’s lymphoma with MACOP-B: A Southwest Oncology Group study. J Clin Oncol 9:748-753, 1991.

9. Wilson WH, Grossbard ML, Pittaluga S, et al: Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: A pharmacodynamic approach with

high efficacy. Blood 99:2685-2693, 2002.

10. Wilson WH, Dunleavy K, Pittaluga S, et al: Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol 26:2717-2724, 2008.

11. Little RF, Pittaluga S, Grant N, et al: Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: Impact of antiretroviral therapy suspension and tumor biology. Blood 101:4653-4659, 2003.

12. Dunleavy K, Little RF, Pittaluga S, et al: The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCHRR) in HIV-associated diffuse large B-cell lymphoma. Blood 115:3017-3024, 2010.

13. Wilson WH, Jung SH, Porcu P, et al: A Cancer and Leukemia Group B multicenter study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica 97:758-765, 2012.

14. Sparano JA, Lee JY, Kaplan LD, et al: Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 115:3008-3016, 2010.

15. Alizadeh AA, Eisen MB, Davis RE, et al: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503-511, 2000.

16. 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 198:851-862, 2003.

17. Zinzani PL, Martelli M, Bertini M, et al: Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis. Haematologica 87:1258-1264, 2002.

The ASCO Post

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Write to The ASCO Post at editor@ASCOPost.com Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. 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 at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) 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. [See Clinical Studies (14.2).]

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) 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.

1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

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. [See Clinical Studies (14.4).]

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. 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. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of 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 data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC)

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs.

19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone.

The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%).

Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

5%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs.

5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs.

1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 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. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone 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%).

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade 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 on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

a

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. 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.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility.

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

03/13 AVA0000765905 Initial U.S. Approval: February 2004 Code Revision Date: March 2013 Avastin® is a registered trademark of Genentech, Inc. © 2013 Genentech, Inc.

S:12.5"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8.

The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8).

[See Warnings and Precautions (5.8).]

Arm 2 IFL+ + Avastin (n = 392) 87%

T:13" S:12.5"

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%).

Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

a

Arm 1 IFL+ + Placebo (n = 396) 74%

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

Indications

Most common adverse events

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

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 Avastintreated 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

©2013 Genentech USA, Inc.

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AVA0001847501

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(07/13)

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 — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

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 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 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.

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