TAP Vol 6 Issue 6

Breast Cancer Genomics

3, 4

| Smoking Cessation

14, 21, 82

| Metastatic Colorectal Cancer

VOLUME 6, ISSUE 6

78, 79, 103

APRIL 10, 2015

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

Genitourinary Cancers Symposium

Clinical Trial Participation: ‘Is It All Worth It?’

No Survival Benefit From Adjuvant Sorafenib or Sunitinib in Kidney Cancer

By Alice Goodman

A

djuvant therapy with sorafenib (Nexavar) or sunitinib (Sutent) failed to make any inroads in improving disease-free survival in patients with locally advanced kidney cancer in the randomized, placebo-controlled, multicenter, phase III Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma (ASSURE) trial. At a planned interim analysis, median disease-free survival data were comparable for sorafenib, sunitinib, and placebo. The median 5-year overall survival has not been reached for the majority of patients on the trial but as of yet shows no difference. Results were presented at the 2015 Genitourinary Cancers Symposium.1 Both sorafenib and sunitinib are vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors. These drugs are considered major advances in treating metastatic kidney cancer and are widely used today in that setting. However, they did not live up to their promise in the adjuvant setting, where it was thought that mov-

ing the administration of effective drugs to earlier in the course of the disease would improve outcomes.

The results of this trial should lay to rest the practice of using either sorafenib or sunitinib in the adjuvant setting, experts agreed.

Naomi B. Haas, MD Nonetheless, it is possible that another well-designed study with different drugs of this type might show a benefit, some noted.

In response to a question at a premeeting press briefing, presenting author Naomi B. Haas, MD, said, “No one is more disappointed [in these results] than I am, except possibly the patients with kidney cancer enrolled in the trial. You do see some benefit while patients are on these drugs, but there is no ulcontinued on page 9

Journal Spotlight

Immune Gene Profile Strongly Associated With Benefit of Adjuvant Trastuzumab in HER2-Positive Breast Cancer

I

©ASCO/Todd Buchanan

C

linical trials have become increasingly complex over the past several years, and unfortunately, this has resulted in the typical scenario described below. We are fortunate that there are so many promising agents available for patients, and we want to encourage their participation in clinical trials, which will advance the field and provide exciting new therapeutic options. However, as physicians, we need to be cognizant of the tremendous impact that participation in a clinical trial has on the quality of life of our patients.

Consider the following scenario: MD: Hello, Ms. Smith. Thanks for coming in today. As we discussed at our last visit, the comcontinued on page 112

Dr. Krug is Associate Attending Physician and Deputy Chief of the Thoracic Oncology Service at M ­ emorial Sloan Kettering Cancer Center, New York.

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

MORE IN THIS ISSUE

By Matthew Stenger n a study reported in the Journal of Clinical Oncology, Edith A. Perez, MD, of the Mayo Clinic, Jacksonville, and colleagues found that an immune function gene profile was associated with significantly improved relapsefree survival among patients with early-stage HER2positive breast cancer who had trastuzumab (Herceptin) added to adjuvant chemotherapy in the North Central Cancer Treatment Group (NCCTG) N9831 trial.1

©ASCO/Todd Buchanan

By Lee M. Krug, MD

Study Details

Whole transcriptome analysis using cDNAmediated annealing, selection, extension, and ligation (DASL) technology was performed on 1,282 samples from NCCTG N9831. Cox proportional hazard ratios (HRs) adjusted for significant clinicopathologic risk factors were used to determine the association of each gene with relapse-free survival in 433 patients who received chemotherapy (paclitaxIncreased expression of a subset of el) alone and 849 patients in two study groups who immune function genes may provide also received trastuzumab a means of predicting benefit from (concurrent with or after paclitaxel). Network adjuvant trastuzumab. and pathway analyses —Edith A. Perez, MD, and colleagues were used to identify key biologic processes linked

Oncology Meetings Coverage Miami Breast Cancer Conference ��������� 3, 4 Genitourinary Cancers Symposium ����������������������������������� 9–12, 16 NCCN 20th Annual Conference ���������������������������������������� 14, 39 In the Clinic �������������������������������18, 32, 68 Jame Abraham, MD, on Breast Cancer Genetics and Adjuvant Therapy �����������������29 Maha Hussain, MD, on Bladder Cancer ��� 41 Direct From ASCO �������������������������� 54–57 State of the Art in GI Cancers ������������������62 Letters to the Editor ��������������������������������111 In Memoriam: Paul Kalanithi, MD ������� 114

continued on page 33

ASCO Annual Meeting, May 29 – June 2, 2015, Chicago

A Harborside Press® Publication

The ASCO Post | APRIL 10, 2015

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

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Louis B. Harrison, MD Moffitt Cancer Center

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Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

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Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

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The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices.

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ASCOPost.com | APRIL 10, 2015

PAGE 3

Miami Breast Cancer Conference Breast Cancer

Should Oncologists Be Ordering Breast Cancer Gene Panels?

By Caroline Helwick

T

wo oncologic surgeons squared off at the 32nd Miami Breast Cancer Conference to debate whether breast cancer genetic susceptibility panel testing is ready for routine use in the clinic. J. Michael Dixon, MD, Professor of Surgery and Consultant Surgeon at the Edinburgh Breast Unit in the United Kingdom, argued against testing, and Pat Whitworth, MD, Director of the Nashville Breast Center in Tennessee, countered.

Panels Don’t Meet WHO Standard There are now 14 next-generation sequencing tests that include BRCA1 and BRCA2, but according to Dr. Dixon, “Just because you can test for susceptibility using these panels doesn’t mean you should…. Gene panels cannot be recommended at present in an evidence-driven health-care system.”

The World Health Organization (WHO) has published criteria to be met for any genetic test to be considered valuable: the disease is an important health problem, the risk in mutation carriers is high in the general population (not just in a high-risk group), mutations for the disease can be accurately identified, and effective interventions exist.

Among the breast cancer susceptibility genes, only BRCA1/2 meets these criteria, although many other genes are included in gene panels—and they are generally not common in breast cancer patients, Dr. Dixon indicated. CHEK2, ATM, BRIP1, PALB2, and RAD51 (among others) demonstrate low penetrance, unclear clinical applicability, and/ or weak associations with cancer risk.

“For most genes in the panel, we have limited data on cancer risk and penetrance and no consensus on the management if mutations are found,” he said.

Variants of Unknown Significance Variants of unknown significance constitute another problem. In a recent study, investigators sequenced 22 cancer susceptibility genes in 278 BRCA1/2-negative women; they found that 31 (11%) had at least one deleterious or likely deleterious variant (guidelines were available for only 2.5%), and 19% of all patients had at least one variant of unknown significance.1 Another 2014 study identified an average of 2.1 variants of unknown significance per breast cancer patient tested.2 Dr. Dixon pointed out that women

often undergo risk-reducing surgical procedures on the basis of findings of variants of unknown significance, although about half of these findings are eventually reclassified, often as benign.

“This information usually arrives too late to inform these decisions,” he said.

Kurian et al documented 16 pathogenic variants in a variety of genes other than BRCA1/2—aberrations for which management guidelines are lacking,2 he added. “We need much more information about which mutations are deleterious, what their associated risks are, and how we should manage these women,” he commented.

He noted that the National Comprehensive Cancer Network (NCCN) recently stated that testing must be focused on identifying a mutation known to be clinically actionable,3 a requirement that is not met by most genes in the panel, he said.

This leaves physicians at a loss as to how to counsel patients, given the uncertain value of these findings. They are not aided by the current clinical and counseling framework, which was developed to support single-gene testing and is not ad-

system is inadequate,” he maintained.

An estimated 220,000 American women are BRCA carriers, yet most carriers have not been identified and informed prior to a breast cancer diagnosis, he said, meaning that most carriers will only be identified after developing cancer.4 He believes the challenge of inade-

Physicians need to be educated and ready…. We’ve come too far, the tests are available, and we need to use them properly on behalf of our patients.

—Pat Whitworth, MD

quate delivery of care where it is needed, and the expansion of testing for other breast cancer susceptibility genes, can best be met through physician education.

Although genetic counselors are important, they are not a substitute, he said.

“Referring our patients to genetic counselors is not solving the problem.

Just because you can test for susceptibility using these large gene panels doesn’t mean you should….

Gene panels cannot be recommended at present in an evidence-driven health-care system.

—J. Michael Dixon, MD

equate for dealing with next-generation sequencing and panel testing.

“Gene panels are like a black hole,” Dr. Dixon concluded. “The problems are deep, and there is no clear light as to how to interpret many of the results.

Undoubtedly, gene testing should be performed—but panels with limited genes are the best bet just now.”

Too Late to Turn Back Dr. Whitworth took the opposite point of view, arguing, “Physicians need to be educated and ready…. We’ve come too far, the tests are available, and we need to use them properly on behalf of our patients.”

“Right now, we are doing a terrible job with BRCA testing. We are not testing those who need it, we are not delivering care where it is needed, and our

lacking, “therefore, experts urge caution outside of clinical trials”; that screening will increase patients’ distress and lead to more unnecessary mastectomies; and that mistakes will ensue because recommendations are based on limited information.

Dr. Whitworth responded, “Yes, we are working with incomplete knowl-

Counselors cannot possibly handle what’s coming. There are approximately 3,000 genetics counselors nationwide, and just less than one-third are focused on cancer, according to the National Society of Genetics Counselors,” he suggested.

Countering the Objections An asymptomatic person worried about an inherited cancer risk could undergo sequencing for cancer-related genes or could have whole-genome sequencing, which may reveal other preventable or treatable conditions. These screening approaches have raised some objections, he acknowledged.

Some of these objections are that the current state of knowledge is incomplete “therefore, we don’t know what to do with the results”; that guidelines are

edge, but we do know what to do with the results. Yes, we lack guidelines, but although guidelines are helpful, they are for followers, not leaders. Distress will not increase; in fact, distress and mastectomies will decrease if we do a good job educating doctors. As for making recommendations based on limited information, we do this every day. We just must proceed with caution.”

According to Dr. Whitworth, panel testing is “logical,” as there are many known pathogenic mutations beyond BRCA. Early studies using a 25-gene panel have indicated that 50% more pathogenic mutations are identified in patients, compared with single-gene testing. Testing for them gives relevant information while avoiding the additional expense and distress of the “diagnostic odyssey” that prevails when BRCA1/2 results are negative.

“Patients know there are other mutations beyond BRCA, and they want this information,” he said. Ultimately, he maintained, testing for known familial mutations will result in more appropriate use of resources (screening, surveillance, intervention) and a reduction in fear, distress, and unnecessary surgeries.

He added that management can be guided by family history, which is a key modifier of risk in the case of moderate penetrance mutations. For example, PALB2 carries a 33% breast cancer risk in the absence of a family history and a 58% breast cancer risk when a family history is present. The risks associated with CHEK2 are 20% and 45%, respeccontinued on page 4

The ASCO Post | APRIL 10, 2015

PAGE 4

Miami Breast Cancer Conference Breast Cancer

Too Early to Use Genome Sequencing for Breast Cancers in the Clinic

By Caroline Helwick

T

he role of next-generation sequencing (high-throughput technologies that allow DNA and RNA to be analyzed more quickly and inexpensively than earlier techniques) in breast cancer remains unclear and at present is primarily a research tool. Therefore, clinicians should be cautious in using genetic profiling to guide treatment, according to Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center, San Francisco.

For the majority of patients, she emphasized, targeting specific markers is of uncertain clinical value. “Individual case studies are encouraging, but they are few and far between,” she noted.

“What we are asking from tumor genome profiling is whether we can look at specific genomic aberrations and find a treatment that is more likely to benefit the patient vs something else. Someday, we may find that we can design treatments based on sequencing, but we are not there yet. I don’t believe tumor genome sequencing is ready for prime time,” Dr. Rugo told attendees at the 32nd Annual Miami Breast Cancer Conference.

Growth of Next-Generation Sequencing The most common approaches to genomic profiling today are whole-genome sequencing, which determines the complete DNA sequence of an organism’s genome at a single time, and whole-exome sequencing, which selectively sequences only the coding areas of the genome.

Falling prices are fueling the growth of sequencing services. Revenue from

Breast Cancer Gene Panels continued from page 3

tively.5-7 None of these findings justifies mastectomy, but special surveillance (ie, with MRI) is warranted.

Revisiting Variants of Unknown Significance Acknowledging that variants of unknown significance are problematic, Dr. Whitworth believes that these issues will be sorted out once broader testing is achieved and with the aid of “well-designed research” and education of physicians. Meanwhile, he suggested “keeping a clinical point of view” in managing variants of unknown significance and not falling prey to one’s own scientific curiosity.

these services (for all health care, not just cancer) totaled $160 million in 2010 and should increase to $550 million by 2016.

“It’s now cheaper to do it, it can be done quickly, and it can be done in many locations,” Dr. Rugo said. “As technology improves, it’s becoming more available and therefore more of an issue for clinicians.”

Limited Candidate Alterations The list of candidate “actionable” genomic alterations in breast cancer numbers nearly 20. These aberrations are theoretically targetable by specific agents

Prognostic Power but Not Predictive Ability Although theoretically attractive, using mutations to guide treatment selection has not been successful in the clinical trial setting. A prime example comes from the BOLERO-2 trial, which evaluated the mTOR inhibitor everolimus (Afinitor) given with exemestane in patients refractory to endocrine treatment.

The combination yielded a progression-free survival benefit, but no correlation was found between the presence of activating mutations (PIK3CA/ PTEN/CCND1 or FGR1/2) and re-

Someday, we may find that we can design treatments based on sequencing, but we are not there yet. I don’t believe tumor genome sequencing is ready for prime time.

—Hope S. Rugo, MD

or those in development, but the reality is that most occur in fewer than 10% of patients—and most affect even less.

Additionally, even with more common mutations, a direct link between mutant status and response to a targeted agent “remains to be seen” for most socalled actionable mutations, she added.

The rare frequency of these mutations makes for huge challenges in accrual to clinical trials in metastatic breast cancer, she pointed out, and this begs the question, Why do screening? “It is unclear whether this will be a rational approach in the future,” she noted.

sponse to treatment. Patients with multiple different mutations had somewhat better outcomes than those without mutations (hazard ratio = 0.78), but the numbers in these subsets were small.1 “We know if your cancer is very disordered, it’s bad-acting, so this was not surprising,” she commented.

Similarly, in the CLEOPATRA study, which evaluated the addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) in HER2-positive disease, biomarker analysis revealed no relative benefit according to PI3KCA mutational status.2 These trials only confirm

The patient should understand that variants of unknown significance do not explain one’s family history and mean nothing with regard to patient care; that the vast majority of variants of unknown significance are benign and only occasionally reclassified as pathogenic; that action based on finding a variant of unknown significance is not appropriate; and that care will be designed according to standard family history and risk.

He indicated that panel testing has become a standard of care at leading institutions; predicted population-based testing is coming soon; and projected that in 10 to 20 years, whole-genome or whole-exome sequencing will guide management. “We will need to navigate there safely, wisely,

and economically,” he added. n Disclosure: Drs. Dixon and Whitworth reported no potential conflicts of interest.

References 1. Maxwell KN, Wubbenhorst B, D’Andrea K, et al: Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. December 11, 2014 (early release online).

2. Kurian AW, Hare EE, Mills MA, et al: Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 32:2001-2009, 2014.

3. Domchek SM: Evolution of genetic testing for inherited susceptibility to breast cancer. J Clin Oncol 33:295-296, 2015.

“what we have known from many studies,” which is that mutations have prognostic power but not predictive ability. The addition of a novel treatment improves outcomes, but patients with a genotypically poor prognosis do not benefit more than other patients.

Numerous clinical trials are now screening for mutations to select patients for experimental drugs, but, for the individual oncologist or patient, this is not yielding abundant fruit, she indicated.

“For instance, in studies of the fibroblast growth factor receptor (FGFR) and the vascular endothelial growth factor inhibitor lucitanib, our center has screened a number of patients and has found only one with the FGFR mutation,” she reported. Furthermore, responses observed in patients with mutations actually do not prove selective efficacy of a drug.

“You don’t know how patients without the mutation would do,” she noted. “In ­BOLERO-2, they did as well.”

An examination of genomic alterations in 1,445 invasive breast cancers by Foundation One paints a clear picture of the challenge. It showed TP53 to be the most common mutation, occurring in 60% of samples, followed by PIK3CA mutations in 30%.

“The problem is that we don’t have targeted agents for these mutations,” she pointed out. “This finding may spur further research, but it doesn’t help us manage our patients today.”

‘N of 1’ Driving Personalized Therapy Most of the data guiding personalized therapy come from “N of 1 case reports,” such as that of the 53-year-old patient 4. Drohan B, Roche CA, Cusack JC Jr, et al: Hereditary breast and ovarian cancer and other hereditary syndromes: Using technology to identify carriers. Ann Surg Oncol 19:1732-1737, 2012.

5. Antoniou AC, Casadei S, Heikkinen T, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497506, 2014.

6. Goldgar DE, Healey S, Dowty JG, et al: Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res 13(4):R73, 2011.

7. Cybulski C, Wokołorczyk Dd, Jakubowska A, et al: Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol 29:3747-3752, 2011.

ASCOPost.com | APRIL 10, 2015

PAGE 5

Miami Breast Cancer Conference with progressive HER2-positive breast cancer, found on genomic profiling to have activating ERBB2 and epidermal growth factor receptor (EGFR) mutations. She was treated with trastuzumab and metronomic chemotherapy, then erlotinib (stopping lapatinib [Tykerb]).

She was still responding at 4 months.

Dr. Rugo also described a patient with triple-negative disease who entered a trial of erlotinib plus bevacizumab (Avastin) 12 years ago. Hers was the only response among 42 patients, and it continued for 11 years, until she stopped treatment for reasons other than disease progression. Interestingly,

no EGFR mutation was identified in the patient’s tumor.

Although “encouraging,” cases such as this, she said, “do not tell us what to do with the patient sitting across the table from us with triple-negative breast cancer.”

Unfortunately, for most patients whose tumors are sequenced, she added, a number of genomic alterations may be identified, but none is actionable.

‘An Ethical Dilemma’ At this point, Dr. Rugo concluded, the use of next-generation sequencing creates “an ethical dilemma” by adding

toxicity and cost without a clear, predictable benefit from the chosen treatment. “To get somewhere, we will need the ability to look at panels of genes correlated to clinical phenotypes and outcomes,” she suggested.

Completed studies and ongoing or planned trials are providing information, but in the meantime, she said, “Treatment with unapproved drugs should be considered only in the setting of clinical trials, and screening should only be used to determine eligibility for marker-driven studies.” n Disclosure: Dr. Rugo reported no potential conflicts of interest.

References 1. Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al: Correlation of molecular alterations with efficacy of everolimus in hormone receptor-positive, HER2-negative advanced breast cancer: Results from BOLERO-2.

2013 ASCO Annual Meeting. Abstract LBA509.

2. Baselga J, Cortés J, Im S-A, et al: Biomarker analyses in CLEOPATRA: A phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S5-1. Presented December 7, 2012.

ASCO Commends U.S. House of Representatives for Voting to Repeal the SGR, Urges Senate to Pass Legislation

Statement From Allen S. Lichter, MD, FASCO, ASCO Chief Executive Officer

W

e applaud the House of Representatives for passing legislation that eliminates the Sustainable Growth Rate [SGR] formula and takes a giant leap toward meaningful and urgently needed Medicare physician payment reform. Cancer incidence among Medicare beneficiaries is expected to increase by 67% by 2030, and maintaining a fundamentally flawed payment system could compromise health-care access for this growing patient population. The bill passed [on March 25, 2015] goes

Allen S. Lichter, MD, FASCO

a long way to restoring stability in one of cancer care’s most vital programs.

The American Society of Clinical Oncology (ASCO) now urges the U.S.

Senate to follow the House’s lead and pass the Medicare Access and CHIP Reauthorization Act of 2015 (H.R. 2).

This bill would finally eliminate the perennial threat and uncertainty that the SGR has created for oncology practices across the country. It would also put in place important incentives to encourage the delivery of highquality care and provide resources to enable practices to move toward alternative payment models.

Without such action by the Senate, physicians and Medicare benefi-

ciaries will be back on a 13-year roller coaster, which has included 17 shortterm patches that have cost nearly $170 billion and caused tremendous uncertainty in oncology practices.

ASCO urges the Senate to act on this unprecedented momentum to replace a dangerously inadequate Medicare reimbursement system with a more rational and reliable one.

To learn more about ASCO’s efforts in Medicare physician payment reform, please visit www.asco.org/ paymentreform. n

Don’t Miss These Important Reports in This Issue of The ASCO Post Theodore S. Hong, MD, on Radiation Therapy in Gastrointestinal Cancer see page 62

Sagar Lonial, MD, on the ASPIRE Trial of Carfilzomib in Relapsed Myeloma see page 65

Anthony L. Back, MD, on Communication With Seriously Ill Patients see page 73

Eric Van Cutsem, MD, PhD, on Cetuximab and Metastatic Colorectal Cancer see page 78

John Seffrin, PhD, on The Fight Against Tobacco see page 82

Jason A. Zell, DO, MPH, on Young Adults and Colorectal Cancer see page 103

Visit The ASCO Post online at ASCOPost.com

APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown.

Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” mCRC = metastatic colorectal cancer; OS = overall survival.

WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information • In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).

Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory.

• Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving

FOLFOX alone (HR = 1.16, 95% CI: 0.94–1.41). Perform the assessment for KRAS mutational 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 treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment.

Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®.

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy.

Discontinue Vectibix® therapy if ILD is confirmed.

• In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS/RAS mCRC • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/ acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

• NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal

harm when administered to pregnant women.

• Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, 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, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program.

Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aflibercept) prescribing information, sanofi-aventis.

Avastin® is a registered trademark of Genentech, Inc. Erbitux® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

Zaltrap® is a registered trademark of Regeneron Pharmaceuticals, Inc. Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 10/14 61007-R7-V1

Visit www.vectibix.com

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Vectibix (panitumumab) ®

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Growth of eyelashes GASTROINTESTINAL DISORDERS Nausea Diarrhea Vomiting Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Mucosal inflammation INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea Cough SKIN AND SUBCUTANEOUS TISSUE DISORDERS Erythema Pruritus Acneiform dermatitis Rash Skin fissures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Study 1 Vectibix® Plus Best Supportive Care Best Supportive Care (N = 234) (N = 229) Any Grade Grade 3-4 Any Grade Grade 3-4 n (%) n (%) n (%) n (%) 13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 1) 4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

2 (< 1) 1 (< 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).

In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix ®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].

In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix ®-treated patients [see Dosage and Administration (2.3)].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.

Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®.

Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3)

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS Diarrhea Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation Asthenia INFECTIONS AND INFESTATIONS Paronychia INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Anorexia Hypomagnesemia Hypokalemia Dehydration RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

116 (36) 96 (30) 68 (21) 26 (8)

14 (4) 21 (7) 32 (10) 8 (2)

85 (26) 26 (8) 42 (13) 10 (3)

46 (14)

30 (9)

6 (2) 1 (< 1) 15 (5) 5 (2)

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

FOLFOX Alone (n = 327) SYSTEM ORGAN CLASS Any Grade Grade 3-4 Preferred Term n (%) n (%) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash 179 (56) 55 (17) 24 (7) 1 (< 1) Acneiform dermatitis 104 (32) 33 (10) Pruritus 75 (23) 3 (< 1) 14 (4) Dry skin 68 (21) 5 (2) 13 (4) Erythema 50 (16) 7 (2) 14 (4) Skin fissures 50 (16) 1 (< 1) 1 (< 1) Alopecia 47 (15) 30 (9) Acne 44 (14) 10 (3) 1 (< 1) Nail disorder 32 (10) 4 (1) 4 (1) Palmar-plantar erythrodysesthesia 30 (9) 4 (1) 9 (3) 2 (< 1) syndrome Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).

Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)].

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.

Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.

In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix ®.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab 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 Vectibix®.

Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in 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, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix® treatment 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.

Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, 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 panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)].

Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-7726436) to enroll.

Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.

Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix ® monotherapy.

Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix ® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

This brief summary is based on the Vectibix® Prescribing Information v22, 10/14.

Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved.

80748-R2-V1 – v22 10/14

S:13”

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)].

• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)].

Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)].

RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes.

Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].

Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.

Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix ®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose.

• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose.

• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.

• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix ®.

Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.

Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®.

Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)].

Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS- and KRAS-Mutant mCRC A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory [see Indications and Usage (1.2)].

Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41).

Perform the assessment for KRAS mutational 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 Vectibix®.

Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).

Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)].

Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix ® versus the risk of pulmonary complications must be carefully considered.

Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix ®.

Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis.

Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).

For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks).

Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

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Genitourinary Cancers Symposium Genitourinary Oncology

Kidney Cancer continued from page 1

timate benefit in the adjuvant setting.”

Dr. Haas is Associate Professor of Medicine with the Abramson Cancer Center at the University of Pennsylvania, Philadelphia.

“Patients in all three arms of the trial did better than expected compared with [how patients fared based on] the knowledge we had when the study was designed,” she added.

Study Details ASSURE enrolled 1,943 patients with resected, intermediate- or highrisk kidney cancer (both clear cell and non–clear cell) and randomly assigned them to 1 year of treatment with sorafenib, sunitinib, or placebo.

Median disease-free survival was 5.8 years in both the sorafenib and sunitinib arms and 6 years in the placebo arm. Five-year disease-free survival rates were 52.8%, 53.8%, and 55.8%, respectively. Five-year overall survival rates were 80.7%, 76.9%, and 78.7%, respectively.

Although neither drug improved outcomes compared with placebo, both agents had significant toxicity. Hypertension, a class effect of VEGF inhibitors, occurred in 16% of the sorafenib arm, 16% of the sunitinib arm, and 4% of the placebo arm. Sorafenib was associated with an increased incidence of hand-foot syndrome (15% vs < 1% for placebo), rash (15% vs < 1% for placebo), and diarrhea (9% vs 0% for placebo). Sunitinib was associated with an increased incidence of fatigue (18% vs 3% for placebo), hand-foot syndrome (33% vs 1% for placebo), and diarrhea (10% vs 0% for placebo).

Grade 3 adverse events necessitating intervention occurred in 67% of those receiving sorafenib, 57% of the sunitinib arm, and 10% of the placebo

arm. In fact, the investigators reduced the initial dose of sorafenib from 400 mg twice daily to 400 mg once daily and the initial dose of sunitinib from 50 mg to 37.5 mg once daily due to side effects and intolerance. After dose reductions were instituted, the dropout rate was reduced from 26% at fulldose treatment to 14%. Dr. Haas said that these findings should be considered when the drugs are used in other ­settings.

Ongoing analysis of ASSURE patients’ tissue samples is being performed to determine if there are any molecular or genomic characteristics

Charles Ryan, MD

Charles Ryan, MD, ASCO Expert and Genitourinary Cancers Symposium Planning member, said that he has not used either of these drugs in the adjuvant setting for kidney cancer. “I was waiting for results of this trial to decide

Patients in all three arms of the trial did better than expected compared with [how patients fared based on] the knowledge we had when the study was designed.

—Naomi B. Haas, MD

that can identify subsets of intermediate- or high-risk patients who might benefit from either drug.

Two studies are currently evaluating the duration of VEGF tyrosine kinase inhibitor therapy in the adjuvant setting. The SORCE trial is comparing 1 vs 3 years of sorafenib vs placebo in resected clear cell and non–clear renal cell cancer. The ATLAS study is exploring prolonged adjuvant therapy with axitinib (Inlyta) for 3 years in very highrisk renal cell carcinoma.

whether I would use either drug,” he noted.

“Anecdotally, I have seen physicians using these drugs as adjuvant therapy, but without any data to support this.

This study provides convincing evi-

dence that this should no longer be the practice,” he stated. Dr. Ryan is Professor of Clinical Medicine and Urology in the Department of Medicine at the University of California, San Francisco.

Dr. Ryan noted that chemotherapy in the adjuvant setting would exert cytotoxic effects, while drugs like VEGF tyrosine kinase inhibitors have different mechanisms of action and exert cytostatic effects. “It is not intuitive that VEGF [tyrosine kinase inhibitors] would eradicate residual cancer cells,” he noted. n Disclosure: Drs. Haas and Ryan reported no potential conflicts of interest.

References 1. Haas N, Manola J, Uzzo RG, et al: Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. 2015 Genitourinary Cancers Symposium. Abstract 403. Presented February 28, 2015.

2. Kantar Health: CancerMPact® Treatment Architecture fact sheet. Available at www.kantarhealth.com/docs/datasheets/ cancermpact-treatment-architecture. pdf?sfvrsn=6. Accessed February 27, 2015.

Clinical Practice?

A recent survey found that 26% of stage III patients receive adjuvant therapy for kidney cancer in the United States, with no evidence to support this practice.2 The same group found that about 45% of kidney cancer patients who do receive adjuvant therapy get either sorafenib or sunitinib.2 At the press briefing, moderator

Adjuvant Sorafenib and Sunitinib in Renal Cell Carcinoma ■■ Adjuvant therapy with sorafenib or sunitinib did not improve outcomes over placebo in locally advanced kidney cancer.

■■ Use of these drugs did increase toxicity.

■■ There is no basis for use of these drugs for adjuvant therapy.

■■ Close observation remains the standard of care following surgery.

Keynote: Individualized Medicine—William George Nelson, MD, PhD (left) was presented an award for Keynote Lecture by Christopher P. Evans, MD (right) for delivering his keynote talk on individualized medicine during the “Prostate Cancer: Year In Review” session at the 2015 Genitourinary Cancers Symposium in Orlando. More than 2,800 experts from around the world attended the Symposium, which was sponsored by the American Society of Clinical Oncology, the American Society of Radiation Oncology, and the Society of Urologic Oncology.

Photo by © ASCO/Todd Buchanan 2015

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | APRIL 10, 2015

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Genitourinary Cancers Symposium Genitourinary Oncology

Androgen-Deprivation Therapy Added to Radiation Therapy Improves Disease Control in Intermediate-Risk Prostate Cancer

By Alice Goodman

T

he addition of 6 months of androgen-deprivation therapy to radiation therapy as primary therapy for intermediate-risk prostate cancer improved biochemical control and disease-free survival but did not translate to an improvement in overall survival, in a phase III trial reported at the 2015 Genitourinary Cancers Symposium.1

Controversial Issue “The role of short-term androgendeprivation therapy in combination with radiotherapy for intermediaterisk prostate cancer has been controversial. Our study showed that shortterm androgen-deprivation therapy added to radiation improved outcomes but did not improve overall survival,” said ­Abdenour Nabid, MD, a radiation oncologist at the Centre Hospitalier Universitaire de Sherbrooke, Quebec, Canada.

“Six months of short-term androgen deprivation therapy combined

with radiotherapy represents one of several therapeutic options in intermediate-risk prostate cancer and should be discussed with patients treated for this type of cancer, taking into account age, comorbidities, erectile function, prognostic factors, and other parameters. It is important to consider the side effects of androgen-deprivation therapy and those of a higher dose of radiotherapy when discussing this with patients,” Dr. Nabid commented further.

The study had four endpoints.

At the meeting, Dr. Nabid reported on the two primary endpoints (biochemical failure and disease-free survival) and a secondary endpoint (overall survival). The fourth endpoint is toxicity related to androgendeprivation therapy and radiotherapy. All of these data are helpful in decision-making.

“These important data will soon be reviewed and will be reported next fall I hope,” he said.

The role of short-term androgendeprivation therapy in combination with radiotherapy for intermediaterisk prostate cancer has been controversial. Our study showed that it improved outcomes but did not improve overall survival.

—Abdenour Nabid, MD

Study Details The study randomized 600 patients with intermediate-risk prostate cancer to one of three arms: • Arm 1—short-term androgendeprivation therapy plus radiation therapy to the prostate with 70 Gy over 7 weeks • Arm 2—short-term androgendeprivation therapy plus radiation therapy to the prostate with 76 Gy over 7.5 weeks • Arm 3—prostate radiation therapy

EXPERT POINT OF VIEW

“I

believe the study by Nabid and colleagues will help inform practice,” said formal discussant D. Andrew Loblaw, MD, radiation oncologist at Odette Cancer Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.

2. “The extra 6 Gy in arm 2 may introduce more side effects,” he added.

“Many of us practicing have been offering dose-escalated externalbeam radiation therapy for over a decade based on randomized data.

While there have been other ran-

I believe short-term androgendeprivation therapy should be considered for all intermediate-risk patients.

—D. Andrew Loblaw, MD

“At a median follow up of 6.3 years, short-term androgen-deprivation therapy plus radiation achieved clinically and statistically significant improvements in biochemical outcomes but no difference in overall survival,” Dr. Loblaw said.

Dr. Loblaw said he didn’t see much difference between arms 1 and

domized studies showing that shortterm androgen-deprivation therapy plus radiation [ie, 66–70 Gy] improved outcomes compared to radiation alone, the doses used in those trials were historic. We believed that dose escalation with radiotherapy alone [ie, 76–78 Gy] was probably equal to adding short-term andro-

gen-deprivation therapy to lower radiation therapy doses.

“But Nabid’s study shows us that 70 Gy+ short-term androgen-deprivation therapy is superior to 76 Gy. Also, we know that 66 Gy+ short-term androgen-deprivation therapy improves overall survival [from RTOG 9408].

So I believe short-term androgen-deprivation therapy should be considered for all intermediate-risk patients,” Dr. Loblaw commented.

“The ASCENDE-RT trial then tells us the added value of a brachytherapy boost for intermediate-risk (and high-risk) patients getting shortterm androgen-deprivation therapy.

A brachytherapy boost significantly improves prostate-specific antigen control over 78 Gy,” he said. n Disclosure: Dr. Loblaw has received grants/research support from Sanofi and Paladin and honoraria from Amgen, AstraZeneca, Elekta, GE, Janssen, Paladin, and Sanofi, is on the advisory boards of Amgen, Astellas, Janssen, and Sanofi, and is associated with the financial groups TSRCC Radiation Oncology Associates and Atlas Global.

alone with 76 Gy over 7.5 weeks Androgen-deprivation therapy was given for a total of 6 months: as neoadjuvant therapy for 4 months and as concomitant therapy with radiation therapy for 2 months.

The three arms were well balanced for baseline characteristics. The median age was 71, the median prostate-specific antigen (PSA) level was around 10 ng/ mL, and the median Gleason score was 7. Overall, about 25% had stage T2b/c disease; 75% had a Gleason score of 7, and 57% had a PSA value of between 10 and 20 ng/mL.

Biochemical Control and Disease-Free Survival Arm 2 had the lowest rate of biochemical failure. At 120 months, biochemical failure was observed in 23.4% of arm 1, 16.6% of arm 2, and 34.5% of arm 3. The number of metastases was significantly lower in arm 1 vs arm 3 (P = .011 for all metastases): node only 1% vs 1.5% respectively; bone metastases 0.5% vs 5%, respectively.

“This could mean that androgen-­ deprivation therapy prevents metastases,” Dr. Nabid suggested.

At a median follow-up of 75.4 months, disease-free survival was reported in 77.2% of arm 1 patients, 89.8% of arm 2 patients, and 64.7% of radiotherapy-alone patients (arm 2 vs arm 3 P < .001).

“Arm 1 and arm 2 are both better than arm 3 at 5 and 10 years. Arm 2 is the best for biochemical failure and disease-free survival,” he stated.

A total of 113 patients (19%) died, with only 6 deaths attributed to prostate cancer. The main cause of death was second cancers, with cardiovascular disease as the second cause of death.

No significant overall survival differcontinued on page 11

ASCOPost.com | APRIL 10, 2015

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Genitourinary Cancers Symposium Genitourinary Oncology

Evidence Mounts for Clinical Utility of AR-V7 in Treatment Selection for Advanced Prostate Cancer

By Alice Goodman

T

he search is on in prostate cancer to identify predictive and prognostic biologic and genomic markers that go beyond traditional ones. Several groups are working in this area. One marker that has received much attention is a splice abnormality in the androgen receptor (AR) called AR-V7.

Two Studies A preliminary study presented at the 2015 Genitourinary Cancers Symposium showed that the presence of AR-V7 in circulating tumor cells was compatible with sensitivity to taxanes in men with

Intermediate-Risk Prostate Cancer continued from page 10

ence was observed between the three arms at 5 and 10 years.

The study was conducted in the primary treatment setting. Dr. Nabid said, “We don’t know yet the answers about androgen-deprivation therapy and radiation in the salvage setting.” n

Disclosure: Dr. Nabid has received a research grant from AstraZeneca, is on the advisory board of Sanofi/Janssen, is a speaker for Sanofi, and received financial support from Sanofi/ AstraZeneca. The PCS III trial was funded by an AstraZeneca Pharmaceuticals grant.

Reference 1. Nabid A, Carrier N, Vigneault E, et al: Place of short-term androgen deprivation therapy in intermediate-risk prostate cancer treated with radiotherapy: A phase III trial.

2015 Genitourinary Cancers Symposium.

Abstract 5. Presented February 26, 2015.

Androgen-Deprivation Therapy and Radiation Therapy ■■ Short-term androgendeprivation therapy added to radiation therapy to the prostate improves biochemical disease-free survival but does not improve overall survival compared with radiation therapy alone in intermediate-risk prostate cancer.

■■ This type treatment is one of several options that can be offered as primary therapy to men with intermediate-risk prostate cancer.

metastatic castration-resistant prostate cancer about to initiate therapy with docetaxel or cabazitaxel ( Jevtana).1

The same group of investigators presented a previous study at the 2014 ASCO Annual Meeting2 and subsequently pub-

lished in The New England Journal of Medicine,3 showing that the presence of AR-V7 continued on page 12

The ASCO Post | APRIL 10, 2015

PAGE 12

Genitourinary Cancers Symposium Clinical Utility of AR-V7 continued from page 11

was predictive of primary resistance to AR-directed therapy with enzalutamide (Xtandi) and abiraterone (Zytiga).

Taken together, these results suggest that AR-V7 may be helpful in selecting therapy for men with metastatic castration-resistant prostate cancer. Men whose tumors are positive for AR-V7 should

than with abiraterone/enzalutamide, whereas outcomes did not differ in ARV7–negative men according to treatment type,” Dr. Antonarakis said.

For example, in the pooled data, in ARV7–positive men, PSA response was observed in 41% of the taxane-treated group and 0% of the abiraterone/enzalutamide group. In addition, median PSA–progression-free survival and median progression-

The present study enrolled 37 men with metastatic castration-resistant prostate cancer slated for chemotherapy with a taxane; 17 of the 37 were positive for AR-V7. All patients responded to therapy equally, regardless of their AR-V7 status. Prostate-specific antigen (PSA) responses (ie, > 50% decline from baseline in PSA value) were achieved in 41% of the AR-V7–positive group and 65% of the AR-V7–negative group.

Median PSA–progression-free survival was comparable in the two groups: 4.5 months vs 6.2 months, respectively.

Median progression-free survival was also comparable in AR-V7–positive and AR-V7–negative patients treated with a taxane: 5.1 months and 6.9 months, respectively. These differences were not statistically significant.

“When we incorporated data from the 62 men in the previous abiraterone/ enzalutamide study, it became clear that clinical outcomes in the AR-V7–positive men were superior with taxanes

■■ The presence of AR-V7 in circulating tumor cells predicted for resistance to enzalutamide and abiraterone, whereas tumors with this abnormality seem to retain sensitivity to taxanes.

■■ Men with tumors that are AR-V7–negative appear to respond to both types of therapy (AR-directed therapy or chemotherapy).

quently in patients who have been heavily pretreated with hormonal therapies.

Standardized Test Needed

—Emmanuel Antonarakis, MD

Predictive Results

■■ An androgen receptor (AR) abnormality called AR-V7 may turn out to be a predictive marker for treatment selection in men with metastatic castrationresistant prostate cancer.

■■ If a test for AR-V7 is developed and certified, it will probably have greater utility for treatment selection in AR-V7–positive patients.

AR-V7 testing may be extremely valuable in guiding treatment decisions for men with hormoneresistant disease in the near future.

probably be offered a taxane and not be treated with abiraterone or enzalutamide, whereas men who are AR-V7–negative can be safely treated with either option.

“We urgently need markers that predict which therapies are going to be effective and which will not … in individual patients with prostate cancer.

AR-V7 testing may be extremely valuable in guiding treatment decisions for men with hormone-resistant disease in the near future,” said lead author Emmanuel Antonarakis, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

“These data need to be validated prospectively in a larger study,” he noted.

Predictive Potential of AR-V7

free survival were significantly longer in taxane-treated men compared with those receiving abiraterone/enzalutamide (P = .001 and P = .003, respectively).

Dr. Antonarakis said that typically, about 30% of men with castration-resistant prostate cancer have the AR-V7 abnormality detected in circulating tumor cells. It is thought to occur more fre-

Dr. Antonarakis utilized a quantitative reverse transcription–polymerase chain reaction assay to identify AR-V7 mRNA in circulating tumor cells. At present, there is no commercially available or standardized test for identifying AR-V7. Several groups of investigators and industry partners are working on developing such a test.

For AR-V7 to find use in the clinical setting, larger prospective trials will have to be conducted to validate this predictive biomarker. In addition, a test approved

by Clinical Laboratory Improvement

Amendments will need to be available. n

Disclosure: Dr. Antonarakis has received honoraria and travel expenses from as well as served as a consultant or advisor to Dendreon, Medivation, and Sanofi. His institution has also received research funding from Aragon Pharmaceuticals, Dendreon, Exelixis, Genentech, Janssen Biotech, Inc, Johnson & Johnson, Millennium, Novartis, and Sanofi.

References 1. Antonarakis ES, et al: 2015 Genitourinary Cancers Symposium. Abstract 138.

Presented February 26, 2015.

2. Antonarakis ES, et al: 2014 ASCO Annual Meeting. Abstract 5001. Presented June 1, 2014.

3. Antonarakis ES, et al: N Engl J Med 371:1028-1038, 2014.

EXPERT POINT OF VIEW

“A

R-V7 is only one of the many prostate cancer predictive biomarker candidates currently under investigation,” said Howard Scher, MD, Chief of the Genitourinary Service at Memorial Sloan Kettering Cancer Center in New York. While preliminary data are promising, further development of AR-V7 will first require ensuring that the assay is analytically valid—one that is reliable

crete aspects of the same biomarker.

Dr. Antonarakis’ group looked for a splice abnormality in the mRNA of the androgen receptor in the blood.

Potential to Improve Decision-Making As drugs are approved for indications, biomarkers are approved for the specific way in which they improve decision-making—their con-

AR-V7 is a promising biomarker that needs to be validated in appropriately designed trials.

—Howard Scher, MD

and reproducible across different laboratories—to measure it, followed by a sequence of trials designed to generate evidence supporting its use within a specific clinical context.

Dr. Scher noted that different assays may be used to measure dis-

text of use, Dr. Scher continued. For example, a biomarker predicting response to therapy could be useful in a patient who has had disease progression on one form of therapy, in need of the decision on what to do next.

“Predictive biomarkers help guide

treatment selection throughout the course of illness,” he stated. “In men experiencing initial hormone resistance, it is important to identify those who are unlikely to respond to hormonal agents such as enzalutamide and abiraterone for whom chemotherapy may be more effective. Similarly, as the disease progresses further and response rates to enzalutamide or abiraterone are lower, the goal is to identify the minority of patients still likely to respond to these agents, while offering alternative treatment to those who are not. The results presented by Dr. Antonarakis suggest that the presence of the AR-V7 predicts for nonresponse to enzalutamide (Xtandi) and abiraterone (Zytiga), and response to a taxane. ” “Early data on AR-V7 is encouraging and warrants further development. A coordinated effort to establish analytically valid AR-V7 assays, and to prospectively evaluate the presence of the variant and clinical outcomes in dedicated trials is already underway,” he stated. n Disclosure: Dr. Scher reported no potential conflicts of interest.

NEW—LIQUID FORMULATION

Start with TREANDA® (bendamustine HCI) Injection for established front-line CLL therapy

Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL).

Efficacy relative to first-line therapies other than chlorambucil has not been established.

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine.

Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions.

Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels.

There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined.

Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.

Please see accompanying brief summary of Full Prescribing Information on the following pages.

Learn more at TREANDAHCP.com

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40090 November 2014

The ASCO Post | APRIL 10, 2015

PAGE 14

National Comprehensive Cancer Network Annual Conference

NCCN Publishes New Guidelines for Smoking Cessation

T

obacco-related diseases are the most preventable cause of death worldwide. According to the American Cancer Society, in 2015, nearly 171,000 of the estimated 589,430 cancer deaths in the United States—more than 25%—will be caused by tobacco

smoking. Smoking cessation leads to improvement in cancer treatment outcomes, as well as decreased recurrence.

To meet the needs of patients who are smokers at the time of a cancer diagnosis, the National Comprehensive Cancer Network® (NCCN) has published

the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Smoking Cessation. The NCCN Guidelines for Smoking Cessation were presented on March 13, 2015, at the NCCN 20th Annual Conference.

The NCCN Guidelines Panel for

™

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once nonhematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.

Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.

Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.

2.3 Preparation for Intravenous Administration Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution.

Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution.

Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature (15°-30°C or 59°-86°F) and room light. Administration of TREANDA must be completed within this period.

3 DOSAGE FORMS AND STRENGTHS TREANDA Injection is supplied in single-use vials containing either 45 mg/0.5mL or 180 mg/2mL of bendamustine HCl. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppressionrelated adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.1)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing

Smoking Cessation, chaired by Peter G. Shields, MD, recommends that treatment plans for all smokers with cancer include the following: evidence-based pharmacotherapy, behavior therapy, and close follow-up with retreatment, as needed.

TREANDA® (bendamustine hydrochloride) Injection reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials.

Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.

In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.

5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman.

Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression (5.1); Infections (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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.

6.1 Clinical Trials Experience in CLL The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial.The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve.

All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days.

Adverse reactions were reported according to NCI CTC v.2.0. Nonhematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).

ASCOPost.com | APRIL 10, 2015

PAGE 15

National Comprehensive Cancer Network Annual Conference More Patient Support Needed “Smoking addiction is a chronic, relapsing disease, and many factors contribute to a person’s success or failure to kick the habit long term. Science has shown us that smokers with cancer have a high level of dependence, and smoking cessation leads to improvement in cancer treatment effectiveness and decreased cancer

Peter G. Shields, MD

recurrence,” said Dr. Shields, who is Deputy Director of The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

“Although the medical community recognizes the importance of smoking cessation, supporting patients in ceasing to smoke is generally not done well. Our

TREANDA® (bendamustine hydrochloride) Injection

TREANDA® (bendamustine hydrochloride) Injection

Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.

Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.

The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%).

Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients

In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.

Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress.

Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients.

No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage.

If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water.

TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1.

16.2 How Supplied TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vial NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vial Vials are supplied in individual cartons.

16.3 Storage TREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F).

Retain in original package until time of use to protect from light.

Number (%) of patients TREANDA (N=153) System organ class Preferred term Total number of patients with at least 1 adverse reaction Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills Immune system disorders Hypersensitivity Infections and infestations Nasopharyngitis Infection Herpes simplex Investigations Weight decreased Metabolism and nutrition disorders Hyperuricemia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash Pruritus

Chlorambucil (N=143)

All Grades

Grade 3/4

All Grades

Grade 3/4

121 (79)

52 (34)

96 (67)

25 (17)

31 (20) 24 (16) 14 (9)

1 (<1) 1 (<1) 2 (1)

21 (15) 9 (6) 5 (3)

1 (<1) 0 0

36 (24) 14 (9) 13 (8) 9 (6)

6 (4) 2 (1) 0 0

8 (6) 8 (6) 6 (4) 1 (<1)

2 (1) 0 0 0

7 (5)

2 (1)

3 (2)

0

10 (7) 9 (6) 5 (3)

0 3 (2) 0

12 (8) 1 (<1) 7 (5)

0 1 (<1) 0

11 (7)

0

5 (3)

0

11 (7)

3 (2)

2 (1)

0

6 (4)

1 (<1)

7 (5)

1 (<1)

12 (8) 8 (5)

4 (3) 0

7 (5) 2 (1)

3 (2) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA N=150

Chlorambucil N=141

Laboratory Abnormality

All Grades n (%)

Grade 3/4 n (%)

All Grades n (%)

Grade 3/4 n (%)

Hemoglobin Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils Decreased

113 (75)

65 (43)

86 (61)

30 (21)

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates.

All rights reserved.

(Label Code: 00016287.06) 9/2013 TRE-40161 This brief summary is based on TRE-009 TREANDA full Prescribing Information.

hope is that by addressing smoking cessation in a cancer patient population, we can make it easier for oncologists to effectively support their patients in achieving their smoking cessation goals,” said Dr. Shields.

According to the NCCN Guidelines for Smoking Cessation, combining pharmacologic therapy and counseling is the most effective treatment approach to smoking cessation. Furthermore, smoking status should be documented in patient health records and updated at regular intervals. Smoking relapse is common, and providers should discuss relapse and provide guidance for patients.

‘Crucial Addition’ to Guidelines “The NCCN Guidelines for Smoking Cessation is a crucial addition to the NCCN Guidelines for Supportive Care,” said Robert W. Carlson, MD, Chief Executive Officer, NCCN. “Addressing the physical and behavioral impact of cigarette smoking dependency and offering a support system for people with cancer can positively impact their quality of life, both during treatment and during survivorship.”

The NCCN Guidelines for Smoking Cessation join a library of 10 additional NCCN Guidelines for Supportive Care,

Robert W. Carlson, MD

which comprise evidence-based treatment recommendations for supportive care areas. NCCN publishes a full library of 61 clinical guidelines detailing sequential management decisions and interventions that currently apply to 97% of cancers affecting people in the United States, as well as cancer prevention, detection and risk reduction, and age-related recommendations.

Watch for continued coverage of the NCCN 20th Annual Conference in upcoming issues of The ASCO Post. For more information about the NCCN and the NCCN Guidelines, visit NCCN. org, and direct patients and caregivers to NCCN.org/patients. n

The ASCO Post | APRIL 10, 2015

PAGE 16

Genitourinary Cancers Symposium Genitourinary Oncology

Cabozantinib Fails to Improve Survival in Metastatic Castration-Resistant Prostate Cancer

By Alice Goodman

F

inal results of the phase III, randomized double-blind, controlled COMET-1 trial were disappointing. Although the oral tyrosine kinase inhibitor cabozantinib (Cometriq) improved several secondary endpoints compared with prednisone, including bone scan response and progression-free survival, the drug failed to meet the primary endpoint of improved overall survival in men with pretreated metastatic castration-resistant prostate cancer,1 according to the final results presented at the 2015 Genitourinary Cancers Symposium.

“Although cabozantinib failed to improve survival, it did improve a number of endpoints,” said presenting

ily pretreated men with metastatic castration-resistant prostate cancer on a variety of metrics, including improvements in bone scan response, decreased pain, and reductions in circulating tumor cells.

However, the final overall survival analysis showed no significant difference between treatment arms, with a hazard ratio of 0.90 and overlapping confidence intervals. Median overall survival was 11 months with cabozantinib vs 9.8 months with prednisone.

In a prespecified subgroup analysis, the effect on overall survival appeared to be greater in patients treated previously with cabazitaxel (Jevtana) as well as in patients with visceral metastases (n = 191).

Salvage therapies after disease pro-

Although cabozantinib failed to improve survival, it did improve a number of endpoints.… The improvement was greatest in patients with visceral metastases.

—Matthew R. Smith, MD, PhD

author Matthew R. Smith, MD, PhD, of Massachusetts General Hospital, Boston. “The improvement was greatest in the patients with visceral metastases, which deserves further study.”

Study Details COMET-1 enrolled 1,028 patients with metastatic castration-resistant prostate cancer that progressed on previous treatment with docetaxel and abiraterone (Zytiga) and/or enzalutamide (Xtandi). The median age of patients was 69 years.

Patients were randomly assigned 2:1 to receive cabozantinib at 60 mg once daily plus placebo or prednisone at 5 mg twice daily plus placebo. Therapy was discontinued in 91% of the cabozantinib group and 95% of the prednisone group, mainly for progressive disease or side effects.

No Difference in Overall Survival Cabozantinib showed excellent activity in a phase II trial of more than 300 heav-

gression were used by 55% of the cabozantinib group and 68% of those assigned to prednisone.

Other Outcomes Although there was no improvement in survival, cabozantinib significantly improved bone scan response (measured as a 30% reduction in lesion volume): 42% vs 3% with prednisone (P < .001).

In addition, cabozantinib significantly improved investigator-assessed progression-free survival: Median progression-free survival was 5.6 months vs 2.8 months, respectively (P < .001).

Also, time to first on-study skeletalrelated event was longer with cabozantinib. Circulating tumor cells normalized in 33% of the cabozantinib group vs 6% of the prednisone group.

Greater Toxicity However, the rates of grades 3 and 4 adverse events were higher in the cabozantinib arm (71% vs 56%, respectively), and treatment discontinuation

EXPERT POINT OF VIEW

E

ric J. Small, MD, of the University of California at San Francisco, discussed what he thought went wrong for cabozantinib (Cometriq) in the ­COMET-1 trial, yet another example of a phase III trial that failed to deliver on the promise of phase II results.

“Although this was a negative study, cabozantinib is an active agent. The activity observed was in intermediate endpoints, however, and not in Eric J. Small, MD the primary endpoint of the study, survival. In my opinion, the toxicity of the drug may have contributed to the negative results.

Although overall negative, the greater impact on survival of cabozantinib in men with visceral metastases bears further study,” Dr. Small said.

Furthermore, Dr. Small found the improved survival in patients with visceral metastasis of interest. “Here is an agent that might be suitable for these patients, who typically have a worse response. Developing predictive and prognostic markers in this group of patients is a priority,” he stated.

“Most of us were astonished by the striking improvement in bone scans on cabozantinib in the phase II trials,” Dr. Small said. “But red flags were raised by the early data.”

Considerable Toxicity “Cabozantinib came on the scene in the setting of extraordinary responses, but with considerable toxicity. Dose reductions were needed in 70% of patients in the phase II experience,” he continued.

At that time, 40 mg was determined as the lowest effective dose. A multicenter nonrandomized trial compared 40 mg with 100 mg, and the 100-mg dose was deemed too toxic, since 84% of patients required dose reductions.

“COMET-1 dosed cabozantinib at 60 mg, thereby allowing patients to undergo a dose reduction if needed and still be dosed at the lowest effective dose. About 70% of patients had a grade 3 or higher adverse event, and onethird discontinued treatment due to toxicity,” he said.

The fact that more patients had dose reductions of cabozantinib on 60 mg in COMET-1 than on 40 mg in the phase II trials (60% vs 31%, respectively) argues that there may be a toxicity threshold just above 40 mg, Dr. Small suggested.

Prior experience with cabozantinib as well as cabazitaxel ( Jevtana) may be an additional factor influencing the phase III results. “The phase II trials were conducted at 14 sites experienced in giving cabozantinib, whereas this was not true in the phase III trial. It is also possible that prior use of cabazitaxel influenced results, because 24% of the phase II patients vs 38% of the ­COMET-1 patients were treated with prior cabazitaxel,” he elaborated. n Disclosure: Dr. Small reported no potential conflicts of interest.

due to adverse events was reported in 33% vs 12% of the prednisone-treated patients. The most common adverse events on cabozantinib were hypertension, fatigue, anemia, and decreased ­appetite. n Disclosure: Dr. Smith has served as a consultant or advisor to and received research funding from Exelixis.

Reference 1. Smith MR, De Bono JS, Sternberg CN, et al: Final analysis of COMET-1: Cabozantinib versus prednisone in metastatic castration-resistant prostate cancer patients previously treated with docetaxel and abiraterone and/or enzalutamide. 2015 Genitourinary Cancers Symposium. Abstract 139. Presented February 26, 2015.

ASCOPost.com | APRIL 10, 2015

PAGE 17

Announcements

State Oncology Societies Join ASCO’s Call on Congress to Replace SGR Formula

I

n a show of solidarity, state oncology societies from across the United States joined ASCO in its call on Congress to repeal Medicare’s Sustainable Growth Rate (SGR) formula before the current payment patch expires.

In a letter to U.S. House and Senate

also rewarding value-based quality care.

“If we do not act, Congress will have to pass another payment patch that will cost billions more dollars, and create additional instability in cancer care,” said

James N. Frame, MD, FACP, Chair of the ASCO State Affiliate Council.

“State oncology societies join ASCO in calling on Congress to use this unprecedented momentum for SGR repeal to

achieve real Medicare reform.”

Individuals can contact their lawmakers regarding SGR Repeal and learn more about SGR at http://www.asco.org/ advocacy/permanently-repeal-sgr-now.

ASCO POST n

State oncology societies join ASCO in calling on Congress to use this unprecedented momentum for SGR repeal to achieve real Medicare reform.

—James N. Frame, MD, FACP

75C, 63M, 63Y 50C, 39M, 39Y

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25K

5

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50

For more information, please call 800-843-8197 or visit www.GILOTRIF.com

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GATF/SWOP Digital Proofing Bar

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leadership, 48 signatories, representing tens of thousands of oncology professionals, expressed support for the SGR Repeal and Medicare Provider Payment Modernization Act of 2015. This legislation, introduced in Congress on March 19, 2015, and passed by the House of Representatives on March 26, seeks to end the cycle of unpredictable patches that have created uncertainty for millions of Medicare providers and beneficiaries for more than a decade.

“Medicare’s outdated and inadequate system for reimbursing physicians is a threat to cancer care across the country,” said ASCO CEO Allen S. Lichter, MD, FASCO. “This show of unity should further encourage Congress to act now on replacing the SGR formula for one that reflects the current state of medical care.”

The oncology community has long advocated for the repeal of this formula, and the adoption of a more reliable payment system that reflects the reality and cost of today’s oncology practice. The “SGR Repeal and Medicare Provider Payment Modernization Act of 2015” mirrors 2014’s legislation that would have repealed the formula, and included incentives for physicians to participate in alternative payment models and clinical improvement activities, while

Copyright © 2013. Boehringer Ingelheim Pharmaceuticals, Inc.

All rights reserved.

(11/13)

GF591301PROF-B

The ASCO Post | APRIL 10, 2015

PAGE 18

In the Clinic Neuro-Oncology

Dinutuximab in Pediatric High-Risk Neuroblastoma

By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n March 10, 2015, the chimeric monoclonal antibody dinutuximab (Unituxin) was approved for use in combination with granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA) for the treatment of pediatric patients with highrisk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy.1,2

Supporting Trial Approval was based on demonstration of improved event-free survival and overall survival in a multicenter, open-label trial conducted by the Children’s Oncology Group.2 Patients had to have achieved at least partial response to prior therapy for newly diagnosed high-risk neuroblastoma, consisting of induction combination chemotherapy, maximum feasible surgical resection, and myeloablative consolidation chemotherapy, and had also received autologous stem cell transplantation and radiotherapy. A total of 226 patients were randomized to the dinutuximab/RA group (n = 113) or the RA-alone group (n = 113) for 6 cycles of treatment. Dinutuximab/RA treatment consisted of dinutuximab in combination with GM-CSF and RA (cycles 1, 3, and 5), dinutuximab in combination with IL-2 and RA (cycles 2 and 4), and RA (cycle 6).

Patients had a median age of 3.8 years (range = 11 months–15 years), 60% were male, 82% were white, 80% had International Neuroblastoma Staging System stage 4 disease, 46% had neuroblastoma that was not

MYCN-amplified and 36% had tumors with known MYCN amplification, and 43% had hyperdiploid tumors and 36% had diploid tumors. Therapy prior to stem cell transplantation resulted in complete response in 35%, very good partial response in 43%, and partial response in 23%.

Median event-free survival was not reached in the dinutuximab/RA group vs 1.9 years in the RA group (hazard ratio [HR] = 0.57, P = .01). An analysis conducted at 3 years after the eventfree survival analysis showed improved overall survival in the dinutuximab group (HR = 0.58, 95% confidence interval = 0.37–0.91), with median survival not yet reached in either group.

OF NOTE Dinutuximab is a chimeric monoclonal antibody that binds to the glycolipid GD2, which is expressed on neuroblastoma cells and on normal cells of neuroectodermal origin (including the central nervous system and peripheral nerves).

How It Works Dinutuximab is a chimeric monoclonal antibody composed of a combination of mouse and human DNA. It binds to the glycolipid GD2, which is expressed on neuroblastoma cells and on normal cells of neuroectodermal origin (including the central nervous system and peripheral nerves).

Dinutuximab binding induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.

How It Is Given The recommended dose of dinutuximab is 17.5 mg/m2/d as IV infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles. Dinu-

First Approved Therapy for High-Risk Neuroblastoma ■■ Dinutuximab (Unituxin) was approved for use in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and 13-cis-retinoic acid for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy.

■■ The recommended dose of dinutuximab is 17.5 mg/m2/d as IV infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles.

OF NOTE Dinutuximab carries boxed warnings for infusion reactions, including life-threatening reactions, and neuropathy, including severe neuropathic pain, peripheral sensory neuropathy, and motor neuropathy.

tuximab is given on days 4, 5, 6, and 7 of 24-day cycles 1, 3, and 5 and on days 8, 9, 10, and 11 of 32-day cycles 2 and 4. Infusion should be initiated at a rate of 0.875 mg/m2/h for 30 minutes. The infusion rate can be gradually increased as tolerated to a maximum rate of 1.75 mg/m2/h. Patients must have adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of treatment.

Required pretreatment includes hydration and analgesic, antihistamine, and antipyretic treatment prior to each infusion.

Permanent discontinuation of dinutuximab is required for grade 3 or 4 anaphylaxis, grade 3 or 4 serum sickness, grade 3 pain unresponsive to maximum supportive measures, grade 4 sensory neuropathy or grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, grade 2 peripheral motor neuropathy, subtotal or total vision loss, and grade 4 hyponatremia despite appropriate fluid management. Dose modifications including dose reduction and interruption are specified in product labeling for infusion-related reactions, capillary leak syndrome, hypotension requiring medical intervention, severe systemic infection or sepsis, and neurologic disorders of the eyes.

Safety Profile Safety data include those from 134 dinutuximab/RA patients (including 25 nonrandomized patients) and 106 RA patients. In the randomized trial, adverse events of grade ≥ 3 were comprehensively collected, but those of grade 1 or 2 were collected sporadically, and laboratory data were not comprehensively collected. The most common grade 3 or 4 adverse events in the dinutuximab/RA group were pain (51% vs 6% in the RA group), lymphopenia (51% vs 20%), pyrexia (40% vs 6%), thrombocytopenia (39% vs 25%), hypokalemia (37% vs 2%), anemia (34% vs 16%), neutropenia (34% vs 13%), infusion reaction (25% vs

1%), capillary leak syndrome (23% vs 0%), hyponatremia (23% vs 4%), and increased alanine transaminase levels (23% vs 3%). The most common serious adverse events occurring in at least 5% of dinutuximab/RA patients were infection, infusion reaction, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. Treatment was discontinued due to adverse events in 19% of the dinutuximab/RA group.

Dinutuximab carries boxed warnings for infusion reactions, including life-threatening reactions, and neuropathy, including severe neuropathic pain, peripheral sensory neuropathy, and motor neuropathy. The drug is contraindicated in patients with a history of anaphylaxis to dinutuximab.

Dinutuximab carries warnings/precautions for capillary leak syndrome and hypotension, infection, neurologic disorders of the eyes, bone marrow suppression, electrolyte abnormalities, atypical hemolytic uremic syndrome, and embryo-fetal toxicity. Peripheral blood cell counts must be monitored during dinutuximab treatment, and serum electrolytes must be closely monitored. Female patients must be advised of the potential risk to a fetus and to use effective contraception. n References 1. U.S. Food and Drug Administration: Approved drugs. Dinutuximab.

Available at http://www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm437480.htm. Accessed March 23, 2015.

2. Unituxin (dinutuximab) injection prescribing information, United Therapeutics Corporation, March 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125516s000lbl.pdf.

Accessed March 23, 2015.

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).

After progression following initial antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (mBC)...

Go with FASLODEX.

Primary Endpoint: Progression-Free Survival (PFS)1,*

A Secondary Endpoint: Overall Survival (OS)1

Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg in CONFIRM2,†

Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg in CONFIRM2

At minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006) 2

• Not statistically significant as no adjustments were made for multiplicity2

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96) 2

Important Safety Information About FASLODEX • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) Please see additional Important Safety Information on reverse and brief summary of full Prescribing Information for FASLODEX on following pages. * PFS is defined as the time between randomization and the

earliest evidence of progression or death from any cause.2 † COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer.1

Go with Confidence Learn more at www.Faslodexhcp.com

FASLODEX is indicated for the treatment of hormone receptor-positive (HR+) metastatic breast cancer (mBC) in postmenopausal women with disease progression following antiestrogen therapy.

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,† • Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2 • Objective response rates (ORRs)‡ were not significantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2 — Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

FASLODEX 500 mg vs 250 mg in the Updated OS Analysis in CONFIRM2,§ • Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg at minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2 • Not statistically significant as no adjustments were made for multiplicity.2 • In the initial OS analysis after a minimum duration of 18 months, there was no statistically significant difference in OS between the 2 treatment groups2

FASLODEX 500 mg Showed a Comparable Safety Profile to FASLODEX 250 mg in CONFIRM1 Additional Important Safety Information About FASLODEX • Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX • The most common, clinically significant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent

Indication For FASLODEX • FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

* The CONFIRM trial was a randomized, double-blind, controlled phase III

study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 † PFS was the primary endpoint.1 ‡ ORR is defined as the number of patients with complete response or partial response.2 § OS was a secondary endpoint.1

Please read brief summary of full Prescribing Information for FASLODEX on following pages.

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Go with Confidence FASLODEX is a registered trademark of the AstraZeneca group of companies.

©2015 AstraZeneca.

All rights reserved.

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ASCOPost.com | APRIL 10, 2015

PAGE 21

Announcements

New Tobacco Atlas Details Scale and Harm of the Tobacco Epidemic

T

he Tobacco Atlas, fifth edition, its companion mobile app, and website TobaccoAtlas.org, were released by the American Cancer Society and World Lung Foundation at the 16th World Conference on Tobacco or Health held March 17–21, 2015 in

Abu Dhabi, United Arab Emirates.

The Atlas details the scale of the tobacco epidemic. It covers the harmful influence of tobacco on health, poverty, Trim: x 11" social justice, and 8.5 the environment; the progress being made in tobacco control; and the latest products and tactics being

FASLODEX® (fulvestrant) Injection

BRIEF SUMMARY For full Prescribing Information, see package insert.

INDICATIONS AND USAGE

FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

DOSAGE AND ADMINISTRATION Recommended Dose

The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter [see Clinical Studies (14) in full Prescribing Information].

Dose Modification Hepatic Impairment:

A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter.

FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Specific Populations].

Administration Technique

The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged.

2. Remove perforated patient record label from syringe.

3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.”

4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap.

5. Twist to lock the needle to the luer connector.

6. Remove needle sheath.

7. Remove excess gas from the syringe (a small gas bubble may remain).

8. Administer intramuscularly slowly in the buttock.

9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered.

10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector.

11. Repeat steps 1 through 10 for second syringe.

For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

CONTRAINDICATIONS

FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX.

WARNINGS AND PRECAUTIONS Blood Disorders

Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.

Hepatic Impairment

The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.

Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration].

FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations].

Use in Pregnancy

Based on its mechanism of action and findings in animals, FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area. There are no adequate and wellcontrolled studies in pregnant women using FASLODEX. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).

Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

used by the industry to protect its profits and delay and derail tobacco control.

For Every Tobacco-Related Death, a $7,000 Profit Among the top six transnational tobacco companies—accounting for 85%

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients and Adverse Reaction

Fulvestrant 500 mg N=361

Fulvestrant 250 mg N=374

Injection Site Pain

42 (11.6)

34 (9.1)

Headache

28 (7.8)

25 (6.7)

Back Pain

27 (7.5)

40 (10.7)

Fatigue

27 (7.5)

24 (6.4)

Pain in Extremity

25 (6.9)

26 (7.0)

Asthenia

21 (5.8)

23 (6.1)

24 (6.6)

22 (5.9)

Nausea

35 (9.7)

51 (13.6)

Vomiting

22 (6.1)

21 (5.6)

Anorexia

22 (6.1)

14 (3.7)

Constipation

18 (5.0)

13 (3.5)

Bone Pain

34 (9.4)

28 (7.5)

Arthralgia

29 (8.0)

29 (7.8)

Musculoskeletal Pain

20 (5.5)

12 (3.2)

Cough

19 (5.3)

20 (5.3)

Dyspnea

16 (4.4)

19 (5.1)

Body as a Whole

Vascular System Hot Flash Digestive System

Musculoskeletal System

Respiratory System

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms.

Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis.

Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2).

Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.

Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5% Body System FASLODEX 250 mg Anastrozole 1 mg N=423 N=423 and Adverse Reactiona (%) (%) Body as a Whole Asthenia Pain Headache Back Pain Abdominal Pain Injection Site Painb Pelvic Pain Chest Pain Flu Syndrome Fever Accidental Injury Cardiovascular System Vasodilatation Digestive System Nausea Vomiting Constipation Diarrhea Anorexia Hemic and Lymphatic Systems Anemia

68.3 22.7 18.9 15.4 14.4 11.8 10.9 9.9 7.1 7.1 6.4 4.5 30.3 17.7 51.5 26.0 13.0 12.5 12.3 9.0 13.7 4.5

67.6 27.0 20.3 16.8 13.2 11.6 6.6 9.0 5.0 6.4 6.4 5.7 27.9 17.3 48.0 25.3 11.8 10.6 12.8 10.9 13.5 5.0

—continued

of all cigarettes smoked globally— profits have reached $44.1 billion, or around $7,000 for every tobacco-related death.

Tobacco use costs the global economy over $1 trillion, according to The ­Atlas. Low- and middle-income councontinued on page 22

The ASCO Post | APRIL 10, 2015

PAGE 22

Announcements Tobacco Atlas continued from page 21

tries represent over 80% of tobacco users and tobacco-related deaths.

Without change, governments around the world will miss targets to improve health and opportunities to reduce the harm of tobacco.

The Atlas authors conclude that

bolder, faster action is needed to reduce tobacco use.

Tobacco Industry Urged to ‘Tell the Truth’ “Whether it’s the link between Trim: 8.5 x 11" tobacco and increasing rates of lung cancer among women, or the everincreasing number of health condi-

tions and deaths related to tobacco use, the health and economic case for reducing tobacco use has never been clearer,” said John R. Seffrin, PhD, Chief Executive Officer of the American Cancer Society. “We encourage public health advocates, governments, economists, educators, and the media to tell people the truth—how a co-

FASLODEX® (fulvestrant) Injection Body System and Adverse Reactiona

FASLODEX 250 mg N=423 (%) Metabolic and Nutritional Disorders 18.2 Peripheral Edema 9.0 Musculoskeletal System 25.5 Bone Pain 15.8 Arthritis 2.8 Nervous System 34.3 Dizziness 6.9 Insomnia 6.9 Paresthesia 6.4 Depression 5.7 Anxiety 5.0 Respiratory System 38.5 Pharyngitis 16.1 Dyspnea 14.9 Cough Increased 10.4 Skin and Appendages 22.2 Rash 7.3 Sweating 5.0 Urogenital System 18.2 Urinary Tract Infection 6.1

Anastrozole 1 mg N=423 (%) 17.7 10.2 27.9 13.7 6.1 33.8 6.6 8.5 7.6 6.9 3.8 33.6 11.6 12.3 10.4 23.4 8.0 5.2 14.9 3.5

a A patient may have more than one adverse reaction. b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American Study 2 received placebo injections.

Post-Marketing Experience

For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria.

Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered.

Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONS

There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics.

Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed.

Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.

Geriatric Use

For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.

Hepatic Impairment

FASLODEX is metabolized primarily in the liver.

The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (ChildPugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (ChildPugh class B) [see Dosage and Administration and Warnings and Precautions].

Renal Impairment

Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.

OVERDOSAGE

Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

Pediatric Use

A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCuneAlbright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8).

The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.

Whether it’s the link between tobacco and increasing rates of lung cancer among women, or the ever-increasing number of health conditions and deaths related to tobacco use, the health and economic case for reducing tobacco use has never been clearer.

—John R. Seffrin, PhD

hesive, well-funded tobacco industry is systematically causing preventable deaths, destroying the environment, and crippling economies—all for its own profit. These truths will help us create support for the change so bitterly opposed by the tobacco i­ ndustry.”

“There is a perception that we know everything about tobacco and the harm it causes, but the truth is that every edition of The Tobacco Atlas reveals something new about the industry, its tactics, and the real harm it causes,” said Peter Baldini, Chief Executive Officer of the World Lung Foundation.

He continued, “Our challenge, as a global community interested in health and development, is to raise awareness, to bring new voices to the table, to encourage governments to implement comprehensive tobacco control measures as quickly as possible, and to help them stand firm against industry threats and interference. Our fervent hope is that the next Atlas will report the fruits of such a strategy.” n

More on Smoking Cessation

Nursing Mothers

It is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FASLODEX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

2

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.

Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known.

Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died.

Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.

In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.

SafetyGlide™ is a trademark of Becton Dickinson and Company.

FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2355400 2/13

For more on tobacco, smoking cessation, and cancer, see page 82 in this issue of The ASCO Post for an in-depth interview with American Cancer Society CEO John R. Seffrin, PhD.

ASCOPost.com | APRIL 10, 2015

PAGE 23

Journal Spotlight Thoracic Oncology

No Benefit of High- vs Standard-Dose Radiotherapy or Addition of Cetuximab to Chemoradiation in Stage IIIA/IIIB NSCLC

By Matthew Stenger

A

s reported in The Lancet Oncology by Jeffrey D. Bradley, MD, of Washington University, and colleagues, the phase III Radiation Therapy Oncology Group 0617 trial showed no survival benefit of high- vs standard-dose

to 66% had stage IIIA disease. Overall, 41% to 47% had epidermal growth factor receptor (EGFR) H-score available (see sidebar, “Calculating H-Score”); of them, 46% to 52% had high EGFR expression (H-score ≥ 200).

No Improvement in Survival

Jeffrey D. Bradley, MD

radiotherapy or addition of cetuximab (Erbitux) to concurrent pacli­ taxel/ carboplatin chemoradiation in patients with inoperable stage IIIA or IIIB non–small cell lung cancer (NSCLC).1 Higher-dose radiation therapy was associated with poorer survival.

Study Details In the open-label 2×2 factorial trial, patients from the United States and Canada were randomly assigned 1:1:1:1 between November 2007 and November 2011 to receive 60-Gy radiotherapy (n = 166), 74-Gy radiotherapy (n = 121), 60-Gy radiotherapy and cetuximab (n = 147), or 74-Gy radiotherapy and cetuximab (n = 110), with all patients receiving concurrent once-weekly chemotherapy with paclitaxel at 45 mg/m2 and carboplatin at area under the curve (AUC) 2.

Two weeks after chemoradiation, patients received two cycles of consolidation paclitaxel at 200 mg/m2 and carboplatin at AUC 6 separated by 3 weeks. Radiation was given in 2-Gy daily fractions with either intensity-modulated or three-dimensional conformal radiation therapy. Cetuximab was given at 400 mg/m2 on day 1 followed by 250 mg/m2 weekly continued through consolidation therapy. The primary endpoint was overall survival.

Patients had a median age of 64 years, and most were male (55%–64%), white (82%–89%), had Zubrod performance status of 0 (55%–59%), and were current smokers (43%–51%); 47% to 54% received three-dimensional conformal radiotherapy, 89% to 91% underwent positron-emission tomography (PET) staging, 42% to 47% had squamous histology and 34% to 42% had adenocarcinoma, and 63%

Median follow-up for the radiotherapy comparison was 22.9 months. Median overall survival was 20.3 months (95% confidence interval [CI] = 17.7– 25.0 months) in the high-dose group vs 28.7 months (95% CI = 24.1–36.9 months) in the standard-dose group (hazard ratio [HR] = 1.38, P = .004).

Median follow-up for the cetuximab comparison was 21.3 months. Median overall survival was 25.0 months (95% CI = 20.2–30.5 months) in the cetuximab group vs 24.0 months (95% CI = 19.8– 28.6 months) in the no cetuximab group (HR = 1.07, P = .29).

Both the radiation and cetuximab comparisons crossed prespecified futility boundaries.

In a planned retrospective analysis, median overall survival was 19.5 months with cetuximab vs 29.6 months without cetuximab in patients with EGFR Hscore < 200 (P = .056) and 42.0 months vs 21.2 months among those with high EGFR expression (P = .032).

Median progression-free survival was 9.8 months in the 74-Gy group vs 11.8 months in the 60-Gy group (P = .12) and 10.8 months in the cetuximab group vs 10.7 months in the no-cetuximab group (P = .89). Two-year local failure rates were 38.6% with 74 Gy vs 30.7% with 60 Gy (P = .13) and 38.2% with cetuximab vs 30.7% without cetuximab (P = .20). Two-year distant metastasis rates were 51.0% with 74 Gy vs 46.6% with 60 Gy (P = .48) and 52.6% with cetuximab vs 42.0% without cetuximab (P = .09).

Toxicity There was no significant difference in the frequency of grade ≥ 3 adverse events between the 74-Gy group and the 60-Gy group (79% vs 76%), but severe esophagitis was more common with high-dose radiotherapy (21% vs 7%, P < .0001). Cetuximab was associated with an increased frequency of grade ≥ 3 adverse events vs no cetuximab (86% vs 70%, P < .0001). Grade ≥ 3 pulmonary events occurred in 19% of the 74-Gy group vs 20% of the 60-Gy

Treating Stage III Lung Cancer ■■ High-dose radiotherapy was associated with worse overall survival vs standard-dose radiotherapy.

■■ The addition of cetuximab to paclitaxel-carboplatin did not improve survival for the entire group, but there was a suggestion of benefit in those with high EGFR expression.

group, and grade ≥ 3 radiation pneumonitis occurred in 4% vs 7%. There were more treatment-related deaths with high-dose vs standard-dose radiotherapy (8 vs 3 patients) and with vs without cetuximab (10 vs 5 patients).

The investigators noted that the median overall survival achieved with standarddose radiotherapy and weekly concurrent followed by consolidation paclitaxel/ carboplatin was higher than expected and appeared to constitute a new benchmark with chemoradiation in this setting. However, they also noted that the use of staging PET in the majority of patients may have resulted in stage migration that contributed to the better-than-expected outcomes.

They concluded: “74-Gy radiation given in 2-Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially

harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for [the entire group, but there was a suggestion of benefit in those with high EGFR expression].” n

Disclosure: The study was funded by the National Cancer Institute and Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Bradley JD, Paulus R, Komaki R, et al: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial phase 3 study. Lancet Oncol 16:187-199, 2015.

See commentary by Laurie E. Gaspar, MD, FASTRO, FACR, MBA, on page 26.

Calculating H-Score

I

mmunohistochemistry results can be further evaluated by a semiquantitative approach used to assign an H-score (or “histo” score) to tumor samples.1,2 First, membrane staining intensity (0, 1+, 2+, or 3+) is determined for each cell in a fixed field. The H-score may simply be based on a predominant staining intensity, or more complexly, can include the sum of individual Hscores for each intensity level seen. By one method, the percentage of cells at each staining intensity level is calculated, and finally, an H-score is assigned using the following formula: [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)] The final score, ranging from 0 to 300, gives more relative weight to higher-intensity membrane staining in a given tumor sample. The sample can then be considered positive or negative on the basis of a specific discriminatory threshold. n References 1. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Epidermal growth factor receptor in non-small-cell lung carcinomas: Correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798-3807, 2003.

2. John T, Liu G, Tsao M-S: Overview of molecular testing in non-small-cell lung cancer: Mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors. Oncogene 28:S14-S23, 2009.

The ASCO Post | APRIL 10, 2015

PAGE 24

FDA Update

FDA Approves First Biosimilar Product Filgrastim-Sndz

T

he U.S. Food and Drug Administration (FDA) has approved filgrastim-sndz (Zarxio), the first biosimilar product approved in the United States.

A biosimilar product is a biologic product that is approved based on a showing that it is highly similar to an already-approved biologic. The biosimilar also must show it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.

Sandoz, Inc’s filgrastim-sndz is biosimilar to Amgen Inc’s filgrastim (­ Neupogen), which was originally licensed in 1991.

Filgrastim-sndz is approved for the same indications as filgrastim and can be prescribed by a health-care professional for

administration, dosage form(s), and strength(s) as the reference product and only for the indication(s) and condition(s) of use that have been approved for the reference product.

The FDA’s approval of filgrastimsndz is based on review of evidence

that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, and other clinical safety and effectiveness data that demonstrate filgrastim-sndz is biosimilar to filgrastim. Filgrastim-sndz has been approved

as biosimilar, not as an interchangeable product. (Under the BPCI Act, a biologic that that has been approved as an “interchangeable” may be substituted for the reference product without the intervention of the health-care provider who prescribed the reference product.) n

patients with cancer receiving myelosuppressive chemotherapy, patients with acute myeloid leukemia receiving induction or consolidation chemotherapy, patients with cancer undergoing bone marrow transplantation, patients undergoing autologous peripheral blood progenitor cell collection and therapy, and patients with severe chronic ­neutropenia.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner M ­ argaret A. Hamburg, MD. “Patients and the health-care community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality ­standards.”

The BPCI Act The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act, which President Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biologic products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biologic product, called the “reference product.” This abbreviated licensure pathway permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product and enables a biosimilar biologic product to be licensed based on less than a full complement of product-specific data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of

© 2014 Genentech USA, Inc. All rights reserved. COB/092414/0002 Printed in USA.

ASCOPost.com | APRIL 10, 2015

PAGE 25

FDA Update

FDA Approves Nivolumab to Treat Metastatic Squamous NSCLC

T

he U.S. Food and Drug Administration (FDA) has approved the PD-1 inhibitor nivolumab (Opdivo) for the treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC) who have progressed on or after platinum-based chemo-

therapy. Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PDL1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response.

Improved Overall Survival The approval was based on the results of an open-label, multicenter, multinational randomized trial of 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum-

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

based chemotherapy regimen. Patients received nivolumab (n = 135) 3 mg/kg intravenously every 2 weeks or docetaxel (n = 137) 75 mg/m2 intravenously every 3 weeks. The primary endpoint of the trial was overall survival.

Nivolumab demonstrated a statistically significant improvement in overall survival as compared with docetaxel at the protocol-prespecified interim analysis. Median overall survival was 9.2 months (95% confidence interval [CI] = 7.3–13.3) for patients receiving nivolumab and 6 months (95% CI = 5.1–7.3) for those receiving docetaxel (hazard ratio = 0.59, 95% CI = 0.44–0.79, P = .00025).

Approval was supported by a singlearm, multinational, multicenter trial in patients with metastatic squamous NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic regimen. Patients (n = 117) received nivolumab 3 mg/kg intravenously every 2 weeks. The major efficacy outcome measure was confirmed objective response rate measured by an independent review committee using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The overall response rate was 15% (95% CI = 9%–22%), and all were partial responses. At the time of analysis, 10 of the 17 responding patients (59%) had response durations of 6 months or longer.

Side Effects The most common side effects of nivolumab are fatigue, shortness of breath, musculoskeletal pain, decreased appetite, cough, nausea and, constipation. The most serious side effects are severe immunemediated side effects involving healthy organs, including the lungs, colon, liver, kidneys, and hormone-producing glands.

Nivolumab for squamous NSCLC was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness in the treatment of a serious condition. The drug is being approved more than 3 months ahead of the prescription drug user fee goal date of June 22, 2015.

The FDA previously approved nivolumab to treat patients with unresectable or metastatic melanoma who no longer respond to other drugs. n

The ASCO Post | APRIL 10, 2015

PAGE 26

Perspective Thoracic Oncology Continued from page 23

Results of RTOG 0617 Reconsidered

By Laurie E. Gaspar, MD, FASTRO, FACR, MBA

R

adiation Therapy Oncology Group (RTOG) 0617 was a study initially designed to address an important issue in radiation oncology regarding the treatment of stage III non–small cell lung cancer (NSCLC): Are outcomes improved with highdose as opposed to standard-dose thoracic radiation therapy? The additional study objective, testing the possible benefit of cetuximab (­ Erbitux), followed encouraging results seen in a prior RTOG phase II study.1 Findings in RTOG 0617 were recently reported

by Bradley and colleagues2 and are reviewed in this issue of The ASCO Post.

The study was closed regarding

• Fewer patients on the high-dose arm completed consolidation chemotherapy.

• High-dose radiation given over 7.5 weeks allowed tumor repopulation to occur.

• Concern regarding treatment toxicity in the high-dose setting may have prompted inappropriately tight radiation fields.

• Higher-dose radiation was associated with a higher heart dose.

• Attributions of cause of death were inaccurate. For example, could higher heart doses have led to undetected treatment-related cardiac deaths?

Further analysis of RTOG 0617

Given the suboptimal rates of local tumor control and survival following standard-dose radiation therapy, the radiation community was surprised and disappointed to learn of the poorer survival outcome associated with higher-dose radiation.

—Laurie E. Gaspar, MD, FASTRO, FACR, MBA

the question of high-dose (74 Gy) vs standard-dose (60 Gy) when the first interim analysis demonstrated that the study had crossed the boundaries for futility. However, the study continued as a two-arm study, with randomization to cetuximab or no cetuximab, with all patients receiving 60 Gy.

Surprising Findings Given the suboptimal rates of local tumor control and survival following standard-dose radiation therapy, the radiation community was surprised and disappointed to learn of the poorer survival outcome associated with higherdose radiation. So far, it appears that the poorer survival following high-dose radiation therapy is related to tumor recurrence/progression as opposed to treatment toxicity. Since the study results are somewhat counterintuitive, Bradley et al put forward several hypotheses to account for this poorer outcome: Dr. Gaspar is Professor in the Department of Radiation Oncology at the University of Colorado School of Medicine in Aurora, Colorado.

regarding the effect of heart dose on treatment outcome will be forthcoming. Although heart dose was an independent negative predictor of survival, it does not yet fully account for the poor results seen in the high-dose arm.

Nevertheless, radiation oncologists need to look more critically at their radiation plans in terms of heart dose.

Debate Over Radiation Dose Continues The authors concluded that the high dose of 74 Gy was “potentially harmful.” However, the findings should discourage prescription of doses higher than the standard 60 Gy outside of a study protocol. Pending the results of RTOG 0617, many radiation oncologists have been prescribing doses in the range of 64 to 66 Gy. This study cannot determine whether such doses are better or worse than 60 Gy, but these intermediate doses are now more difficult to rationalize. And, despite the results of RTOG 0617, the radiation dose issue will continue to be controversial.

An important ongoing study is

RTOG 1106/ACRIN 6697, a randomized phase II study comparing standard 60 Gy of radiation therapy with highdose radiation therapy using adaptive (shrinking) radiation therapy techniques. Patients on the high-dose arm will receive up to 80 Gy in 6 weeks, or a dose delivering a mean lung dose of 20 Gy or less. The study will determine the feasibility, treatment toxicity, and survival associated with high-dose radiation therapy using adaptive radiation fields. The high doses are delivered only to tumor sites that remain fluorodeoxyglucose positron emission tomography (FDG-PET)–positive following the initial 4 weeks of concurrent chemoradiotherapy.

Role of Cetuximab The other issue addressed in RTOG 0617 was the role of cetuximab in the treatment of stage III NSCLC. RTOG 0617 was initiated at a time when it was not standard of care to perform molecular analysis on tumor specimens in such patients. Epidermal growth factor receptor (EGFR) mutation analysis was not necessary for trial entry, and tissue was available for subsequent EGFR Hscore testing (see sidebar on page 23) in less than 50% of accrued patients.

No survival difference was seen in the whole study set when comparing the cetuximab and no-cetuximab arms. This is disappointing given the improvement in survival outcome observed in an unselected population (regarding EGFR status) of patients with squamous cell cancer of the head and neck.3 Bradley et al reported no difference in survival outcomes according to H-score. However, a planned subset analysis determined that for patients with an H-score greater than 200, cetuximab was associated with statistically significant longer overall survival. The authors of RTOG 0617 caution against using cetuximab outside of the protocol setting.

‘Positive’ Outcomes and Beyond The “positive” outcomes of RTOG 0617 should not be ignored. The median survival of 28.7 months in the 60Gy study arms is excellent when compared with prior cooperative group studies in stage III NSCLC. The use of PET scans in approximately 90% of

enrolled patients may account somewhat for this good survival.

RTOG 0617 also supports the benefit of intensity-modulated radiation therapy in the treatment of lung cancer. Although critics have pointed to the high financial cost associated with intensity-modulated radiation therapy, a plenary session presented at the 2013 American Society for Radiation Oncology (ASTRO) Annual Meeting by Movsas et al4 reported the improved quality of life experienced by patients on RTOG 0617 at 3 and 12 months following intensity-modulated radiation therapy as opposed to three-dimensional computed tomography planning. Intensity-modulated radiation therapy is often helpful in reducing the heart dose.

The possible benefit of cetuximab in patients with high H-scores is also intriguing. It should prompt enthusiastic support of RTOG 1306, in which patients with EGFR tyrosine kinase mutations or EML4-ALK fusion arrangements are treated with neoadjuvant erlotinib or crizotinib (Xalkori), respectively. RTOG 0617 and ongoing RTOG studies underscore the goal of defining the best treatment for individual patients. n Disclosure: Dr. Gaspar reported no potential conflicts of interest.

References 1. Blumenschein GR Jr, Paulus R, Curran WJ, et al: Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 29:2312-2318, 2011.

2. Bradley JD, Paulus R, Komaki R, et al: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617). Lancet Oncol 16:187-199, 2015.

3. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006.

4. Movsas B, Hu C, Sloan J, et al: Quality of life analysis of the randomized radiation dose escalation NSCLC trial (RTOG 0617): The rest of the story. 2013 American Society for Radiation Oncology Annual Meeting. Plenary Session. Presented September 23, 2013.

Take a bite out of G-CSF acquisition costs Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration

Indication » GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40582 January 2015.

The ASCO Post | APRIL 10, 2015

PAGE 28

Announcements

James P. Allison, PhD, Wins 2015 Paul Ehrlich and Ludwig Darmstaedter Prize

J

ames P. Allison, PhD, Chair of Immunology at The University of Texas MD Anderson Cancer Center, has received the 2015 Paul Ehrlich and Ludwig Darmstaedter Prize in recognition of his work in the field of immunotherapy.

“In immunotherapy, it’s not the tu-

mor but the immune system that is targeted. This marks a new therapeutic principle in oncology,” wrote the Scientific Council of the Paul Ehrlich Foundation, explaining its decision to honor Dr. Allison with the prestigious international prize.

Dr. Allison also is Executive Director of MD Anderson’s immunotherapy platform, which supports immunotherapy research across multiple cancer types.

“This award is special to me because it’s named for Paul Ehrlich, the GerJames P. Allison, PhD

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian.

In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.

Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.

This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

man scientist who was first to suggest immune system surveillance of cancer more than 100 years ago,” Dr. Allison said. “It’s also wonderful recognition of the progress that immunotherapy is making against cancer.”

Immune Checkpoint Blockade Dr. Allison pioneered a new way to treat cancer by blocking molecules on immune system T cells, which act as a brake on immune response. The treatment, called immune checkpoint blockade, grew out of his basic science research into the biology of T cells, the immune system’s customized attack cells. He developed an antibody to block CTLA-4, a checkpoint molecule on T cells, unleashing an immune attack on tumors. The resulting drug, ipilimumab (Yervoy), has extinguished untreatable late-stage melanoma in 22% of patients for at least 10 years.

The U.S. Food and Drug Administration approved the drug for metastatic melanoma in 2011. Since then, ipilimumab and new drugs that impede other checkpoints have been applied to other solid tumor cancers, including lung, bladder, and kidney cancers.

He shares the 2015 prize with Carl June, MD, of the University of Pennsylvania, who pioneered an approach that customizes a patient’s T cells to attack leukemia.

Other Roles Dr. Allison is also Deputy Director of the David H. Koch Center for Applied Research of Genitourinary Cancers and holds the Vivian L. Smith Distinguished Chair in Immunology at MD Anderson. He is a member of the National Academy of Sciences and the Institute of Medicine.

Dr. Allison launched his research in T-cell biology during his first stay at MD Anderson, making seminal findings in the early 1980s before moving to the University of California, where his research led to the development of ipilimumab. He then moved to Memorial Sloan Kettering Cancer Center before returning to MD Anderson in 2012. n

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Clinical Perspective Breast Cancer

Breast Cancer Management in Review Part 1. Genetics and Adjuvant Therapy

By Jame Abraham, MD, FACP

A

nyone who has attended the major oncology meetings knows that research from clinical trials in breast cancer often dominates the stage, with countless abstracts featuring new and updated results. To help the readers of The ASCO Post stay up to date with the latest discoveries and findings impacting the treatment of women with breast cancer, I have assembled highlights from a collection of newsworthy studies featured over the past year and into early 2015.

Presented here is Part 1 of this review, which centers on genetics and adjuvant therapy for several different receptor types of breast cancer. Part 2, which will appear in an upcoming issue of The ASCO Post, will focus on new therapeutic options for metastatic disease (such as palbociclib [Ibrance] and pictilisib) as well as several survivorship issues (such as fertility preservation, diet, and exercise).

Mutations in PALB2 In a study by Antoniou and colleagues,1 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2— the “partner and localizer of BRCA2,” whose protein product works with and stabilizes the BRCA2 protein—were assessed to determine the cumulative risk of breast cancer. Germline lossof-function mutations in this gene are known to confer a predisposition to breast cancer. The investigators used a modified segregation-analysis approach to estimate the age-specific breast cancer risk for carriers of PALB2 mutations.

Key Findings: Compared with the general population, the risk of breast cancer for female PALB2 mutation carriers was eight to nine times higher among those younger than age 40, six to eight times higher among those between the ages of 40 and 60, and five times higher among those older than age 60. The absolute breast cancer risk was 33% (95% confidence interval [CI] = 25%–44%) for these PALB2 mutation carriers by age 70 with no family history of breast cancer and 58% (95% CI = 50%–66%) for those with two or Dr. Abraham is Director of Breast Medical Oncology at Taussig Cancer Institute and Co-Director of the Comprehensive Breast Cancer Program at the Cleveland Clinic, Cleveland, Ohio.

more first-degree relatives with breast cancer at 50 years of age.

The investigators think their data suggest that the breast cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.

In addition, PALB2 is identified as the second most important susceptibility gene for familial pancreatic cancer, right after BRCA2.

Clinical Perspective: BRCA1 and BRCA2 are well studied, and the related risk of breast and ovarian cancers is well established. In the clinic, however, we see many patients who have a strong family history of early breast and ovarian cancers but are negative for the BRCA mutation. Identification of more genes such as PALB2 will help us to treat these patients better and craft risk-reduction strategies. Genetic evaluation, counseling, testing, and preventive approaches will continue to evolve as data accumulate on these mutations.

Adjuvant Therapy: Focus on Treatments

by Receptor Status Highlighted here are the SWOG S0221 study on high-risk, early-stage breast cancer; two related studies (the TEXT and SOFT trials) on hormone receptor–positive breast cancer; and two studies on HER2-positive breast cancer.

SWOG S0221 In the phase III SWOG S0221 study, Budd and colleagues attempted to determine the optimal dose and

Based on the SOFT and TEXT trial results, it is important to discuss ovarian suppression in addition to endocrine therapy with estrogen receptor–positive, high-risk premenopausal patients.

—Jame Abraham, MD, FACP

schedule combining anthracycline and taxane administration in the adjuvant treatment of 3,250 women with early-stage node-positive or high-risk node-negative breast cancer.2 The four comparison regimens included a continuous schedule of doxorubicin-cyclophosphamide, six cycles of doxorubicin-cyclophosphamide once every 2 weeks, paclitaxel once a week, and six cycles of paclitaxel once every 2 weeks.

Key Findings: Patients achieved a similar disease-free survival on any of the regimens studied, with interim analyses crossing the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-week regimens. However, according to a subset analysis, once-every-2-week dosing may be best for women with triple-negative breast tumors (estrogen receptor– negative, hormone receptor–negative, and HER2-negative).

Clinical Perspective: The updated results of ECOG 1199 confirmed that weekly paclitaxel is superior to every3-week paclitaxel.3 In that particular study, a dose-dense regimen was not

Clinical Trials in Breast Cancer ■■ Compared with the general population, the risk of breast cancer was higher across all age groups in women with mutations in PALB2, the partner and localizer of BRCA2.

■■ Disease-free survival was similar with once weekly vs once-every-2-week regimens of anthracycline and taxane for women with early-stage breast cancer, although once-every-2-week dosing may be more effective in triplenegative breast cancer.

■■ Ovarian suppression and endocrine therapy reduced tumor recurrence in high-risk premenopausal women with estrogen receptor–positive, earlystage breast cancer.

■■ Treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early tumor recurrence of about 2% in women with stage I HER2positive breast cancer.

■■ Adding trastuzumab to chemotherapy led to a 37% relative improvement in overall survival in women with early-stage HER2-positive breast cancer, with low long-term cardiac toxicity.

tested. SWOG S0221 is the only study to compare weekly paclitaxel with every-2-week treatment and suggests that either regimen is acceptable for estrogen receptor–positive patients but that every-2-week treatment may be better for triple-negative disease.

TEXT and SOFT Trials The TEXT and SOFT trials focused on the use of adjuvant ovarian suppression in combination with an aromatase inhibitor4 or tamoxifen5 in the treatment of premenopausal women with hormone receptor–positive breast cancer. In the two phase III studies, the investigators compared the use of the aromatase inhibitor exemestane plus ovarian suppression with tamoxifen plus ovarian suppression for 5 years. The gonadotropinreleasing hormone agonist triptorelin (Trelstar), oophorectomy, or ovarian irradiation was used to achieve suppression of ovarian estrogen production. Combined data from 4,690 patients in the two trials were included in the primary analysis.

Key Findings: Adjuvant treatment with exemestane plus ovarian suppression significantly reduced tumor recurrence over tamoxifen plus ovarian suppression. The disease-free survival at 5 years was 91% in the group that received the aromatase inhibitor and 87% in the group that received tamoxifen (hazard ratio [HR] for disease recurrence, second invasive cancer, or death was 0.72, 95% CI = 0.60–0.85, P < .001).

Furthermore, adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. For high-risk women who remained premenopausal, the addition of ovarian suppression improved disease outcomes.

Clinical Perspective: From the Oxcontinued on page 30

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Clinical Perspective Breast Cancer Review continued from page 29

ford overview analysis and other studies, it is well known that ovarian suppression will potentially benefit patients with early-stage breast cancer.

However, we lacked direct evidence in the form of a prospective, randomized trial. Now, with the SOFT and TEXT trial results showing a clear benefit, it is important to consider ovarian suppression in addition to endocrine therapy for estrogen receptor–positive, high-risk premenopausal patients.

followed by paclitaxel with or without trastuzumab.

Key Findings: Adding trastuzumab to chemotherapy led to a 37% relative improvement in overall survival (HR = 0.63, 95% CI = 0.54–0.73, P < .001) as well as an increase in the 10-year overall survival rate from 75% to 84%. In addition to these results, an improve-

ment in disease-free survival of 40% (HR = 0.60, 95% CI = 0.53–0.68, P < .001) was reported. Finally, all patient subgroups benefited from the addition of this targeted anti-HER2 agent.

Clinical Perspective: Two key findings from this long-term follow-up analysis are the continued benefit of trastuzumab beyond 5 years and up

to 10 years as well as the very low rate of long-term cardiac toxicity in the patients who were treated with trastuzumab. n Disclosure: Dr. Abraham reported no potential conflicts of interest.

References 1. Antoniou AC, Casadei S, Heikki-

Adjuvant Paclitaxel and Trastuzumab In a phase II study of more than 400 patients with node-negative, small HER2-positive breast tumors (measuring up to 3 cm in greatest dimension),6 Tolaney and colleagues assessed the weekly treatment of paclitaxel and trastuzumab (Herceptin) for 12 weeks, followed by 9 months of trastuzumab monotherapy. Most of these women were ineligible for the pivotal trials of adjuvant trastuzumab.

Key Findings: The 3-year invasive disease-free survival rate was 98.7% (95% CI = 97.6–99.8), which the investigators considered to be “better than expected” based on the historic data. Of the 12 relapses reported, 2 were the result of distant metastatic breast cancer. The investigators concluded that treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early tumor recurrence of about 2% in women with predominantly stage I HER2-positive breast cancer. However, they noted that 6% of patients withdrew from the study because of protocol-specific adverse events.

Clinical Perspective: For women with small HER2-positive, estrogen receptor–positive tumors, the role or benefit of chemotherapy in addition to HER2 blockade and endocrine therapy has not been clear. This study and regimen clearly offer a less-toxic regimen with trastuzumab, which should change our practice in these low-risk patients.

NSABP B-31 and NCCTG N9831 The joint analysis from NSABP B-31 and NCCTG N9831 focused on the use of trastuzumab along with adjuvant chemotherapy for more than 4,000 women with HER2-positive breast cancer.7 In both trials, women with operable breast tumors received doxorubicin and cyclophosphamide

REFERENCES: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240-2247.

2. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616-1622. 3. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay.

Clin Cancer Res. 2011;17(5):1169-1180. 4. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-792. 5. Pao W, Miller VA,

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Clinical Perspective

nen T, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.

2. Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: A phase III trial comparing chemotherapy schedules in highrisk early-stage breast cancer. J Clin Oncol 33:58-64, 2015.

3. Sparano JA, Zhao F, Martino S, et

al: Ten year update of E1199: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk nodenegative breast cancer. 2014 San Antonio Breast Cancer Symposium. Abstract S303. Presented December 11, 2014.

4. Pagani O, Regan MM, Walley BA,

et al: Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371:107-118, 2014.

5. Francis PA, Regan MM, Fleming GF, et al: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015.

6. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab

for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.

7. Perez EA, Romond EH, Suman VJ, et al: Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32:3744-3752, 2014.

EMPEROR Science Award Program

S

In EGFRm+ NSCLC

It’s time to uncover what comes next T790M resistance mutations emerge in at least 60% of patients and limit your therapeutic options1-3 Nearly all patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy will experience disease progression. And in nearly two-thirds of these patients, the cause of progression is the EGFR resistance mutation T790M.1-5 The emergence of the T790M mutation reduces the effectiveness of currently available EGFR inhibitors.6 T790M mutations may be detected in both tissue and plasma.1-3,7,8 However, currently, there are no approved therapies to address this driver of EGFR TKI resistance when it emerges.

At Clovis Oncology, we’re exploring new approaches in EGFR-mutated non–small cell lung cancer (NSCLC) to address TKI-acquired resistance.

Learn more at T790M.com Clovis Oncology is leading the fight

Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73. doi:10.1371/journal.pmed.0020073.

6. Yun C-H, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105(6):2070-2075. 7. Zheng D, Ye X, Sun Y, et al.

Noninvasive monitoring of dynamics of acquired EGFR-T790M mutation and discovery of its heterogeneity in patients with advanced NSCLC treated with EGFR-TKI. J Clin Oncol. 2014;32(15)(suppl):11049.

8. Taniguchi K, Uchida J, Nishino K, et al. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res. 2011;17(24):7808-7815.

Copyright © 2015 Clovis Oncology. DARO-102(1) 2/15

tand Up To Cancer (SU2C) and PBS LearningMedia announced The ­EMPEROR Science Award Program. This initiative will encourage students from disadvantaged high schools to pursue careers in science, with a particular emphasis on cancer research, through a year of mentorship with a scientist from a leading research institution or industry. The education initiative, announced recently by SU2C Cofounder Katie Couric at Columbia University, is being launched in connection with Ken Burns Presents Cancer: The Emperor of All Maladies, A Film by Barak Goodman, a three-part documentary on the history of cancer that aired recently on PBS. “When we launched this documentary effort in 2013, Siddhartha Mukherjee told us that even with all the exciting developments in cancer research, we will not beat cancer in the long run if we don’t engage new generations of young people to enter the field of science, particularly cancer research,” said SU2C Cofounder Sherry Lansing.

“As we learn in Cancer: The Emperor of All Maladies, our most effective weapons in the war against cancer are bright minds and people who are passionately committed to finding a cure,” said Alicia Levi, Vice President of Education, PBS. “To find the next Sidney Farber or MaryClaire King, we need to make sure that all students have an opportunity to pursue their scientific ambitions.”

Applications will be available in August 2015 for the program on PBS LearningMedia’s website at pbslearningmedia.org. Students may apply for awards themselves, or may be nominated by teachers. The first 100 Awardees, high school students from Title I, or similarly “economically disadvantaged” schools, will be announced in late 2015. The awardees will receive one-on-one science mentoring, as well as $1,500 grants.

The first 300 EMPEROR Science Awards have been fully funded over 3 years, with 100 being donated by ­Genentech, Bristol-Myers Squibb, and Novartis, respectively. n

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In the Clinic Supportive Care

Biosimilar Filgrastim-sndz in Filgrastim Indications

By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n March 6, 2015, the granulocyte colony-stimulating factor filgrastim-sndz (Zarxio) was approved as a biosimilar to U.S.-licensed Neupogen (filgrastim) for the five indications for which filgrastim is approved.1,2 Filgrastim-sndz is the first biosimilar to be approved in the United States. The formulation of filgrastim-sndz differs from that of filgrastim in one inactive component.

The five indications of use consist of (1) to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever; (2) to reduce the time to neutrophil recovery and duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia (AML); (3) to reduce the duration of neutropenia and neutropenia-related clinical sequelae in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation; (4) to mobilize autologous

OF NOTE Filgrastim-sndz is highly similar to filgrastim in structure and clinical function and biologic activity, with minor differences in clinically inactive components.

hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and (5) to reduce the incidence and duration of sequelae of severe neutropenia in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.

Supporting Data Approval was based on demonstration that filgrastim-sndz is highly similar to filgrastim in structure and clinical function and activity, with minor differences in clinically inactive components. Filgrastim-sndz has the same

of 80% to 125%. The 95% confidence interval for area under the effect curve (AUEC) for absolute neutrophil count and maximum absolute neutrophil count after a single dose were within the predefined limits of 80% to 125%, and the 95% confidence interval for AUEC and maximum count for CD34-positive cell counts after multiple doses were within the 80% to 125% limits.

How It Is Given The recommended doses and schedules for filgrastim-sndz given intravenously or subcutaneously are the same as for U.S.-licensed filgrastim in all indi-

First Approved Biosimilar in the United States ■■ Filgrastim-sndz (Zarxio) was approved as a biosimilar to U.S.-licensed filgrastim (Neupogen) for the five indications for which filgrastim is approved. Filgrastim-sndz is the first biosimilar to be approved in the United States.

■■ The recommended doses and schedules for filgrastim-sndz given intravenously or subcutaneously are the same as for U.S.-licensed filgrastim in all indications.

amino acid sequence as filgrastim and similar biologic activity and receptor binding, physicochemical properties such as higher-order structure, product-related substances and impurities, and stability profile.

Four studies evaluated subcutaneous doses of 1 to 10 µg/kg of filgrastimsndz in healthy subjects and compared the pharmacokinetics and pharmacodynamics of filgrastim-sndz with U.S.licensed filgrastim (one study) or European Union–approved filgrastim (three studies). The 90% confidence interval for area under the concentration-time curve (AUC) and maximum concentration of filgrastim-sndz after a single dose were within the predefined limits

cations—ie, in the settings of patients with cancer receiving myelosuppressive chemotherapy or induction and/or consolidation chemotherapy for AML, patients with cancer undergoing bone marrow transplantation, patients undergoing autologous peripheral blood progenitor cell collection and therapy, and patients with congenital, cyclic, or idiopathic neutropenia.

OF NOTE Filgrastim-sndz carries warnings/precautions for fatal splenic rupture, acute respiratory distress syndrome, serious allergic reactions (including anaphylaxis), and fatal sickle cell crises.

Filgrastim-sndz carries warnings/ precautions for fatal splenic rupture, acute respiratory distress syndrome, serious allergic reactions (including anaphylaxis), and fatal sickle cell crises. Filgrastim-sndz is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products. n References 1. U.S. Food and Drug Administration: Filgrastim-sndz. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm436953.htm. Accessed March 23, 2015.

2. Zarxio (filgrastim-sndz) injection prescribing information, Sandoz Inc, March 2015. Available at www.accessdata.fda.gov/ drugsatfda_docs/label/2015/125553lbl. pdf. Accessed March 23, 2015.

Safety Profile Safety data for filgrastim-sndz were evaluated in 204 healthy subjects and 214 patients with breast cancer. The safety profile was similar to that of the U.S.-licensed or European Union–approved filgrastim.

The ASCO Post Like us on Facebook facebook.com/TheASCOPost

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).

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Journal Spotlight Breast Cancer

Immune Gene Profile continued from page 1

to relapse-free survival, and the final gene signature was built using a voting scheme.

Immune Function Genes In pathway analyses, integrin signaling, Alzheimer disease-presenilin pathway, and G to M cell-cycle transition pathways were the most significant pathways associated with reduced relapse-free survival among patients receiving trastuzumab. The most significant pathways associated with increased relapse-free survival in these patients were cytokine-cytokine receptor interaction, T-cell–receptor signaling in CD8-positive T cells, interferon gamma pathway, tumor necrosis factor– receptor signaling pathway, cell-surface interaction at the vascular endothelium, and class I PI3K signaling events. The fact that four of six significant pathways are involved in immunologic functions strongly suggested an association between immune response and increased relapse-free survival with trastuzumab in HER2-positive disease.

Similarly, 10 of 13 Gene Ontology biologic process terms for genes with a significant hazard ratio for relapsefree survival that were enriched among trastuzumab patients were for immune functions, including T-cell and B-cell responses, chemokine signaling and

chemotaxis, and inflammation. Among 87 immune function genes defined by the 10 immune function Gene Ontology terms, 14 exhibiting a significant probe by treatment group interaction were included in the final profile (AFAP1L2, AMICA1, CCL21, CCR4, CD1E, CD40LG, CXCL12, FYN, HLA-DOB, IGFBP4, IRF8, PTGDR, ­PTGER4, and TLR10).

Relapse-Free Survival A model was developed that defined immune gene enrichment based on expression of any 9 or more of the 14 im-

enriched tumors (HR = 0.89, 95% CI = 0.62–1.28, P = .53).

On multivariate analysis, which showed a significant interaction of immune-enrichment status and treatment group (P < .001), relapse-free survival was significantly prolonged for trastuzumab patients with enriched tumors vs chemotherapy patients with enriched tumors (HR = 0.36, 95% CI = 0.23–0.56, P < .001). There was no difference observed between trastuzumab patients and chemotherapy patients with nonenriched tumors (HR = 0.98, 95% CI = 0.68–1.41, P = .91).

Immune Function Genes in HER2-Positive Breast Cancer ■■ Trastuzumab patients with tumors enriched for immune function genes had significantly better relapse-free survival than chemotherapy patients with enriched tumors.

■■ No difference was observed between trastuzumab patients and chemotherapy patients with nonenriched tumors.

mune function genes at or above the 0.40 quantile for the population. Compared with patients with enriched tumors in the chemotherapy group, relapse-free survival was significantly prolonged among trastuzumab patients with enriched tumors (HR = 0.35, 95% confidence interval [CI] = 0.22–0.55, P < .001) but not among chemotherapy patients with nonenriched tumors (HR = 0.9, 95% CI = 0.6–1.37, P = .64) or trastuzumab patients with non-

“Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzu­mab,” concluded the investigators.

They observed: “The potential clinical significance of our results, within the context of identification of patients who are likely to benefit (increased [relapsefree survival]) from adjuvant trastuzumab, is considerable. Identification of

patients who are unlikely to benefit from trastuzumab on the basis of evaluation of the immune status of the tumor before initiation of therapy may have even greater significance. Patients with low immune function gene expression scores might be enrolled onto trials to test the efficacy of HER2-targeted regimens that combine trastuzumab with some other therapeutic agent. Alternatively, these patients might be the focus of future clinical trials designed to evaluate therapeutic approaches that might enhance the immune activity within HER2-positive tumors and thereby sensitize the tumors to biologic therapies.”

One strategy in this regard cited by the investigators is the inhibition of immunosuppressive signaling pathways—eg, with agents targeting PD-1 (programmed cell death protein 1) or its ligand PD-L1. Another strategy is to increase immunoreactivity via modification of the immunoglobulin backbone of anti-HER2 antibodies. n

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

Reference 1. Perez EA, Thompson EA, Ballman KV, et al: Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. J Clin Oncol 33:701708, 2015.

Understanding the Role of Immune Function in the Treatment of HER2-Positive Breast Cancer

By Randy F. Sweis, MD, and Olufunmilayo I. Olopade, MD

T

he addition of trastuzumab (Herceptin) to adjuvant chemotherapy undoubtedly transformed HER2positive breast cancer from one of the most deadly subtypes to a highly treatable disease. Randomized phase III trials established adjuvant trastuzumab as standard of care in HER2-positive breast cancer.1,2 Despite the resounding success of targeting HER2 in breast cancer, a small fraction of patients still suffer from tumor recurrence. Thus, it is critical to better understand the biology driving resistance and develop predictive biomarkers to identify patients unlikely to respond to HER2targeted therapy.

In their recently reported study, Dr. Sweis is a hematology/oncology fellow at the University of Chicago. Dr. Olopade is Director of the Center for Clinical Cancer Genetics, University of Chicago Medicine.

reviewed in this issue of The ASCO Post, Perez and colleagues identified a subset of immune genes that are linked with improved relapse-free survival for patients treated with trastuzumab.3 The data presented in this study have several important translational implications as well as some important limitations.

Mechanism of Action and Tumor Immunity Extensive preclinical and clinical research has been aimed at defining the precise mechanism of action of trastuzumab. Early in clinical development, it was thought that inhibition of HER2 signaling and downregulation of the receptor was the primary driver of clinical activity. However, subsequent evidence suggests that efficacy also critically depends on activation of immune-mediated tumor destruction.4 Both innate and adaptive im-

mune pathways have emerged as potential mechanisms of action.

The findings in this study build on the notion that trastuzumab efficacy depends on the presence of a basal immune activity within the tumor. Enrichment in immune function genes may represent a marker of localized immune competency, facilitating antibody-­ dependent cellular cytotoxicity as well as adaptive immunity with trastuzumab therapy.

pathways that lead to a blunted immune response and target them with other agents? Can immune checkpoint inhibitors overcome this resistance?

These are questions that cannot be answered without a deeper biologic understanding of the subset of tumors without immune gene enrichment.

Correlation of gene-expression patterns with the presence of tumor-associated immune cells may be a critical starting point.

Questions About Resistance

Tumor-Infiltrating Lymphocytes

In this study, patients without enrichment in immune gene expression appeared to have no benefit from the addition of trastuzumab to chemotherapy, with a hazard ratio for relapsefree survival of 0.98 (95% confidence interval = 0.68–1.41, P = .98). What is responsible for this interpatient heterogeneity? Can we identify molecular

The findings in this study highlight a growing breadth of evidence that efficacy of cancer therapy is dependent on immune response. Histologically, the presence of tumor-infiltrating lymphocytes has emerged as a prognostic and predictive biomarker continued on page 34

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Perspective

Drs. Sweis and Olopade continued from page 33

across several malignancies.5 At the 2014 San Antonio Breast Cancer Symposium, the authors presented data from the same N9831 study showing that the benefit of trastuzumab appeared isolated to those patients lacking tumor-infiltrating lymphocytes. This again supports the concept of immune activation as an important mode of action of trastuzumab.

Therefore, “rescuing” patients with tumors lacking tumor-infiltrating lymphocytes may account for the majority of trastuzumab’s clinical efficacy. Conversely, the addition of trastuzumab to chemotherapy in patients with lymphocytes already present in their tumors appeared to lack any benefit. More research is needed in this area to realize the promise of precision medicine for HER2-positive breast cancers.

leads to difficulty in interpretation and variability of gene expression, since detected transcripts may be arising from numerous cell types (ie, tumor cells, immune cells, vascular endothelial cells).6 Limitations specific to the current study include the observation

and prognostic gene-expression biomarkers have been published, but an exceedingly small number have demonstrated clinical utility.

Using an empirical, unbiased methodology, Perez and colleagues

As the nuances of breast cancer tumor immunology continue to be dissected, refinement of our treatment algorithms and the addition of novel therapies will undoubtedly improve outcomes.

—Randy F. Sweis, MD, and Olufunmilayo I. Olopade, MD

that immune-enriched tumors were significantly smaller than nonimmune-enriched tumors (P < .0001).

This finding is problematic and potentially confounds the results. As with any proposed biomarker, extensive prospective validation would be necessary before its incorporation into clinical practice. In reality, hundreds of publications on predictive

Disclosure: Drs. Sweis and Olopade reported no potential conflicts of interest.

Future Directions

Biomarker Development These results should catalyze development of robust clinical biomarkers, so patients likely to fail to respond to HER2-targeted therapy can be steered toward innovative clinical trials testing new approaches.

However, one must be cautious when interpreting retrospective gene-expression profiling studies due to numerous pitfalls. Some limitations are generalizable to all gene-expression biomarker studies. For instance, tissue heterogeneity of tumor samples

types, we envision with great excitement its eventual expansion into breast cancer. n

identified a strong association between immune gene expression and the efficacy of adjuvant trastuzumab.

As the nuances of breast cancer tumor immunology continue to be dissected, refinement of our treatment algorithms and the addition of novel therapies will undoubtedly improve outcomes. Given the recent success of immune therapies in other tumor

References 1. Perez EA, Romond EH, Suman VJ, et al: Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 29:3366-3373, 2011.

2. Perez EA, Suman VJ, Davidson NE, et al: Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol 29:44914497, 2011.

3. Perez EA, Thompson EA, Ballman KV, et al: Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. J Clin Oncol 33:701-708, 2015.

4. Bianchini G, Gianni L: The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol 15:e58-e68, 2014.

5. Gajewski TF, Schreiber H, Fu YX: Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014-1022, 2013.

6. Rodriguez-Gonzalez FG, Mustafa DA, Mostert B, et al: The challenge of gene expression profiling in heterogeneous clinical samples. Methods 59:4758, 2013.

Announcements

Michael H. Levy, MD, PhD, Receives Lifetime Achievement Award

M

ichael H. Levy, MD, PhD, Director of the Pain and Palliative Care Program at Fox Chase Cancer Center, and one of the founding leaders of the American hospice and palliative care movement, has received the Lifetime Achievement Award from the American Academy of Hospice and Palliative Medicine (AAHPM).

The AAHPM Lifetime Achievement Award recognizes outstanding contributions and significant publications that have helped shape the direction of the field of hospice and palliative medicine. Dr. Levy received

the award during the AAHPM and Hospice and Palliative Nurses Association Annual Assembly held recently in Philadelphia.

A Career Focused on Palliative Care “I’ve dedicated 35 years to integrating hospice and palliative medicine into comprehensive cancer care, so this recognition is a great honor,” says Dr. Levy.

“My goal has been, and still is, to carry the message that hospice and palliative care are the completion, not the antithesis, of state-of-the-art cancer care.” n

Michael H. Levy, MD, PhD, receives Lifetime Achievement Award from AAHPM Past President Jean S. Kutner, MD, MSPH, FAAHPM.

DID YOU KNOW? SINCE THE APPROVAL OF DOCETAXEL IN 1999, NO SECOND-LINE REGIMEN HAS EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF METASTATIC 1-3 NSCLC PATIENTS

NSCLC=non-small cell lung cancer.

NEW FDA APPROVAL CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

ADVANCING THE SECONDLINE TREATMENT OF METASTATIC NSCLC4 CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.4

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

•

Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment.

Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with

•

antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe events.

The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event.

In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

•

Impaired Wound Healing CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing.

If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

•

Clinical Deterioration in Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with ChildPugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

•

CYRAMZA PLUS DOCETAXEL DEMONSTRATED A STATISTICALLY SIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL VS DOCETAXEL4 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

10.5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)4

15% INCREASE IN MEDIAN OS

MONTHS

0.8

OS PROBABILITY

MAJOR OUTCOME MEASURE

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

3

6

12

15

18

21

24

27

30

33

36

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

9

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 4

527

415

329

231

156

103

70

45

23

11

2

0

501

386

306

197

129

86

56

36

23

9

0

0

• Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively • ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progressionfree survival; ORR=objective response rate. *ITT population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.5 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253) The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.4

VISIT www.CYRAMZAHCP.com Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Use in Specific Populations •

Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

•

Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

•

Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Most Common Adverse Reactions •

•

The most commonly reported adverse reactions (all grades; Grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in Study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

The most common serious adverse events with CYRAMZA plus docetaxel in Study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colonystimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

•

Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%).

The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

•

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions •

No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on the next page.

RB-L HCP ISI 17DEC2014 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol.

2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/ fda-docetaxel/print. Accessed August 26, 2014. 4. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014. 5. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.

Lancet. 2014;384(9944):665-673.

RB93740 12/2014 PRINTED IN USA © Lilly USA, LLC 2014.

ALL RIGHTS RESERVED. CYRAMZA® is a registered trademark of Eli Lilly and Company.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3.

CONTRAINDICATIONS None.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3

WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZAtreated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.

In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment.

Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA plus docetaxel (N=627) All Grades Grade 3-4 (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 Neutropenia 55 49 Thrombocytopenia 13 3 Gastrointestinal Disorders Stomatitis/Mucosal 37 7 inflammation Eye Disorders Lacrimation increased 13 <1 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 Peripheral edema 16 0 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 Vascular Disorders Hypertension 11 6 Adverse Reactions (MedDRA) System Organ Class

Placebo plus docetaxel (N=618) All Grades Grade 3-4 (Frequency %) (Frequency %) 10 46 5

10 40 <1

19

2

5

0

50 9

11 <1

7

<1

5

2

Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 19 clinical trials, 70/2131 (3.3%) of CYRAMZA-treated patients with post baseline serum samples tested positive for treatment-emergent antiramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 12 of the 70 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel.

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease.

Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intratumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36).

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population PK analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1.0-1.5 times ULN and any AST)

CYRAMZA® (ramucirumab) injection

CYRAMZA® (ramucirumab) injection

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.

RB-L HCP BS 17Dec2014

RB-L HCP BS 17Dec2014

based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility.

Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA.

ASCOPost.com | APRIL 10, 2015

Announcements

NCCN Honors Joseph V. Simone, MD, FASCO, and John A. Gentile, Jr, at Group’s 20th Annual Conference

A

t the National Comprehensive Cancer Network (NCCN) 20th Annual Conference held last month in Hollywood, Florida, NCCN honored Joseph V. Simone, MD, FASCO, and John (Jack) A. Gentile, Jr, with the NCCN Board of Producers Award.

For toxicities related to docetaxel, refer to the current respective prescribing information.

PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Of increased risk of an arterial thromboembolic event.

• To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

PAGE 39

Joseph V. Simone, MD, FASCO

Dr. Simone is President of Simone Consulting Company, which advises organizations on cancer program organization, quality, and development. Dr. Simone is Clinical Director Emeritus of Huntsman Cancer Institute and Professor Emeritus of Pediatrics and Medicine at University of Utah School of Medicine.

Additional information can be found at www.CYRAMZAhcp.com.

John (Jack) A. Gentile, Jr

Unsung Heroes The award is presented to individuals who have made major contributions to NCCN over the past years. Recipients are unsung heroes who have provided exemplary service in helping NCCN achieve its mission through their passion to improve the care of people with cancer.

Dr. Simone was the first Chair of the Board of Directors of NCCN and was instrumental in its founding. Mr. Gentile played a key role in the early days of NCCN, particularly in helping to facilitate NCCN’s first annual conference in 1996. Mr. Gentile currently publishes JNCCN and serves as Secretary of the NCCN Foundation Board of Directors.

Past Awardees The NCCN Board of Producers Award has been presented for the past 10 years. Past recipients have also included Robert C. Young, MD, President of RCY Medicine and former Chancellor, President, and Chief Executive Officer of Fox Chase Cancer Center in Philadelphia; David C. Hohn, MD, President Emeritus and Executive Director of Health Policy at Roswell Park Cancer Institute; Terry S. Langbaum, MAS, Chief Administrative Officer of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; and Mara G. Bloom, JD, MS, Executive Director of Administration at Massachusetts General Hospital Cancer Center.

Watch for continued coverage of the NCCN 20th Annual Conference in upcoming issues of The ASCO Post. n

A nn N ua CC lC N on 20 fe th re nc e

Mr. Gentile is Chairman of Harborside Press, in Cold Spring Harbor, New York. Harborside Press publishes the Journal of the National Comprehensive Cancer Network (JNCCN), The ASCO

Post, and the Journal of the Advanced Practitioner in Oncology (JADPRO).

Visit ASCOPost.com to view interviews with leaders at the 2015 NCCN Annual Conference, held this past month in Hollywood, Florida. Watch for continued coverage of the conference in future issues of The ASCO Post.

Eli Lilly and Company, Indianapolis, IN 46285, USA

Visit http://video.ascopost.com/

Copyright © 2014, Eli Lilly and Company. All rights reserved.

RB-L HCP BS 17Dec2014 CYRAMZA® (ramucirumab) injection

RB-L HCP BS 17Dec2014

The ASCO Post | APRIL 10, 2015

PAGE 40

Journal Spotlight Genitourinary Oncology

No Overall Survival Difference for Immediate vs Deferred Chemotherapy After Radical Cystectomy in Muscle-Invasive Bladder Cancer

By Matthew Stenger

I

n the European Organisation for Research and Treatment of Cancer (EORTC) 30994 trial, a phase III intergroup study reported in The Lancet Oncology,1 Cora N. Sternberg, MD, FACP, Chief of Medical Oncology at San Camillo and Forlanini Hospitals,

of 61 years, 80% were male, 61% had pT3 and 17% had pT4 disease, and 70% had pN+ disease. In the immediate- and deferred-chemotherapy groups, 18% and 19% were pN− based on < 15 dissected nodes, 12% in both groups were pN− based on ≥ 15 nodes,

An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of [bladder cancer] patients.

—Cora N. Sternberg, MD, FACP, and colleagues

Rome, and colleagues found no overall survival difference between immediate and delayed adjuvant chemotherapy after radical cystectomy in patients with muscle-invasive urothelial carcinoma of the bladder.1 Immediate treatment was associated with improved median and 5-year progression-free survival.

The trial was closed due to slow recruitment after enrollment of 284 of a planned 660 patients. Nevertheless, this is the largest randomized trial in this setting to date.

Study Details In this open-label trial, 284 patients from 12 countries in Europe (n = 272) or Canada with pT3–pT4 or N+ M0 disease after radical cystectomy and bilateral lymphadenectomy and no evidence of microscopic residual disease were randomly assigned within 90 days of cystectomy, between April 2002 and August 2008, to receive immediate chemotherapy (n = 141) or chemotherapy delayed until relapse (n = 143).

Immediate chemotherapy consisted of four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin (highdose MVAC), or MVAC; deferred chemotherapy consisted of six cycles of treatment. The primary endpoint was overall survival in the intention-to-treat population.

Overall, patients had a median age

43% and 46% were pN+ based on < 15 nodes, and 28% and 23% were pN+ based on ≥ 15 nodes. The median time from cystectomy to randomization was 63 days.

In total, 195 patients received chemotherapy, which consisted of gemcitabine plus cisplatin in 165 (85%). In the imme-

diate-treatment group and 82 (57%) in the deferred-treatment group had died, with death due to bladder cancer occurring in 37% and 45%. Five-year overall survival was 53.6% (95% confidence interval [CI] = 44.5%–61.8%) vs 47.7% (39.1%–55.8%) and median overall survival was 6.74 years (95% CI = 3.85 years–not reached) vs 4.60 years (2.15–6.25 years), yielding an adjusted hazard ratio (HR) of 0.78 (95% CI = 0.56–1.08, P = .13).

Five-year mortality due to bladder cancer was 38.6% vs 43.5% (competing risk–adjusted HR = 0.80, P = .22). No significant difference in mortality due to other or unknown causes was observed (competing risk HR = 0.84, P = .61).

As of the data cutoff, progression or death had occurred in 45% of the immediate-treatment group vs 62% of the deferred-treatment group, including distant spread at first diagnosis of progression in 28% vs 37%. Five-year progression-free survival was 47.6% vs 31.8% and median progression-free survival was 3.11 years vs 0.99 years (HR = 0.54, P < .0001).

Timing of Postcystectomy Chemotherapy in Bladder Cancer ■■ No significant difference in overall survival was observed between immediate and delayed chemotherapy.

■■ Immediate treatment was associated with better median and 5-year progression-free survival.

diate-chemotherapy group, treatment was started in 128 (91%) of 141 patients, with 28 receiving fewer than four cycles. Among patients in the deferredtreatment group, 3 (2%) requested and received immediate chemotherapy, 64 (45%) started deferred chemotherapy at the time of progression, and 76 (53%) never started deferred treatment; of the latter, 53 (70%) did not exhibit progression. Among the 64 patients who received deferred treatment, 44% received fewer than six cycles.

Survival Data Data cutoff occurred in August 2013. After median follow-up of 7.0 years (interquartile range = 5.2–8.7 years), 66 patients (47%) in the imme-

Homogeneity of Effects in Subgroups Post hoc exploratory analyses to assess the effect of treatment according to age, sex, pT category, pN category, pTN category, and time from cystectomy to randomization showed a significant interaction for pN category (pN− vs pN+, P = .026 for interaction) for overall survival and no significant interactions for progression-free survival. A significant interaction for overall survival by extent of lymph node sampling was also observed (P = .028 for interaction), but interpretation of the finding is unclear due to the small numbers of patients in the subcategories.

Five-year overall survival was 79.5% vs 59.0% (HR = 0.37, P = .012) in pa-

tients without lymph node involvement at baseline and 42.7% vs 42.9% (HR = 0.94, P = .72) in those with involvement at baseline. A second primary cancer or myelodysplastic syndrome occurred in 1% vs 7% in these subgroups, respectively.

Toxicity Grade 3 or 4 myelosuppression occurred in 26% of 128 patients who received treatment in the immediatechemotherapy group and 35% of 68 who received treatment in the deferredchemotherapy group, including neutropenia in 38% and 53%, thrombocytopenia in 28% and 38%, and anemia in 8% and 16%. A cycle of treatment was postponed for a maximum of 2 weeks due to adverse events in 59% and 70%, dose reduction occurred in 51% and 78%, and treatment was discontinued due to adverse events in 11% and 10%. Death due to toxicity occurred in two patients: one in the immediate-chemotherapy group (neutropenic sepsis) and one in the deferred-chemotherapy group (unknown cause 2 weeks after completing treatment).

The investigators concluded: “Our data did not show a significant improvement in overall survival with immediate vs deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients.” n

Disclosure: The study was funded by Eli Lilly and the Canadian Cancer Society Research Institute. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Sternberg CN, Skoneczna I, Kerst JM, et al: Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): An intergroup, open-label, randomised phase 3 trial. Lancet Oncol 16:76-86, 2015.

ASCOPost.com | APRIL 10, 2015

PAGE 41

Perspective

Adjuvant Chemotherapy and Overall Survival in Muscle-Invasive Bladder Cancer: Still Climbing the Mountain

By Maha Hussain, MD, FACP, FASCO

M

uscle-invasive bladder cancer can be a lethal disease despite curative intent local therapy, with 5-year survival that can be as low as 30% based on the extent of T status and/or lymph node involvement. The use of neoadjuvant chemotherapy with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or CMV (cisplatin, methotrexate, and vinblastine) has been shown to significantly improve overall survival, based on the results of two randomized phase III trials.1,2 Yet adopting this approach in the general patient population has been less than optimal in the United States.

Clinical Trials in High-Risk Patients The desire to optimize the risk/benefit ratio based on better patient selection and to avoid delay of potentially curative local therapy has fueled several adjuvant clinical trials in high-risk patients, particularly those with pT34 disease or those with node-positive disease post radical cystectomy and pelvic lymph node dissection. Historically, several phase II trials have been conducted, but they had multiple design and conduct limitations.

Since 2001, three randomized phase III trials were attempted in highrisk patients based on pT or N+ status, testing the survival impact of adjuvant cisplatin-based chemotherapy post radical cystectomy and pelvic lymph node dissection. One of these trials was negative,3 whereas the other was reportedly positive, although no manuscript has been published to date.4 The third trial (European Organisation for Research and Treatment of Cancer [EORTC] 30994) was recently reported by Dr. Sternberg and colleagues in ­Lancet Oncology5 and is reviewed in this issue of The ASCO Post.

Trial Similarities and Differences There are several common features across these three trials, including Dr. Hussain is Associate Director for Clinical Research and Co-Leader of the Prostate Cancer/GU Oncology Program at the University of Michigan Comprehensive Cancer Center, Ann Arbor.

the key eligibility criteria and type of chemotherapy. Gemcitabine-cisplatin was used in one trial, and the combination of gemcitabine, cisplatin, and paclitaxel was used in another. EORTC 30994 allowed the institution’s choice of gemcitabine-cisplatin, MVAC, or high-dose MVAC, although most of the patients (108 of 128) received gemcitabine-cisplatin. Unfortunately, all of these trials were closed due to slow accrual and were thus underpowered for the primary endpoint.

speculation of “what if ”—specifically, could these results have been statistically significant if the study had reached full accrual? The genitourinary medical oncology community in general has adopted gemcitabinecisplatin for managing advanced bladder cancer based on what is deemed to be clinically comparable outcomes, better toxicity profile, and better feasibility in metastatic disease; yet to date, the only positive prospective level 1 evidence for overall survival

Meta-analysis indicates a favorable effect of adjuvant cisplatin-based therapy—however, that does not equal level 1 evidence.

—Maha Hussain, MD, FACP, FASCO

However, relative to the other trials, EORTC 30994 had a larger number of patients recruited: 284 of a planned 660 patients. Despite significant improvements with immediate treatment in 5-year progression-free survival (47.6% vs 31.8%) and median progression-free survival (3.11 vs 0.99 years, hazard ratio = 0.54, P < .0001), there was no “statistically” significant difference in overall survival. There was, however, a trend in favor of the immediate treatment group: 5-year overall survival was 53.6% (95% confidence interval [CI] = 44.5%–61.8%) vs 47.7% (95% CI = 39.1%–55.8%), and median overall survival was 6.74 years (95% CI = 3.85 years to not reached) vs 4.60 years (2.15–6.25 years), with a hazard ratio of 0.78 (95% CI = 0.56– 1.08, P = .13).

Technically, this study is negative for a confirmed overall survival advantage; however, it is rather difficult to ignore the significant difference in progression-free survival in a disease in which relapse invariably predicts death and the trends in median and 5-year overall survival all favoring adjuvant chemotherapy.

It is also difficult to resist the

in the perioperative setting has been with MVAC or CMV, and no combination chemotherapy in metastatic disease has eclipsed MVAC. So “what if ” the three adjuvant trials had been conducted with MVAC? Could the results have been different despite the small sample size?

“Absence of proof ” is not “proof of absence,” so when there are no definitive data from prospective randomized trials, large data pools can serve to provide some guidance. In the setting of adjuvant chemotherapy, a recent updated systematic review and meta-analysis of randomized trials indicated a pooled hazard ratio in favor of adjuvant cisplatin-based chemotherapy of 0.77 (95% CI = 0.59–0.99, P = .049), translating into a 23% relative decrease in risk of death with adjuvant chemotherapy vs control.6

Weighing the Pros and Cons So, with the totality of the data from perioperative chemotherapy trials to date, what should the standards be for patients with muscle-invasive bladder cancer in 2015? I would argue that the best available level 1 evidence to date with regard to survival, feasibility, safety, and tolerance supports

the use of “neoadjuvant” cisplatinbased chemotherapy when possible.

Adjuvant chemotherapy-based trials have not been feasible to conduct successfully. Meta-analysis indicates a favorable effect of adjuvant cisplatinbased therapy—however, that does not equal level 1 evidence.

Managing patients requires both the “science and art” of medicine.

When the scientific evidence is not conclusive, informed joint decisions based on considering the pros and cons of adjuvant chemotherapy are certainly warranted in the setting of high-risk patients with resected muscle-invasive bladder cancer who did not receive neoadjuvant chemotherapy but who are medical candidates for chemotherapy.

New Treatment Strategies Moving forward, it is critical that new treatment strategies/paradigms be expeditiously investigated to overcome the stagnation and current limitations of our therapies. With the exciting preliminary data from the PD-L1 (programmed death-ligand 1) inhibitors, including their overall promising safety profile, and other biologic discoveries in this disease come the promise of improving outcomes for patients with advanced urothelial carcinoma in general and muscle-invasive bladder cancer in the perioperative setting in particular—where cure is possible. n

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

References 1. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003.

2. International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, et al: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemothercontinued on page 42

The ASCO Post | APRIL 10, 2015

PAGE 42

In Memoriam Oncology Worldwide

Global Oncology Launches Global Cancer Project Map With NCI

N

onprofit Global Oncology, Inc (GO) announced the launch of the Global Cancer Project Map, a novel online resource and virtual information exchange connecting the global cancer community. Developed by Global Oncology in collaboration with the National Cancer Institute (NCI) Center for Global Health, the Map enables worldwide access to cancer projects and

global health funding for cancer is committed to oncology in developing countries. However, Africa, Asia, Central America, and South America account for 60% of the world’s new cancer diagnoses and 70% of the world’s cancer deaths, according to the World Health Organization.

“The Map is an important and innovative step forward in our ef-

With cancer rates rapidly increasing in low-resource settings, the Map creates a place where the global cancer community can share and access information that is critical to providing better treatment and care.

—Michele Barry, MD, FACP

expertise, improving cancer practices and patient outcomes, especially in lowresource settings.

The Map was unveiled at the Symposium on Global Cancer Research on March 25, 2015.

The Global Cancer Project Map was developed by Global Oncology to fill a crucial need for shared resources. According to the World Bank, only 5% of

Maha Hussain, MD, FACP, FASCO continued from page 41

apy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial.

J Clin Oncol 29:2171-2177, 2011.

3. Cognetti F, Ruggeri EM, Felici A, et al: Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at

fort to reduce health-care disparities and strengthen human capital in underserved areas of the world,” said Michele Barry, MD, FACP, Director of Stanford University’s Center for Innovation in Global Health. “With cancer rates rapidly increasing in lowresource settings, the Map creates a place where the global cancer community can share and access information

relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: An Italian, multicenter, randomized phase III trial. Ann Oncol 23:695700, 2012.

4. Paz-Ares LG, Solsona E, Esteban E, et al: Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/ cisplatin to observation in patients with

that is critical to providing better treatment and care.”

The Global Cancer Project Map is an interactive online database that allows users to search for cancer experts and research projects by country and cancer type and then to initiate contact with project principal investigators and program directors. The Map launched with more than 700 projects spanning six continents. The goal is for the Map to grow exponentially as awareness builds. An online tool is to be added in late 2015, allowing users to upload projects directly.

The Global Cancer Project Map covers a wide range of projects, from cancer prevention and screening, to capacity training, clinical programs, and palliative care. Projects include: • Improving diagnostic accuracy of mammograms for breast cancer in Turkey through new methods • Preventing arsenic-induced skin cancer in Bangladesh through the study of vitamin E and selenium supplementation • Creating an early screening test for gastric cancer in Mexico through biomarker identification leading to an early screening test According to Ted Trimble, MD, MPH, Director of NCI’s Center for

resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study.

2010 ASCO Annual Meeting. Abstract LBA4518.

5. Sternberg CN, Skoneczna I, Kerst JM, et al: Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 uro-

Global Health, though many dedicated researchers and caregivers are conducting groundbreaking cancer programs around the world, until today they could not reference the collective knowledge and experiences of their colleagues in one central place.

“Before it was difficult, or often impossible, to find information about cancer projects or experts, especially in resource-limited settings,” said Global Oncology Cofounder Ami S. Bhatt, MD, PhD, Assistant Professor, Stanford University. “The Map now makes it possible to connect colleagues in the global cancer community with a maximum of six clicks of a mouse.”

“We have the ambitious goal of providing access to all cancer research, care, and outreach programs in the world through the Map,” said Global Oncology Cofounder Franklin W. Huang, MD, PhD, Instructor at DanaFarber Cancer Institute and Harvard Medical School. “[Global Oncology] encourages anyone working in cancer to use the Map to get and give valuable information about their projects, contributing to cancer care for patients no matter where they are.”

Find the Global Cancer Project Map here: http://gcpm.globalonc.org. n

thelial carcinoma of the bladder (EORTC 30994): An intergroup, open-label, randomised phase 3 trial. Lancet Oncol 16:76-86, 2015.

6. Leow JJ, Martin-Doyle W, Rajagopal PS, et al: Adjuvant chemotherapy for invasive bladder cancer: A 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 66:42-54, 2014.

Download

The ASCO Post iPad App FREE from iTunes today!

when it’s time for

first-line Cll treAtment

indication GAZYVA® (obinutuzumab), in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

Boxed WArninGs: HePAtitis B VirUs reACtiVAtiOn AnD PrOGressiVe MUltifOCAl leUKOenCePHAlOPAtHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation Progressive Multifocal leukoencephalopathy (PMl) including fatal PMl, can occur in patients • receiving GAZYVA

For the first-line treatment of CLL in combination with chlorambucil1 ®

stArt with GAZYVA

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) include obinutuzumab (GAZYVA®) + chlorambucil as a preferred first-line regimen for CLL patients with comorbidities, without del(17p) 2,a,b a

b

NCCN treatment suggestions for patients with del(17p) are not segmented by age or comorbidities. Obinutuzumab (GAZYVA) + chlorambucil is included as a suggested treatment for this patient population. Suggested treatment regimens are listed in alphabetical order.

Obinutuzumab (GAZYVA) + chlorambucil is listed first as a suggested treatment regimen for this patient population. Treatment regimens are listed in order of preference.

Note: All recommendations are category 2A unless otherwise indicated.

iMPOrtAnt sAfetY infOrMAtiOn Hepatitis B Virus reactivation

• Hepatitis B virus (HBV) reactivation, in some cases

•

resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies including GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive.

Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive) HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level, or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive.

Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death

• Screen all patients for HBV infection by measuring HBsAg

• •

and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation

neArLY A 1-YeAr imProVement in meDiAn Pfs (23.0 months Vs 11.1 months; hr=0.16; 95% Ci, 0.11-0.24; P<0.0001)1 siGnifiCAntlY sUPeriOr Pfs: GAZYVA in combination with Clb more than doubled median Pfs vs Clb monotherapy1 1.0 Hr=0.16; 95% CI, 0.11-0.24; P<0.0001

0.9 0.8

84% risk reduction

0.7

Pfs

0.6 0.5 0.4 0.3

11.1

0.2 GAZYVA + chlorambucil (n=238) Chlorambucil (n=118)

0.1

23.0

0.0

GAZYVA + chlorambucil Chlorambucil

0 n at risk

3

6

9

12

15

18

21

24

27

time (months)

238

208

201

146

111

69

39

16

2

0

118

91

76

46

21

6

2

0

0

0

PFS, progression-free survival; Clb, chlorambucil; HR, hazard ratio; CI, confidence interval.

Cll-11 trial Design1: GAZYVA, in combination with chlorambucil, was evaluated in a Phase III, open-label, multicenter, 3-arm, randomized, parallel-group comparative study in patients with previously untreated CD20+ chronic lymphocytic leukemia and coexisting medical conditions and/or reduced renal function. Patients with creatinine clearance <30 mL/min or inadequate liver function were excluded. The primary endpoint was progression-free survival. Overall response rate and complete response rate were secondary endpoints.

enhanced response rates1 • GAZYVA + Clb more than doubled response rates vs Clb monotherapy (75.9% vs 32.1%, respectively) • More than 1 in 4 patients receiving GAZYVA + Clb achieved a complete response (27.8% vs 0.9%, respectively) the most common Grade 3-4 adverse reactions were infusion reactions, neutropenia, and thrombocytopenia1 • The most common adverse reactions were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders

iMPOrtAnt sAfetY infOrMAtiOn (COnt’D) Progressive Multifocal leukoencephalopathy (PMl)

wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new • Premedicate patients with acetaminophen, antihistamine, onset or changes to preexisting neurologic manifestations. and a glucocorticoid. Institute medical management Evaluation of PML includes, but is not limited to, for infusion reactions as needed. Closely monitor patients consultation with a neurologist, brain MRI, and lumbar during the entire infusion. Infusion reactions within 24 puncture. Discontinue GAZYVA therapy and consider hours of receiving GAZYVA have occurred discontinuation or reduction of any concomitant • For patients with any Grade 4 infusion reactions, including chemotherapy or immunosuppressive therapy in patients but not limited to anaphylaxis, acute life-threatening who develop PML respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently infusion reactions discontinue GAZYVA therapy • GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mgs infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (eg, bronchospasm, larynx and throat irritation,

• JC virus infection resulting in PML, which can be fatal, was

Please see the following pages for additional important safety information and brief summary of full Prescribing information, including Boxed WArninGs.

iMPOrtAnt sAfetY infOrMAtiOn (COnt’D) infusion reactions (cont’d)

• For patients with Grade 1, 2, or 3 infusion reactions: •

Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions.

Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to and during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication

thrombocytopenia (cont’d)

Fatal hemorrhagic events during Cycle 1 have also been reported. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (ie, platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle

immunization

• The safety and efficacy of immunization with live or

attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery

tumor lysis syndrome (tls)

• Acute renal failure, hyperkalemia, hypocalcemia,

hyperuricemia, and/or hyperphosphatemia from TLS can occur within 12-24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (>25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12-24 hours prior to the infusion of GAZYVA. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated

Pregnancy: Category C

• Women of childbearing potential should use effective

contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Geriatric Use

• Two hundred and forty previously untreated CLL patients

received GAZYVA in combination with chlorambucil. Of the 109 patients ≥75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients <75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) experienced an adverse event leading to death. Similar rates were observed in the comparator arm

infections

• Serious bacterial, fungal, and new or reactivated viral

infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection

neutropenia

• GAZYVA, in combination with chlorambucil, caused Grade

• •

3 or 4 neutropenia in 34% of patients. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days) Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered

thrombocytopenia

• GAZYVA, in combination with chlorambucil, caused Grade 3 or 4 thrombocytopenia in 11% of patients in the trial. In 5% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion.

Visit GAZYVA.com for more information

Additional important safety information

• The most common adverse reactions (≥10%) were: infusion •

reactions (69%), neutropenia (40%), thrombocytopenia (15%), anemia (12%), pyrexia (10%), cough (10%), and musculoskeletal disorders (17%) Grade 3/4 adverse reactions were: infusion reactions (21%), neutropenia (34%), thrombocytopenia (11%), anemia (4%), leukopenia (5%), and pyrexia (<1%)

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. references: 1. GAZYVA full Prescribing information. south san francisco, CA: Genentech UsA, inc.; June 2014. 2. referenced with permission from the nCCn Clinical Practice Guidelines in oncology (nCCn Guidelines®) for non-hodgkin’s Lymphomas V.1.2014. © national Comprehensive Cancer network, inc. 2014. All rights reserved. Accessed march 31, 2014. 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.

Please see the following pages for brief summary of full Prescribing information, including Boxed WArninGs.

© 2014 Genentech USA, Inc. All rights reserved. GAZ0002401103 Printed in USA. August 2014

ASCOPost.com | APRIL 10, 2015

PAGE 43

Announcements

Jim Hu, MD, Joins NewYork-Presbyterian Hospital and Weill Cornell Medical College

J

im Hu, MD, has been appointed Director of the LeFrak Center for Robotic Surgery at NewYork-Presbyterian/Weill Cornell Medical Center and recruited as the Ronald Lynch

Chair of Urologic Oncology at Weill Cornell Medical College. He assumed his new role on February 1.

Dr. Hu is an expert in the use of robotic and minimally invasive surgery to GAZYVA® (obinutuzumab)

Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information.

WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].

• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive.

Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

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

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations.

Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.

Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

Premedicate patients with acetaminophen, antihistamine and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

treat prostate cancer. As Director of the LeFrak Center, he will lead cutting-edge clinical and research efforts in urologic oncology, as well as other areas such as otolaryngology, obstetrics and gynecolFor patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)].

For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction.

Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication.

ogy, and ophthalmology. Dr. Hu will also spearhead clinical efforts in prostate cancer at the recently established Sandra and Edward Meyer Cancer Center continued on page 44 The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

Table 3 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) Adverse Reactions (MedDRAa) System Organ Class

5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion.

Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Injury, poisoning, and procedural complications Infusion 69 21 0 0 reactions Blood and lymphatic system disordersb Neutropenia 41 35 18 8

4

Anemia

12

5

10

4

Leukopenia

7

5

0

0

Infections and infestations Urinary tract 6 2 infection

3

<1

Musculoskeletal and connective tissue disorder Back pain 5 <1 2 0

Table 4 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Adverse Reactions (MedDRAa) System Organ Class

5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion.

Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary.

Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

Injury, poisoning and procedural complications Infusion 66 20 38 4 reactions Blood and lymphatic system disordersb Neutropenia 38 33 32

28

Thrombocytopenia 14

10

7

3

Leukopenia

4

2

<1

6

General disorders and administration site conditions Pyrexia 9 <1 7 <1

5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

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.

11

Respiratory, thoracic, and mediastinal disorders Cough 10 0 7 <1

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.

16

Thrombocytopenia 15

General disorders and administration site conditions Pyrexia 10 <1 7 0

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)] • Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy.

Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection.

Patients with a history of recurring or chronic infections may be at increased risk of infection.

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

GAZYVA + Chlorambucil n = 241

Gastrointestinal disorders Diarrhea 10 2

8

<1

Constipation

5

0

8

0

Infections and infestations Nasopharyngitis 6 <1 Urinary tract infection

5

1

3

0

2

<1

a

MedDRA coded adverse reactions as reported by investigators.

b

Adverse events reported under “Blood and lymphatic system disorders” reflect those reported by investigator as clinically significant.

The ASCO Post | APRIL 10, 2015

PAGE 44

Announcements Jim Hu, MD continued from page 43

at Weill Cornell Medical College and NewYork-Presbyterian Hospital, in addition to serving on Weill Cornell’s faculty.

“We are thrilled to welcome Dr. Hu,” said Peter Schlegel, MD, Urologist-inChief at NewYork-Presbyterian/Weill Cornell and the James J. Colt Professor

Table 5 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) GAZYVA + Chlorambucil n = 241

Investigations

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia

78

48

53

27

Lymphopenia

80

40

9

3

Leukopenia

84

37

12

<1

Chemistry Hypocalcemia

38

3

33

2

Hyperkalemia

33

5

18

3

Hyponatremia

30

8

12

3

AST (SGOT increased)

29

1

16

0

Creatinine increased

30

<1

20

2

ALT (SGPT increased)

27

2

16

0

Hypoalbuminemia

23

<1

15

<1

Alkaline phosphatase 18 increased

0

11

0

Hypokalemia

1

5

<1

15

Table 6 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Investigations

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia

76

46

69

41

Lymphopenia

80

39

50

16

Leukopenia

16

84

35

62

Thrombocytopenia 48

13

40

8

Anemia

39

10

37

10

Chemistry Hypocalcemia

37

3

32

<1

Hyperkalemia

14

1

10

<1

Hyponatremia

26

7

18

2

AST 27 (SGOT increased)

2

21

<1

ALT 28 (SGPT increased)

2

21

1

Hypoalbuminemia 23

<1

16

<1

Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see Dosage and Administration (2)].

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (Table 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab treated arm.

and Chairman of the Department of Urology at Weill Cornell Medical College. “He has a truly outstanding track record of excellence and innovation in both urologic oncology and robotic-assisted surgery.”

Earlier Posts Dr. Hu joins NewYork-Presbyterian and Weill Cornell from the David Gef-

(7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (Table 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the GAZYVA and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion).

The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the rituximab treated arm.

Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%).

Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity.

6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Of the GAZYVA treated patients, 7% (18/271) tested positive for anti-GAZYVA antibodies at one or more time points. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

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. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

6.3 Additional Clinical Trial Experience Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers.

Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Infection: The incidence of infections was similar between GAZYVA and rituximab treated arms. Thirty-eight percent of patients in the GAZYVA treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to 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 obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab treated arm

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

fen School of Medicine at UCLA, where he served as Director of Minimally Invasive and Robotic Surgery and Professor of Urology, in addition to holding the Henry E. Singleton Chair. Prior to his tenure at UCLA, he was the Director of Robotic Urologic Surgery and the Director of Prostate Cancer at the Dana-Farber Cancer Institute while also serving

8.5 Geriatric Use Of 336 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

• Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].

• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)].

• Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)].

• Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA® [obinutuzumab]

Initial US Approval: 2013

Manufactured by: Genentech, Inc.

Code Revision Date: December 2014

A Member of the Roche Group South San Francisco, CA 94080-4990

GAZYVA is a registered trademark of Genentech, Inc.

U.S. License No: 1048

GAZ/011615/0009 1/15 © 2015 Genentech, Inc.

With a team of brilliant physicians and state-of-theart resources, I’m confident we will make great strides in personalized cancer treatment and robotic surgery.

—Jim Hu, MD

as A ­ ssociate Professor of Surgery at Harvard Medical School and Associate Surgeon at Brigham and Women’s Hospital.

Dr. Hu earned his undergraduate and Master of Public Health degrees from Johns Hopkins University and his medical degree from Baylor College of Medicine. He completed his surgery and urology residency training at UCLA and a fellowship in urologic oncology and robotic surgery at City of Hope National Medical Center.

“NewYork-Presbyterian Hospital and Weill Cornell Medical College’s track record of developing innovative, patient-friendly treatments is exemplary,” Dr. Hu said. “With a team of brilliant physicians and state-of-the-art resources, I’m confident we will make great strides in personalized cancer treatment and robotic surgery.” n

Erratum

I

n the March 10, 2015, issue of The ASCO Post (“The Current State of Hematologic Malignancies, A Conversation with Carl E. Freter, MD, PhD, FACP,”) Dr. Freter’s title was cited incorrectly.

Dr. Freter is Professor and Director of the Division of Hematology/Oncology and Bone Marrow and Stem Cell Transplantation, Saint Louis University School of Medicine (SLU), and Associate Director and Rosalie Fusz Chair of Hematology, Saint Louis University Cancer Center.

We apologize to Dr. Freter and to our readers for the error. n

ASCOPost.com | APRIL 10, 2015

PAGE 45

Expert’s Corner Issues in Oncology

Current Progress Against Cancer and What Lies Ahead in the Next Decade A Conversation With Gregory A. Masters, MD, FACP, FASCO

By Jo Cavallo

Key Advances

Gregory A. Masters, MD, FACP, FASCO

I

n January, ASCO released its report, Clinical Cancer Advances 2015: An Annual Report on Progress Against Cancer,1 which details research advances over the past decade that have led to longer survival and better quality of life for the more than half-a-million people diagnosed with cancer each year.

For the first time, ASCO announced its Cancer Advance of the Year: gains made in the treatment of chronic lymphocytic leukemia (CLL). The Society also cited the approval of four new drugs—two immunotherapy agents for previously untreated CLL, obinutuzumab (Gazyva) and ofatumumab (Arzerra), and two molecularly targeted drugs for treatment-resistant or relapsed CLL, ibrutinib (Imbruvica) and idelalisib (Zydelig)—as filling a major unmet need in patients with the disease.

Now in its 10th year of publication, the current annual report features several new sections, including A Decade in Review, which looks at the biggest changes in cancer care over the past 10 years; The 10-Year Horizon, which previews trends likely to shape the next decade of cancer care; and Progress in Rare Cancers, which examines early achievements in treating three rare childhood cancers and two rare ovarian cancers affecting young women. (See “ASCO Releases Annual Report on Progress Against Cancer” in the February 10, 2015, issue of The ASCO Post.)

In a wide-ranging interview with The ASCO Post, Gregory A. Masters, MD, FACP, FASCO, Co–Executive Editor of Clinical Cancer Advances 2015 and Attending Physician at the Helen F. Graham Cancer Center in Newark, Delaware, discussed the report’s findings, the impact of the Affordable Care Act on cancer care, how CancerLinQ™ will improve patient care, and anticipated big advances in cancer care over the next decade.

Please talk about how far advances in cancer research have come over the past decade and how those advances will translate into a reduction in cancer deaths and increased survivorship?

It’s great to look over the past 10 years with some perspective, because sometimes, in treating patients with cancer and in looking at cancer care, we tend to get caught up in how slow progress seems. But when we take a broader perspective of what has changed over the past decade, we see the development of whole new ways to treat cancer.

Now we have a better understanding of the molecular biology and the genomics of the disease, and that has allowed us to come up with a number of new targeted therapies. Some of these drugs target the mutations that occur in cancer

motherapy, which can be difficult for older patients to tolerate.

What we have seen over the past few years as newer types of therapies have come on the market is if we can target CLL more specifically, we can treat the disease with safer and more effective treatments and move away from aggressive chemotherapy that is toxic. That is why we thought the approval of the immunotherapy agents obinutuzumab and ofatumumab for previously untreated CLL, and the molecularly targeted drugs ibrutinib and idelalisib for treatment-resistant or relapsed CLL, represented such an important advance in treatment.

Improved Patient Care A number of improvements in patient and survivorship care were cited in the re-

It’s great to look over the past 10 years with some perspective, because sometimes, in treating patients with cancer and in looking at cancer care, we tend to get caught up in how slow progress seems. But when we take a broader perspective of what has changed over the past decade, we see the development of whole new ways to treat cancer.

—Gregory A. Masters, MD, FACP, FASCO

genes, and some target the mechanisms that cancer cells use to grow.

As we increase our understanding of these things, we will be able to use that knowledge not only in the treatment of patients with advanced cancer, but also in treating patients with earlier-stage disease, thereby improving the cure rates.

We are also refining our ability to screen for cancer and our understanding of supportive measures to improve quality of life for patients.

‘Advance of the Year’ Please talk about the significance of the gains made in the treatment of CLL, which ASCO named its Advance of the Year.

CLL affects older patients and tends to linger for many years, so although only about 15,000 people are diagnosed with CLL each year in the United States, there are more than a hundred thousand survivors living with the disease. Also, until recently, CLL patients were treated with fairly aggressive che-

port, including a new way to preserve fertility in young women. What other major improvements have there been along these lines?

Care provided by oncologists and other cancer care specialists spans the entire spectrum of general health because when we see patients, we are not just treating their cancer and dealing with the side effects of that treatment. We also have to take into account other chronic health conditions and mental health.

Caring for the whole patient in this way is especially important when we have the potential to cure patients. So we need to think about not just the short-term effects of treatment, but the long-term effects as well. Preserving fertility in a young woman with potentially curable early-stage cancer by blocking hormones during chemotherapy is one example of how we can help make the rest of her life as fulfilling as possible.

We also recognize the importance of exercise in improving quality of life for patients. In addition, some studies show that patients who exercise regu-

larly have a better outcome, less chance of recurrence, and longer survival. Over the last decade, we have improved quality of life for patients by addressing treatment side effects like nausea and chronic neuropathy, providing better nutritional counseling, preventing infection, and stimulating blood cell growth.

Progress in Rare Cancers Another big advance in cancer care mentioned in the report is in rare cancers.

Please talk about the progress being made in these diseases.

The report includes promising research findings in three childhood cancers: pigmented villonodular synovitis, a rare joint disease that affects about 600 mostly young Americans each year; alveolar and embryonal rhabdomyosarcoma; and diffuse intrinsic pontine glioma.

If early reports from small studies of oral therapies targeting the protein CSF-R1 in pigmented villonodular synovitis are confirmed in larger studies, the therapies may offer patients an alternative to surgery and the possibility of joint replacement or amputation. Our improved understanding in the genetic mechanisms of rhabdomyosarcoma is leading to the first targeted therapy for this disease, which currently is treated with chemotherapy, radiation therapy, and surgery. And findings from two studies are showing new genetic alterations in diffuse intrinsic pontine glioma, which suggest possible therapeutic interventions that may offer hope for improving treatment outcomes in this disease.

The report also cites early results from clinical studies showing that bevacizumab (Avastin) may be active against recurrent sex cord–stromal tumors of the ovaries, a rare form of ovarian cancer. New research is also revealing genetic causes of small cell carcinoma of the hypercalcemic type, a rare but aggressive ovarian cancer that primarily affects girls and women younger than age 40.

One of the benefits of having a greater understanding of the molecular basis of the more common cancers is it has given us insight into the role genes play in cancer development in general and allows us to treat cancers we didn’t have good options for previously.

It is still harder to do research on rare diseases, but the more we undercontinued on page 46

The ASCO Post | APRIL 10, 2015

PAGE 46

Expert’s Corner Gregory A. Masters, MD, FACP, FASCO continued from page 45

stand cancer generally, the better we can apply that knowledge to less common diseases.

Impact of Health-Care Reform Full implementation of the Affordable Care Act went into effect a year ago. What is its impact so far on cancer care?

It’s too early to know for sure. I look at the ramifications of the Affordable Care Act in two ways. First, the law will benefit all of society if we can get more people insured with good-quality health insurance so they have access to physicians, nurses, and programs that improve their health and allow them to get preventive care. Those things will reduce cancer incidence and improve quality of life. So, to me, improved access to health care is the big plus of the Affordable Care Act. Second, if one of the goals of the Affordable Care Act is to increase patients’ responsibility for payment for some parts of their care, will it result in pricing the more expensive cancer treatments out of the range of patients with limited access and resources? I’m not saying that is happening. I’m just raising

the issue and think it is something we are going to need to monitor.

The questions society has to answer are: How do we pay for this expensive care, and how do we make sure there is equitable care that is accessible to all segments of society? Beyond the United States, how do we make sure there is access to quality health care globally?

Role of Information Technology How will Big Data systems like CancerLinQ improve patient care, especially for patients with rare cancers?

Health information technology systems like ASCO’s CancerLinQ offer possibilities for improving the quality of cancer care and patient outcomes that we haven’t had before because they allow us to learn from every patient instead of just the roughly 3% of patients who participate in clinical trials. CancerLinQ also gives us the mechanism to store the outcomes of different interventions and shows how different ways of managing specific cancers affect overall survival, functional status, and quality of life. That information will allow us to not only better understand cancer, but also to find better ways to treat and cure the disease.

Next Big Advances Where do you see the next big advances being made in cancer care?

It is hard to extrapolate from what is happening now and predict where that information will lead us in 10 years and whether we are going to have a better grasp of cancer genetics, immunotherapy, and targeted therapies, because our understanding of all of those areas is still in its infancy.

Nevertheless, recent developments in fundamental and translational cancer research are giving us a glimpse into what the future may hold. For example, the 10-Year Horizon section of the Clinical Cancer Advances 2015 report focuses on cancer stem cells, exploring the theory that cancer stem cells are biologically different from regular cancer cells, have the ability to self-renew, and are more resistant to chemotherapy. These insights are leading to the development of treatments that specifically attack cancer stem cells, which could allow us to treat cancer more effectively.

Other promising areas that may start impacting patient care over the next decade include faster and less expensive next-generation sequencing, liquid biopsies to more accurately

detect circulating tumor DNA and microRNA in the blood and determine effective treatment, and cancer prevention vaccines.

Over the next 10 years, we will be able to less invasively figure out what types of cancer patients are most at risk for developing recurrences and determine how to hone in on specific screening or surveillance strategies for those individuals. We are improving our understanding of cancer, and that understanding is leading to more effective treatments for our patients. n

Disclosure: Dr. Masters reported no potential conflicts of interest. For full disclosures of the authors of Clinical Cancer Advances 2015, visit jco.ascopubs.org.

Reference 1. Masters GA, Krilov L, Bailey HH, et al: Clinical cancer advances 2015: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 33:786-809, 2015.

To download a copy of Clinical Cancer Advances 2015: ASCO’s Annual Report on Progress Against Cancer, go to cancerprogress.net/ cca/clinical-cancer-advances-2015

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For patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapyâ&#x20AC;Ś

What if You Could Do More?

Expect More. Do More.

Proven Superior Survival With the Only Immuno-Oncology Therapy in Previously Treated Metastatic Squamous NSCLC INDICATION OPDIVO速 (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

SELECT IMPORTANT SAFETY INFORMATION OPDIVO is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, other adverse reactions; and embryofetal toxicity.

For patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy

OPDIVO Demonstrated Superior Survival vs Standard of Care1-5 100

MEDIAN OS 9.2 MONTHS vs 6.0 MONTHS

90

Probability of Survival (% of Patients)

80

(95% CI: 7.3-13.3 vs 5.1-7.3) HR=0.59; 95% CI: 0.44-0.79; P=0.00025

70 60 50 40 30 20 10 0 0

Number at risk OPDIVO 135 137 DOCETAXEL

3

6

9

113 103

86 68

69 45

12

15

18

21

24

31 14

15 7

7 2

0 0

OS (Months) 52 30

Refer to Figure 1 in the Full Prescribing Information for data on censored patients.

CI=confidence interval; HR=hazard ratio; IV=intravenous; OS=overall survival; PD-1=programmed death-1; PD-L1=programmed death ligand 1.

Study design: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV every 2 weeks (n=135) vs docetaxel 75 mg/m2 IV every 3 weeks (n=137). The primary endpoint of the study was overall survival.1,6 Results were based on the prespecified interim analysis conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the OPDIVO arm and 113 in the docetaxel arm).1 ■

This study included patients regardless of PD-L1 status; PD-L1 testing is not required for a treatment decision

Based on the unprecedented results, OPDIVO achieved the benchmark goal of improving overall survival in metastatic squamous NSCLC The safety of OPDIVO (3 mg/kg IV over 60 minutes every 2 weeks) was evaluated in CHECKMATE 063 (Trial 3), a singlearm study of 117 patients with metastatic squamous NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen.1,7 Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction.

Serious Adverse Reactions ■

In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions ■

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see additional Important Safety Information on the following page.

Responding to Your Needs in 24 Hours or Less

IMPORTANT SAFETY INFORMATION Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immunemediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 3. In Trial 3, immunemediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO including five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3.

Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO. Immune-Mediated Hepatitis In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immunemediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction In Trial 3, the incidence of elevated creatinine was 22%. Immunemediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO. Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients

receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse

administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, GuillainBarré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm

when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because

many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 3, serious adverse reactions occurred in 59% of patients

receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported

with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see brief summary of Full Prescribing Information on the following pages.

References: 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 2. Taxotere [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2014. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer V.4.2015. ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed February 3, 2015. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 4. Garassino MC, Martelli O, Broggini M, et al; on behalf of the TAILOR trialists. 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. 2013;14(10):981-988. 5. Kawaguchi T, Ando M, Asami K, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced nonsmall-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014;32(18):19021908. 6. Bristol-Myers Squibb. Study of BMS-936558 (nivolumab) compared to docetaxel in previously treated advanced or metastatic squamous cell non-small cell lung cancer (NSCLC) (CheckMate 017).

Identifier: NCT01642004. https://clinicaltrials.gov/ct2/show/NCT01642004. Updated December 31, 2014.

Accessed February 5, 2015. 7. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257-265.

reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction and vasculitis. Across clinical trials of OPDIVO OPDIVO® and the related logo are trademarks of Bristol-Myers Squibb Company. ©2015 Bristol-Myers Squibb Company. All rights reserved.

Printed in USA. 1506US15BR00482-02-01 03/15

OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGE OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy [see Clinical Studies (14.2) in full Prescribing Information].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO. No cases of fatal pneumonitis occurred in Trial 3; all five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient).

In Trial 3, pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including five Grade 3 and two Grade 2 cases, all immune-mediated. The median time to onset was 3.3 months (range: 1.4 to 13.5 months). All seven patients discontinued OPDIVO for pneumonitis or another event and all seven patients experienced complete resolution of pneumonitis following receipt of high-dose corticosteroids (at least 40 mg prednisone equivalents per day).

Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.2) in full Prescribing Information].

Immune-Mediated Colitis In Trial 3, diarrhea occurred in 21% (24/117) of patients. Immune-mediated colitis (Grade 3) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 6.7 months. The patient received high-dose corticosteroids and was permanently discontinued from OPDIVO (nivolumab). Complete resolution occurred.

Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for Grade 2 or 3 immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information].

Immune-Mediated Hepatitis In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). No cases of immunemediated hepatitis occurred in this trial.

Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions].

Immune-Mediated Nephritis and Renal Dysfunction In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 0.8 months. The patient received high-dose corticosteroids.

OPDIVO was withheld, and the patient discontinued due to disease progression prior to receiving additional OPDIVO. Immune-mediated renal dysfunction was ongoing.

Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue OPDIVO. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold OPDIVO and administer

corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue OPDIVO (nivolumab) [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions].

Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 3, patients were evaluated for thyroid function at baseline, first day of treatment, and every 6 weeks. Hypothyroidism occurred in 4.3% (5/117) of patients. The median time to onset for these five cases was 4.1 months (range: 1.4 to 4.6 months). All five patients with hypothyroidism received levothyroxine.

Complete resolution of hypothyroidism occurred in one patient allowing discontinuation of levothyroxine. Interruption of OPDIVO did not occur in these five patients.

Hyperthyroidism occurred in 1.7% (2/117) of patients. One patient experienced Grade 2 hyperthyroidism 5.2 months after the first dose of OPDIVO, requiring treatment with high-dose corticosteroids and methimazole. Thyroid laboratory tests returned to normal 4.7 months later.

Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism.

Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur.

Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy.

The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients (n=385): adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis.

Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, GuillainBarré syndrome, and myasthenic syndrome.

For any suspected immune-mediated adverse reactions, exclude other causes.

Based on the severity of the adverse reaction, withhold OPDIVO, administer highdose corticosteroids, and if appropriate, initiate hormone-replacement therapy.

Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.2) in full Prescribing Information].

Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Immune-Mediated Pneumonitis [see Warnings and Precautions] • Immune-Mediated Colitis [see Warnings and Precautions] • Immune-Mediated Hepatitis [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Hypothyroidism and Hyperthyroidism [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] 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.

The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 3, a single-arm trial in patients with metastatic squamous non-small cell lung cancer (NSCLC).

Clinically significant adverse reactions were evaluated in a total of 691 patients enrolled in Trials 1, 3, or an additional dose finding study (n=306) administering OPDIVO (nivolumab) at doses of 0.1 to 10 mg/kg every 2 weeks [see Warnings and Precautions].

Metastatic Squamous Non-Small Cell Lung Cancer The safety of OPDIVO was evaluated in Trial 3, a single-arm multinational, multicenter trial in 117 patients with metastatic squamous NSCLC and progression on both a prior platinum-based therapy and at least one additional systemic therapy [see Clinical Studies (14.2) in full Prescribing Information].

Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks. The median duration of therapy was 2.3 months (range: 1 day to 16.1+ months). Patients received a median of 6 doses (range: 1 to 34).

Trial 3 excluded patients with active autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis. The median age of patients was 65 years (range: 37 to 87) with 50% ≥65 years of age and 14% ≥75 years of age.

The majority of patients were male (73%) and white (85%). All patients received two or more prior systemic treatments. Baseline disease characteristics of the population were recurrent Stage IIIb (6%), Stage IV (94%), and brain metastases (1.7%). Baseline ECOG performance status was 0 (22%) or 1 (78%).

OPDIVO was discontinued due to adverse reactions in 27% of patients. Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction.

Serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Table 1 summarizes adverse reactions that occurred in at least 10% of patients.

The most common adverse reactions (reported in at least 20% of patients) were fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, and constipation.

Table 1:

Adverse Reactions Occurring in ≥10% of Patients for All NCI CTCAE* Grades or ≥5% for Grades 3-4 (Trial 3)

Table 1: (Continued)

Adverse Reactions Occurring in ≥10% of Patients for All NCI CTCAE* Grades or ≥5% for Grades 3-4 (Trial 3) OPDIVO (nivolumab) (n=117)

Adverse Reaction

All Grades

Investigations Decreased weight Infections and Infestations Pneumoniag

13

0.9

10

5

*a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0.

Includes face edema, peripheral edema, local swelling, localized edema, lymphoedema.

Includes chest discomfort and noncardiac chest pain.

Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, spinal pain. d Includes arthritis and osteoarthritis. e Includes abdominal pain lower, abdominal pain upper, gastrointestinal pain. f Includes maculopapular rash, rash erythematous, erythema, dermatitis, dermatitis exfoliative, and dermatitis acneiform. g Includes lung infection and pneumonia aspiration. b c

Other clinically important adverse reactions in less than 10% of patients in Trial 3 were: General Disorders and Administration Site Conditions: stomatitis Nervous System Disorders: peripheral neuropathy Infections and Infestations: bronchitis, upper respiratory tract infection Table 2:

Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients for all NCI CTCAE Grades or ≥2% for Grades 3-4 (Trial 3) Percentage of Patients with Worsening Laboratory Test from Baselinea

Grades 3-4

Percentage (%) of Patients General Disorders and Administration Site Conditions Fatigue Asthenia Edemaa Pyrexia Chest painb Pain Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Cough Musculoskeletal and Connective Tissue Disorders Musculoskeletal painc Arthralgiad Metabolism and Nutrition Disorders Decreased appetite Gastrointestinal Disorders Nausea Constipation Vomiting Diarrhea Abdominal paine Skin and Subcutaneous Tissue Disorders Rashf Pruritus

Grades 3-4

Percentage (%) of Patients

OPDIVO (n=117) Adverse Reaction

All Grades

50 19 17 17 13 10

7 1.7 1.7 0 0 2.6

38 32

9 1.7

36 13

6 0

35

2.6

29 24 19 18 16

1.7 0 0.9 2.6 1.7

16 11

0.9 0.9 (Continued)

Test Chemistry Hyponatremia Increased creatinine Hypercalcemia Hypokalemia Hypomagnesemia Hypocalcemia Hyperkalemia Increased AST Increased alkaline phosphatase Increased ALT Hematology Lymphopenia Anemia Thrombocytopenia a

All Grades

Grades 3-4

38 22 20 20 20 18 18 16 14 12

10 0 2.6 2.6 0 1.8 4.4 0.9 0 0

47 28 14

16 2.6 0

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (range 111 to 114 patients).

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity.

Of 281 patients who were treated with OPDIVO 3 mg/kg every 2 weeks and evaluable for the presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-product binding antibody development based on the population pharmacokinetic and exposure-response analyses.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample

collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to OPDIVO (nivolumab) with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO. USE IN SPECIFIC POPULATIONS

Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO (nivolumab) has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE There is no information on overdosage with OPDIVO.

Pregnancy

PATIENT COUNSELING INFORMATION

Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) in full Prescribing Information] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in full Prescribing Information]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of OPDIVO, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions].

• Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions].

• Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions].

• Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions].

• Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism [see Warnings and Precautions].

Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions].

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations].

Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations].

Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations].

Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-doserelated increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.

In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.

Lactation Risk Summary It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. Females and Males of Reproductive Potential Contraception Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO. Pediatric Use The safety and effectiveness of OPDIVO have not been established in pediatric patients.

Geriatric Use Clinical studies of OPDIVO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 117 patients treated with OPDIVO in Trial 3, 50% of patients were 65 years or older and 14% were 75 years or older.

Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321663A1

Revised: March 2015 1506US15BR00210-02-01

The ASCO Post | APRIL 10, 2015

PAGE 54

Direct From ASCO

Researcher Spotlight: Conquering Cancer With Emily Ko, MD, MSCR

O

ne of the best ways to prevent cancer is by finding new, better treatments for conditions that are considered risk factors. That is why

Endometrial hyperplasia can also progress to a severe form that is even more strongly associated with endometrial cancer.

To do this kind of work involves quite a bit of coordinated care— between all the clinicians, the researchers, the patients, and the support staff. For this reason, I think having the generosity of grant donors and the Conquer Cancer Foundation is immensely helpful.

late the endometrium, particularly for women who have irregular cycles,” said Dr. Ko. Historically, women with endometrial hyperplasia have taken progesterone-based drugs that often have unwanted side effects, such as mood changes, gastrointestinal problems, and weight gain, the last of which is itself a risk factor for various cancers. “Metformin may actually help some women lose weight. It’s not the purpose of using this drug, but it’s a noted potential benefit,” said Dr. Ko. “If there’s an option to try a different agent that might confer additional benefits, as well as have less of a side-effect profile, it might open up

more opportunities for patients.”

Dr. Ko’s Conquer Cancer Foundation–funded clinical trial is ongoing, actively enrolling patients at both the University of Pennsylvania and the University of North Carolina. The results should be forthcoming in the next year.

“We’re trying to find new ways to treat something, resulting in a better treatment situation for the patient,” said Dr. Ko. “Without the donors’ generosity, it would be much more difficult to conduct this kind of research for all of us young investigators.” n © 2015. American Society of Clinical Oncology. All rights reserved.

—Emily Ko, MD, MSCR

Emily Ko, MD, MSCR, Assistant Professor of Obstetrics and Gynecology at the University of Pennsylvania School of Medicine, is investigating a new method for treating endometrial hyperplasia.

Endometrial hyperplasia, an unusual development of the lining of the uterus, is a precursor to endometrial cancer. It may cause other complications, including very heavy periods that may lead to anemia, sometimes even requiring blood transfusions.

Metformin in Endometrial Hyperplasia Dr. Ko’s 2012 Conquer Cancer Foundation of ASCO Young Investigator Award is supporting a clinical trial examining metformin for the treatment of endometrial hyperplasia. Metformin is a drug traditionally used to treat diabetes in adults. “There has been increasing research that suggests metformin might be very helpful as a treatment or adjunct treatment for various solid tumors, and it might also help to regu-

Stay Up to Date on New Patient Materials From Cancer.Net

E

ncourage your patients to use social media to stay up to date with the new resources available on Cancer.

Net. It is easier than ever for patients to get the latest cancer information on their computer or mobile device. Subscribe to the Cancer.Net Blog at www.

cancer.net/blog; connect to Cancer.

Net’s Facebook (www.facebook.com/ CancerDotNet), Google+ (plus.google .com), or YouTube (www.youtube .com/CancerDotNet) page; and follow CancerDotNet on Twitter (www.twitter .com/CancerDotNet). n © 2015. American Society of Clinical Oncology. All rights reserved.

Accelerating Breakthroughs Launching Careers Improving Cancer Care

ConquerCancerFoundation.org

ASCOPost.com | APRIL 10, 2015

PAGE 55

Direct From ASCO

Conquer Cancer Foundation Grants and Awards Program

C

onquer Cancer Foundation of the American Society of Clinical Oncology (CCF) is fueling cancer research and pursuing dramatic advances in the diagnosis, prevention, treatment, and cure of all kinds of cancer.

At critical points for researchers, CCF is there with essential funding to power the next generation of

• 95% of all grant recipients are currently publishing.

• 98% of all grantees since 1984 are still active in oncology research today.

• 11 impactful awards, important support for oncology experts in key

career stages.

• Rigorous and highly competitive selection process, in line with the exacting standards of the National Institutes of Health and CCF’s parent organization, ASCO. Please visit ConquerCancerFoun-

dation.org to learn more about the CCF Grants and Awards Program and to make a donation to support cancer research. n © 2015. American Society of Clinical Oncology. All rights reserved.

E FP red F a t rin ) Cle P a 0(k m m 51 Ma FDA w No breakthroughs that help improve the lives of millions of people touched by ­cancer.

From medical students to physicians and scientists in the early stages of their work and beyond, we fund promising researchers when it really matters.

We provide early, lifeline funding to the brightest young minds in cancer research, so they can stay in cancer research.

Lasting Impact For more than 3 decades, the CCF Grants and Awards program has been instrumental in launching careers and accelerating breakthroughs. Our impact: • More than $92 million has been awarded to over 1,200 cancer professionals in 65 countries.

• 1,475 grants and awards went to 337 academic medical institutions and nonprofit organizations.

• 99% of recipients said their grant was important to advancing their careers.

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MammaPrint® provides more informaton about your patent’s breast cancer recurrence risk with defnitve, High Risk/Low Risk results. BluePrint® classifes Luminal-type, Basal-type and HER2-type functonal molecular subtypes. Together, they reveal more clinically actonable biology: • MammaPrint + BluePrint can reclassify up to 25% of breast cancers with potental therapeutc and prognostc implicatons, according to a study published in Cancer Research.1 • Most recently, NBRST, a prospectve neoadjuvant study, concluded that BluePrint may be a beter guide than IHC-FISH tests in making decisions about how to treat early-stage breast cancer before surgery.2 For more clinically actonable informaton, order MammaPrint + BluePrint to uncover your patent’s functonal molecular subtype. The diference is clear.

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Agendia, Inc. 22 Morgan, Irvine, CA 92618 (888) 321-2732 www.agendia.com © 2015 1 Cristofanilli M, et al. Cancer Res. 2012;72(24 Suppl):Abstract nr P3-05-01.

2 Whitworth P, et al. Ann Surg Oncol. 2014 Aug 7.

[Epub ahead of print];doi: 10.1245/s10434-014-3908-y.

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The ASCO Post | APRIL 10, 2015

PAGE 56

Direct From ASCO

Researchers and Scientists Honored for Improving Cancer Prevention, Treatment, and Patient Care

T

he ASCO Special Awards recognize the dedication and significant contributions of researchers, patient advocates, and leaders of the global oncology community to enhancing cancer prevention, treatment, and patient care. Among this year’s awardees are an international leader in geriatric oncology and a hematologic oncologist whose work has improved patient care and the education of health-care providers in Honduras.

“This year’s Special Awards recipients have made outstanding contributions to the field of oncology, leading a global effort to transform cancer care and improve the lives of people living with cancer,” said Clifford A. Hudis, MD, FACP, Immediate Past President of ASCO and Chair of the Special Awards Selection Committee. “It is our honor to recognize their innovation and dedication with the highest honors that ASCO awards every year.”

The 2015 Special Awards Honorees are:

understanding of geriatric oncology to fellows and junior faculty.

• Silvio Monfardini, MD, Director of the Geriatric Oncology Program at Istituto Palazzolo, Fondazione Don Gnocchi, in Milan, Italy

James P. Allison, PhD

partment of Immunology in the Division of Basic Science Research

ASCO-American Cancer Society Award and Lecture First presented in 1993, the ASCOACS Award and Lecture recognizes significant contributions to cancer prevention and control, research, or practice.

First presented in 1970, the David A. Karnofsky Memorial Award and Lecture honors Dr. Karnofsky by recognizing an oncologist who has made outstanding contributions to cancer research, diagnosis, and/or treatment.

Suzanne L. Topalian, MD

• Suzanne L. Topalian, MD, Professor of Surgery and Oncology, and Director of the Melanoma Program in the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine

Science of Oncology Award and Lecture Created in 2005, the Science of Oncology Award and Lecture is presented annually in recognition of a recipient’s outstanding contributions to basic or translational research in cancer.

• James P. Allison, PhD, Professor and Chair of The University of Texas MD Anderson Cancer Center De-

Distinguished Achievement Award Created in 2009, the Distinguished Achievement Award recognizes leadership or mentorship by a scientist, practitioner, or researcher in any subspecialty of oncology that has benefited ASCO members and/or their patients.

George Bosl, MD

David A. Karnofsky Memorial Award and Lecture Ernest Hawk, MD, MPH

• Ernest Hawk, MD, MPH, Vice President and Head of the Division of Cancer Prevention and Population Sciences at The University of Texas MD Anderson Cancer Center, Co-Leader of the Cancer Control Platform, Executive Director of the Duncan Family Institute for Cancer Prevention and Risk Assessment, and the Boone Pickens Distinguished Chair for Early Prevention of Cancer

• George Bosl, MD, Chair of the Department of Medicine, Patrick M. Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, and Professor of Medicine at Weill Cornell Medical College

• Matthew Ellis, MD, PhD, Co-Leader for The Cancer Genome Atlas (TCGA) Breast Project, Co-Principal Investigator for the Clinical Proteomic Tumor Analysis Consortium, Director of the Lester and Sue Smith Breast Center, and Professor of Medicine and Cellular and Molecular Biology at Baylor College of Medicine

Humanitarian Award First presented in 2011, the Humanitarian Award recognizes an oncologist going above and beyond the call of duty, in providing outstanding patient care through innovative means, exceptional service, or leadership, in the United States or abroad.

First awarded in 2014, the Excellence in Teaching Award recognizes an ASCO member who has had a demonstrable impact on their trainees and has inspired and shaped their students’ practice of cancer medicine.

Jose Angel Sanchez, MD

• Jose Angel Sanchez, MD, Hematologic Oncologist at Hospital Escuela, University of Honduras

Partners in Progress Award Dean F. Bajorin, MD, FACP

• Dean F. Bajorin, MD, FACP, Attending Physician and Member at Memorial Hospital, Memorial Sloan Kettering Cancer Center, and Professor of Medicine at Weill Cornell Medical College

Gianni Bonadonna Breast Cancer Award and Lecture Silvio Monfardini, MD

Matthew Ellis, MD, PhD

Excellence in Teaching Award

B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology Created in 2007 in honor of B.J. Kennedy, MD, this award and lectureship recognizes an ASCO member who has made outstanding contributions to the research, diagnosis, and treatment of cancer in the elderly and in bringing an

Bonadonna, MD, this award recognizes an active clinical and/or translational researcher with a distinguished record of accomplishments in advancing the field of breast cancer.

First presented in 2007 and named in honor of cancer research pioneer Gianni

First awarded in 2003, the Partners in Progress Award recognizes a person involved in patient advocacy activities that impact public awareness about cancer, its causes, cures, or treatment, or activities that result in additional support either legislatively or fiscally for cancer research, treatment, prevention, or care.

• Mary Lou Smith, JD, MBA, Cofounder of the Research Advocacy Network (RAN), Co-Chair of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Re-

ASCOPost.com | APRIL 10, 2015

PAGE 57

Direct From ASCO in areas of clinical oncology, cancer research, clinical trials, and patient advocacy activities, or outstanding long-term service to ASCO and/or to clinical oncology.

Mary Lou Smith, JD, MBA

Kathy S. Albain, MD

Lillian L. Siu, MD, FRCPC

Craig Earle, MD

Eric J. Small, MD

search Advocate Committee, and member of the National Cancer Institute Board of Scientific Advisors

Pediatric Oncology Award and Lecture First presented in 2002, the Pediatric Oncology Award recognizes the career and achievements of an individual who has contributed outstanding laboratory, clinical, or epidemiologic work of major importance to the field of pediatric oncology.

Stephen E. Sallan, MD

• Stephen E. Sallan, MD, Professor of Pediatrics at Harvard Medical School, and Pediatric Oncologist at Dana-Farber Cancer Institute and Boston Children’s Hospital

Special Recognition Award Created in 1992, the Special Recognition Award honors achievements of an individual whose research and innovations have had a transforming and lasting effect

Archie Bleyer, MD

• Archie Bleyer, MD, Clinical Research Professor at the Knight Cancer Institute of the Oregon Health & Science University

Fellows of the American Society of Clinical Oncology The Fellow of the American Society of Clinical Oncology (FASCO) distinction recognizes ASCO members for their extraordinary volunteer service, dedication, and commitment to ASCO. Their efforts benefit ASCO, the specialty of oncology, and, most importantly, the patients they serve. The 2015 recipients of this distinction are: • Kathy S. Albain, MD • Craig Earle, MD • Roscoe F. Morton, MD, FACP • Lori J. Pierce, MD • Lillian L. Siu, MD, FRCPC • Eric J. Small, MD • Sandra M. Swain, MD, FACP All of the awards listed above and the Fellows of the American Society of Clinical Oncology will be presented at the 2015 ASCO Annual Meeting taking place in Chicago, May 29 to June 2, with

Roscoe F. Morton, MD, FACP

Lori J. Pierce, MD

the exception of the Gianni Bonadonna Breast Cancer Award and Lecture, which will be presented at the 2015 Breast Cancer Symposium, taking place September 25 to 27 in San Francisco.

Sandra M. Swain, MD, FACP

The ASCO Special Awards acknowledges the generous support of the American Cancer Society for the ASCO-American Cancer Society Award and Lecture; the Alliance for Academic Internal Medicine and The John A. Hartford Foundation for the B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology; and GlaxoSmithKline Oncology for the Gianni Bonadonna Breast Cancer Award and Lecture. n © 2015. American Society of Clinical Oncology. All rights reserved.

Worker Safety When Handling Hazardous Drugs Is Focus of Statement by Oncology Societies

A

SCO, the Hematology/Oncology Pharmacy Association (HOPA), and the Oncology Nursing Society (ONS) issued a joint position statement on improving the safety of health-care workers who handle dangerous drugs and other hazardous materials across various health-care settings.

The statement offers seven recommendations for organizations in which hazardous drugs are present. The recommendations include establishing evi-

dence-based policies and procedures for safe handling of these drugs that comply with regulatory requirements, such as providing and maintaining engineering controls and appropriate personal protective equipment to reduce worker exposure to hazardous drugs; disposing of hazardous drug waste according to regulatory guidelines and in a manner that protects staff and the environment; and protecting the right of staff who are trying to conceive or who are pregnant or nurs-

ing to engage in alternative duties that do not require hazardous drug handling.

Furthermore, the statement recommends that organizations provide education and training about safe handling to staff members who could potentially be exposed to hazardous drugs that are specific to each worker’s role. This education should extend to patients who receive these drugs, as well as their caregivers, to minimize unintended exposure. Lastly, the position statement suggests that pro-

fessional societies continue to explore evidence-based strategies for mitigation of risk associated with handling hazardous drugs and share findings with their respective members.

To read the joint position statement, please go to http://www.asco.org/ s i te s / w w w. a s co.o rg / f i l e s / s a f e _ handling_final_022015.pdf. n © 2015. American Society of Clinical Oncology. All rights reserved.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION:

SHAPING THE WAY FORWARD

Indication KyprolisÂŽ (carfilzomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma.

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis, and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. Š2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100826J November 2014 Printed in USA

for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.

Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported.

Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline.

Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be

Kyprolis® (carfilzomib) for Injection: 003-A1 Phase 2 Study Results* n

22.9% OVERALL RESPONSE RATE (ORR) (95% CI: 18.0, 28.5)1

n

7.8-MONTH MEDIAN DURATION OF RESPONSE (95% CI: 5.6, 9.2)1

n

Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event1,2 - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each)1

*Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and whose disease had a ≤25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly.

Interrupt KYPROLIS until TLS is resolved.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%.

Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%).

KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate.

Monitor liver enzymes frequently.

Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).

The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of full Prescribing Information on adjacent pages.

References: 1. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012. 2. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753-1761.

The ASCO Post | APRIL 10, 2015

PAGE 60

Announcements

St. Jude Children’s Research Hospital Appoints Chair of Department of Radiation Oncology

S

t. Jude Children’s Research Hospital has named Thomas E. Merchant, DO, PhD, as Chair of the Department of Radiation Oncology. Dr. Merchant will hold the Baddia J. Rashid

Endowed Chair in Radiation Oncology.

“Dr. Merchant is a proven leader in pediatric radiotherapy and will be instrumental in helping St. Jude define the next generation of treatments that hold

the best hope for improved outcomes and better long-term quality of life for children with brain and solid tumors,” said James R. Downing, MD, St. Jude President and Chief Executive Officer.

B:16.75”

Since joining St. Jude in 1996, Dr. Merchant helped pioneer new radiotherapy treatments that serve as standards in the field. His work with conformal radiation therapy for central

T:16.25” S:14.625”

a Table 2: Dose Table Modifications 2: Dose Modifications for Toxicityafor during Toxicity KYPROLIS duringTreatment KYPROLIS(continued) Treatment (continued) Renal Toxicity Renal Toxicity • Withhold until renal function has • Withhold until renal function has recovered to recovered Grade 1 to Grade 1 to baseline and monitor monitor renal function.renal function.

• Serum creatinine • Serum creatinine equal to or equal toororto baselineorand • Iftoattributable KYPROLIS, at the next scheduled • If attributable KYPROLIS,to restart at the restart next scheduled than 2 × baseline greater than 2greater × baseline 2 at a reduced (from treatment at atreatment reduced dose (from 27dose mg/m to 27 mg/m2 to Adverse Reactions] [see Adverse [see Reactions] 2 202,mg/m OR from to 15 20 mg/m mg/m22).to 15 mg/m2).

20 mg/m2, OR20from mg/m KYPROLIS™KYPROLIS™ (carfilzomib) (carfilzomib) for Injectionfor Injection Brief Summary BriefofSummary Prescribing of Prescribing Information.Information.

Please see Please the KYPROLIS see the package KYPROLISinsert package insert • If not attributable • If nottoattributable KYPROLIS,torestart KYPROLIS, at the restart dose used at the dose used for full prescribing for full prescribing information.information. prior to the event. prior to the event.

INDICATIONS INDICATIONS AND USAGE: AND KYPROLIS USAGE:is KYPROLIS indicated for is indicated the treatment for theof treatment patients with of patients multiplewith multiple • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the myeloma who myeloma have received who haveat received least twoat prior least therapies two prior including therapiesbortezomib including and bortezomib an and an previous doseprevious at the discretion dose at the of the discretion physician. of the physician. immunomodulatory immunomodulatory agent and have agentdemonstrated and have demonstrated disease progression disease on progression or within on 60 ordays within of 60 Peripheral days of Neuropathy Peripheral Neuropathy • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. completion ofcompletion the last therapy. of the Approval last therapy. is based Approval on response is based rate on response [see Clinical rate Studies [see Clinical section Studies of fullsection of full • Restart at •theRestart dose used at the prior dose to used the event priororto reduced the event or reduced • Grade 3 or• 4 Grade 3 or 4 PI]. Clinical benefit, PI]. Clinical such benefit, as improvement such as improvement in survival or in symptoms, survival orhas symptoms, not beenhas verified. not been verified.

2 2 dose (from 27dose mg/m (from to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from 20 mg/m2 [see Adverse [see Reactions] Adverse Reactions] DOSAGE AND DOSAGE ADMINISTRATION: AND ADMINISTRATION: Dosing Guidelines.

Dosing Guidelines.

KYPROLIS is KYPROLIS administered is administered intravenously intravenously 2 2 to 15 mg/m ),toat15themg/m discretion ), at the of the discretion physician. of the physician. over 2 to 10 over minutes, 2 to on 10two minutes, consecutive on twodays, consecutive each week days,foreach threeweek weeks for (Days three weeks 1, 2, 8,(Days 9, 15,1,and 2, 8, 9, 15, and • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the 16), followed 16), by a followed 12‑day rest by aperiod 12‑day (Days rest 17 period to 28).

(Days Each 1728‑day to 28). Each period28‑day is considered period isone considered treatmentone treatment previous doseprevious at the discretion dose at the of the discretion physician. of the physician.

2 cycle (Table 1). cycle In Cycle (Table1,1).

KYPROLIS In Cycle is 1, administered KYPROLIS is administered at a dose of 20 at mg/m a dose2.ofIf tolerated 20 mg/min . IfCycle tolerated 1, thein Cycle 1, the Other Other • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. dose should be dose escalated should to be27 escalated mg/m2 beginning to 27 mg/m in2 Cycle beginning 2 andincontinued Cycle 2 and at 27 continued mg/m2 in at subsequent 27 mg/m2 in subsequent • Consider restarting • Consider at the restarting next scheduled at the next treatment scheduled treatment • Grade non‑hematological 3 or 4 non‑hematological cycles. Treatment cycles. may Treatment be continued may be untilcontinued disease progression until diseaseorprogression until unacceptable or until unacceptable toxicity occurstoxicity [see occurs [see 3 or• 4 Grade 2 with one dosewith levelone reduction dose level (from reduction 27 mg/m (from to 27 mg/m2 to toxicities toxicities Dosage and Administration].

Dosage and Administration].

The dose is calculated The dose isusing calculated the patient’s using the actual patient’s body surface actual body area surface at area at 2 2 2 2 20 ,mg/m OR from to 20 15 mg/m ).to 15 mg/m2).

20 mg/m , OR20from mg/m baseline. Patients baseline. with Patients a body surface with a body area surface greater than area 2.2 greater m2 should than 2.2 m2 should receive a dosereceive basedaupon doseabased upon a 2 • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the body surface body area of surface 2.2 marea of 2.2 m2. Dosedo . Dose adjustments adjustments not need todobenot made needfortoweight be made changes for weight of less changes than of less than previous doseprevious at the discretion dose at the of the discretion physician. of the physician. or equal to 20%. or equal to 20%. a Table 1: KYPROLIS Table 1:Dosage KYPROLIS Regimen Dosage forRegimen Patients for with Patients Multiple with Myeloma Multiple Myeloma National CanceraNational InstituteCancer Common Institute Terminology Common Criteria Terminology for Adverse Criteria Events for Adverse (NCI CTCAE) Events Version (NCI CTCAE) 3.0. Version 3.0.

Administration Administration Precautions.Precautions.

The quantity The of KYPROLIS quantity ofcontained KYPROLIS in contained one single‑use in onevial single‑use (60 mg vial (60 mg Cycle 1 Cycle 1 carfilzomib) may carfilzomib) exceed may the required exceed the dose. required Cautiondose. should Caution be used should in calculating be used inthe calculating quantity the quantity Week 1 Week 1 Week 2 Week 2 Week 3 Week Week 3 4 Week 4 delivered to prevent delivered overdosing. to prevent Do overdosing. not mix KYPROLIS Do not mix with KYPROLIS or administer with or as administer an infusion as with an infusion other with other DaysDayDayDays Day Day DaysDayDayDays Day Day DaysDayDays Days Days Day Day Day medicinal Theproducts. intravenous Theadministration intravenous administration line should beline flushed shouldwith be normal flushed saline with normal or 5% saline or 5% 2 1 3–7 2 8 3–79 10–14 8 9 1510–14 16 15 17–2116 22–28 17–21 medicinal 22–28 products.

1 Dextrose Injection, Dextrose USPInjection, immediately USP before immediately and after before KYPROLIS and after administration.

KYPROLIS administration.

KYPROLIS should KYPROLIS not should not KYPROLIS KYPROLIS 20 20 No 20 20 No20 20No 20 20 No 20 20 No 20 No No No 20 administered be administered as a bolus. KYPROLIS as a bolus. should KYPROLIS be administered should be administered over 2 to 10 minutes. over 2 toReconstitution 10 minutes. Reconstitution (20 mg/m2):(20 mg/m2): Dosing Dosing Dosing Dosing Dosing Dosing Dosing be Dosing and Preparation and Preparation for Intravenous for Intravenous Administration.

Administration.

KYPROLIS vials KYPROLIS containvials no antimicrobial contain no antimicrobial a Cycles 2 andCycles Beyond 2 and Beyonda preservativespreservatives and are intended and are onlyintended for singleonly use.forUnopened single use. vials Unopened of KYPROLIS vials of areKYPROLIS stable until arethe stable until the Week 1 Week 1 Week 2 Week 2 Week 3 Week Week 3 4 Week 4 date indicated date on the indicated package on when the package stored in when the original stored inpackage the original at 2°C package to 8°Cat(36°F 2°C to to 8°C 46°F).

(36°F Theto 46°F). The DaysDayDayDays Day Day DaysDayDayDays Day Day DaysDayDays Days reconstituted Days Day Day Day reconstituted solution contains solution carfilzomib contains atcarfilzomib a concentration at a concentration of 2 mg/mL.ofRead 2 mg/mL. the complete Read the complete 2 1 3–7 2 8 3–79 10–14 8 9 1510–14 16 15 17–2116 22–28 17–21 preparation 22–28 1 instructions preparationprior instructions to reconstitution. prior to reconstitution.

Reconstitution/Preparation Reconstitution/Preparation Steps: 1. Remove Steps:vial 1. Remove vial KYPROLIS KYPROLIS 27 27 No 27 27 No27 27No 27 27 No 27 27 No 27 No No No refrigerator 27 from fromjust refrigerator prior to use. just prior 2. Aseptically to use. 2.reconstitute Aseptically each reconstitute vial by each slowlyvial injecting by slowly 29 injecting mL 29 mL Dosing Dosing Dosing Dosing Dosing Dosing Sterile DosingWater Sterile (27 mg/m2):(27 mg/m2): Dosing Water USP, for Injection, the solution ontoWALL the INSIDE OFminimize THE VIAL to minimize for Injection, directingUSP, the directing solution onto the INSIDE OF THEWALL VIAL to a If previous cycle a If dosage foaming.

Gently invert swirl and/or slowly for about 1 minute, or until complete dissolution foaming. 3. Gently swirl3.and/or the vialinvert slowlythe forvial about 1 minute, or until complete dissolution previousiscycle tolerated. dosage is tolerated. of powder any cakeoccurs. or powder occurs.

DO to NOT SHAKE avoid foamIfgeneration.

If foaming cake or DO NOT SHAKE avoid foamtogeneration. foaming occurs, allowoccurs, allow Hydration and Hydration Fluid Monitoring. and Fluid Monitoring.

Hydrate patients Hydrate to reduce patients thetorisk reduce of renal the toxicity risk of renal and oftoxicity tumor andofofany tumor solution to rest in vial for about 2 to 5 minutes, until foaming subsides.

4.

After reconstitution, solution to rest in vial for about 2 to 5 minutes, until foaming subsides.

4.

After reconstitution, lysis syndrome lysis (TLS) syndrome with KYPROLIS (TLS) withtreatment KYPROLIS [see treatment Warnings[see andWarnings Precautions]. and Precautions].

Maintain adequate Maintain adequate KYPROLIS is ready for intravenous administration.

The reconstituted product should be a clear, KYPROLIS is ready for intravenous administration.

The reconstituted product should be a clear, fluid volume status fluid volume throughout statustreatment throughout andtreatment monitor blood and monitor chemistries bloodclosely. chemistries Prior closely. to each Prior dose to in each dose in colorless If any discoloration particulate matter do is observed, not use the reconstituted colorless If anysolution. discoloration or particulateormatter is observed, not use thedoreconstituted Cycle 1, give Cycle 250 mL 1, give to 500 250mLmLoftointravenous 500 mL ofnormal intravenous salinenormal or othersaline appropriate or otherintravenous appropriatefluid. intravenous fluid.solution. product.

5. When administering in anbag, intravenous calculated dose and [see Dosage and product. 5. When administering in an intravenous withdrawbag, the withdraw calculatedthe dose [see Dosage Give an additional Give an250 additional mL to 250 500 mL mL to of 500 intravenous mL of fluids intravenous as needed fluids following as neededKYPROLIS following KYPROLIS and50dilute into Dextrose 50 mL 5% Dextrose USP bag. intravenous bag. from the vialfrom and the dilutevialinto mL 5% Injection, USPInjection, intravenous administration. administration.

Continue intravenous Continue hydration, intravenousashydration, needed, in as subsequent needed, in cycles. subsequent Also cycles. monitorAlsoAdministration] monitor Administration] 6. Immediately the vialthe containing unused of reconstituted 6. Immediately discard the discard vial containing unused the portion.

The portion. stabilitiesTheof stabilities reconstituted patients during patients this period during for thisfluid period overload for fluid [seeoverload Warnings [see andWarnings Precautions]. and Precautions].

Dexamethasone Dexamethasone KYPROLIS various and temperature container shown variousunder temperature containerand conditions areconditions shown in are Table 3. in Table 3.

Premedication.

Premedication.

Pre‑medicatePre‑medicate with dexamethasone with dexamethasone 4 mg orally or4intravenously mg orally or intravenously prior to all doses priorofto allKYPROLIS doses of under Table of 3: Reconstituted Stability of Reconstituted Table 3:toStability KYPROLIS KYPROLIS KYPROLIS during KYPROLIS Cycle during 1 and prior Cycleto1alland KYPROLIS prior to all doses KYPROLIS during doses the first during cyclethe of dose first cycle escalation of dose to escalation 2 27 mg/m2 to 27 mg/m reduce the toincidence reduce the andincidence severity ofand infusion severity reactions of infusion [seereactions Warnings[see andWarnings Precautions]. and Precautions]. a Stabilitya perStability Container per Container Reinstate dexamethasone Reinstate dexamethasone premedicationpremedication (4 mg orally or(4intravenously) mg orally or intravenously) if these symptoms if these develop symptoms or develop or Storage of Conditions of Reconstituted Storage Conditions Reconstituted reappear during reappear subsequent during cycles. subsequent Dosecycles.

Modifications Dose Modifications based on Toxicities. based on Recommended Toxicities. Recommended IV Bag IV Bag KYPROLIS KYPROLIS actions and dose actions modifications and dose modifications are presentedare in Table presented 2. in Table 2.

Vial Vial Syringe Syringe (D5Wb) (D5Wb) a Table 2: Dose Table Modifications 2: Dose Modifications for Toxicityafor Toxicity during KYPROLIS duringTreatment KYPROLIS Treatment RefrigeratedRefrigerated (2°C to 8°C;(2°C 36°Ftoto8°C; 46°F) 36°F to 46°F) 24 hours 2424 hours hours 2424hours hours 24 hours HematologicHematologic Toxicity Recommended Action Toxicity Recommended Action

• Withhold dose.

• Withhold dose.

• Grade 3a or Neutropenia • 4Grade 3a or 4 Neutropenia Room Temperature Room Temperature (15°C to 30°C; (15°C 59°F to to 30°C; 86°F) 59°F to 86°F) 4 hours 4 hours 4 hours 4 4hours hours 4 hours • If fully recovered • If fully before recovered next scheduled before next dose, scheduled continue dose, continue • Grade 4 Thrombocytopenia • Grade 4 Thrombocytopenia a b b Total time fromaTotal reconstitution time fromtoreconstitution administration to should administration not exceed should 24 hours. not exceed 5% 24 Dextrose hours.Injection, 5% Dextrose USP. Injection, USP. at same doseatlevel. same dose level. [see Warnings[see andWarnings Precautions] and Precautions] AND PRECAUTIONS: AND PRECAUTIONS: Cardiac Arrest, Cardiac Congestive Arrest, Congestive Heart Failure, Heart Myocardial Failure, Myocardial • If recovered • toIf recovered Grade 2 neutropenia to Grade 2 or neutropenia Grade 3 or Grade 3 WARNINGS WARNINGS Ischemia. Death Ischemia. due toDeath cardiacdue arrest to cardiac has occurred arrest has within occurred a day of within KYPROLIS a day of administration.

KYPROLIS administration.

New New thrombocytopenia, thrombocytopenia, reduce dose by reduce one dose level by one dose level onset onset or of worsening pre‑existingofcongestive pre‑existingheart congestive failure with heartdecreased failure withleftdecreased ventricularleftfunction ventricular or function or 2 2 2 (from 27 mg/m (from to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from to 20 mg/m to or worsening myocardial ischemia myocardial have ischemia occurred have following occurred administration following administration of KYPROLIS. of Cardiac KYPROLIS. failure Cardiac events failure events 15 mg/m2). 15 mg/m2). (e.g., cardiac (e.g., failurecardiac congestive, failurepulmonary congestive,edema, pulmonary ejection edema, fraction ejection decreased) fractionwere decreased) reportedwere in 7% reported in 7% • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the of patients. Monitor of patients. for cardiac Monitorcomplications for cardiac complications and manage and promptly. manage Withhold promptly.

KYPROLIS Withhold forKYPROLIS Grade 3 for Grade 3 previous doseprevious at the discretion dose at the of the discretion physician. of the physician. or 4 cardiac events or 4 cardiac until recovery events until and recovery consider and whether consider to restart whether KYPROLIS to restart based KYPROLIS on a benefit/risk based on a benefit/risk Non-Hematologic Non-Hematologic Toxicity Toxicity Recommended Recommended Action Action assessment [see assessment Dosage [see and Administration].

Dosage and Administration].

Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and Class III and IV heart myocardial failure,infarction myocardial in infarction the preceding in the6 preceding months, and 6 months, conduction and abnormalities conduction abnormalities Cardiac Toxicity Cardiac Toxicity • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. IV heart failure, by uncontrolled medications by were medications not eligible werefornottheeligible clinicalfortrials. the clinical These patients trials. These may patients be at greater may be at greater • After of: resolution, • Afterconsider resolution, if restarting considerKYPROLIS if restarting at KYPROLISuncontrolled at Grade 3 or 4, new Grade onset 3 oror4,worsening new onsetof: or worsening 2 risk for cardiac riskcomplications. for cardiac complications.

Pulmonary Pulmonary Hypertension.

Hypertension.

Pulmonary arterial Pulmonary hypertension arterial hypertension (PAH) (PAH) a reduced is appropriate dose is(from appropriate 27 mg/m (from to 27 mg/m2 to • congestive•heart congestive failure; heart failure; a reduced dose 2 2 2 2 2 was reported was in 2% reported of patients in 2% treated of patients with KYPROLIS treated with and KYPROLIS was Grade and 3 was or greater Grade in 3 less or greater than 1% in less of than 1% of 20 ,mg/m OR from to 20 15 mg/m ).to 15 mg/m ). mg/m • decreased•leftdecreased ventricularleft ventricular 20 mg/m , OR20from patients. withEvaluate cardiac with imaging cardiac and/or imaging other and/or tests as other indicated. tests asWithhold indicated.

KYPROLIS WithholdforKYPROLIS for • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedpatients. to the Evaluate function; function; pulmonary hypertension until resolveduntil or returned resolved to or baseline returned and to baseline considerand whether consider to restart whether to restart at the discretion dose at the of the discretion physician. of the physician.pulmonary hypertension • or myocardial • orischemia myocardial ischemia previous doseprevious KYPROLIS based KYPROLIS on a based benefit/risk on a assessment benefit/risk assessment [see Dosage[see and Dosage Administration]. and Administration].

Pulmonary Pulmonary [see Warnings[see andWarnings Precautions] and Precautions] Complications.

Complications.

Dyspnea wasDyspnea reported was in 35% reported of patients in 35% enrolled of patients in clinical enrolled trials. in clinical Grade 3trials. dyspnea Grade 3 dyspnea occurred no Grade in 5%; 4 events, no Grade and4 1events, death and (Grade 1 death 5) was (Grade reported.

5) was Monitor reported. and Monitor manage and manage Pulmonary Hypertension Pulmonary Hypertension • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. occurred in 5%; dyspnea immediately; dyspnea immediately; interrupt KYPROLIS interrupt until KYPROLIS symptoms until have symptoms resolved have or returned resolved to or baseline returned [see to baseline [see • Restart at •theRestart dose used at the prior dose to used the event priororto reduced the event or reduced [see Warnings[see andWarnings Precautions] and Precautions] 2 2 Administration and Administration and Adverse and Reactions].

AdverseInfusion Reactions].

Reactions.

Infusion Infusion Reactions. reactions Infusion were reactions were to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from 20Dosage mg/m2 and Dosage dose (from 27dose mg/m (from 2 by a spectrum by ofa systemic spectrum symptoms of systemicincluding symptoms fever, including chills, arthralgia, fever, chills, myalgia, arthralgia, facialmyalgia, facial to 15 mg/m2),toat15themg/m discretion ), at the of the discretion physician. of the physician.characterizedcharacterized edema,facial vomiting, edema, weakness, vomiting, shortness weakness, of breath, shortness hypotension, of breath, syncope, hypotension, chest syncope, tightness, chest tightness, • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedflushing, to the facialflushing, or angina. reactions These canreactions occur immediately can occur following immediately or up following to 24 hours or up after to 24administration hours after administration of of previous doseprevious at the discretion dose at the of the discretion physician. of the physician.or angina. These KYPROLIS.dexamethasone Administer dexamethasone prior to KYPROLIS prior toto KYPROLIS reduce theto incidence reduce the andincidence severity and of severity of Pulmonary Complications Pulmonary Complications • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. KYPROLIS. Administer reactions [seereactions Dosage [see and Administration].

Dosage and Administration].

Inform patients Inform of thepatients risk and of symptoms the risk andand symptoms to contactand to contact • Consider restarting • Consider at the restarting next scheduled at the next treatment scheduled treatment • Grade 3 or• 4 Grade 3 or 4 physician if symptoms physicianofif symptoms an infusionofreaction an infusion occurreaction [see Patient occurCounseling [see PatientInformation].

Counseling Tumor Information].

LysisTumor Lysis 2 with one dosewith levelone reduction dose level (from reduction 27 mg/m (from to 27 mg/m2 to [see Warnings[see andWarnings Precautions] and Precautions] Syndrome.

Tumor Syndrome. lysis syndrome Tumor lysis (TLS) syndrome occurred (TLS) following occurred KYPROLIS following administration KYPROLIS administration in < 1% of in < 1% of 2 202,mg/m OR from to 20 15 mg/m mg/m22).to 15 mg/m2).

20 mg/m2, OR20from mg/m patients. Patients patients. withPatients multiple with myeloma multiple andmyeloma a high tumor and aburden high tumor should burden be considered should betoconsidered be at to be at • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedgreater to the risk for greater TLS. Prior risk for to receiving TLS. PriorKYPROLIS, to receivingensure KYPROLIS, that patients ensure that are well patients hydrated are well [seehydrated Dosage [see Dosage previous doseprevious at the discretion dose at the of the discretion physician. of the physician.and Administration]. and Administration].

Monitor for evidence Monitor for of TLS evidence duringoftreatment, TLS duringand treatment, manage and promptly. manage Interrupt promptly. Interrupt Hepatic Toxicity Hepatic Toxicity • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. KYPROLIS until KYPROLIS TLS is resolved until TLS[see is resolved Dosage [see and Dosage Administration].Thrombocytopenia. and Administration].Thrombocytopenia.

KYPROLIS KYPROLIS • After consider resolution, if restarting considerKYPROLIS if restarting is KYPROLIS iscauses thrombocytopenia • Grade 3 or• 4 Grade elevation 3 orof4 elevation•of After resolution, causes thrombocytopenia with platelet with nadirsplatelet occurring nadirs around occurring Day 8around of each Day28‑day 8 of each cycle28‑day and cycle and may appropriate; be reinitiated may at beareinitiated reduced dose at a reduced (from doserecovery (from to baseline transaminases, transaminases, bilirubin or other bilirubin orappropriate; other recoverybytothe baseline start ofbythe thenext start28‑day of the cycle. next 28‑day In patients cycle. with In patients multiple with myeloma, multiple 36% myeloma, of 36% of 2 27 mg/m2 to 20 27 mg/m22, to OR20from mg/m 202mg/m , OR from to 15 20 mg/m mg/m22) to 15patients mg/m2) experienced liver abnormalities liver abnormalities patients experienced thrombocytopenia, thrombocytopenia, including Grade including 4 in 10%.

Grade Thrombocytopenia 4 in 10%. Thrombocytopenia following following with frequentwith monitoring frequentofmonitoring liver function. of liver function.

KYPROLIS administration KYPROLIS administration resulted in aresulted dose reduction in a dose in reduction 1% of patients in 1% and of patients discontinuation and discontinuation of of [see Warnings[see andWarnings Precautions] and Precautions] • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedtreatment to the with treatment KYPROLIS within KYPROLIS < 1% of patients. in < 1%Monitor of patients. platelet Monitor counts platelet frequently countsduring frequently treatment during treatment previous doseprevious at the discretion dose at the of the discretion physician. of the physician.with KYPROLIS. withReduce KYPROLIS. or interrupt Reduce dose or interrupt as clinically dose indicated as clinically [seeindicated Dosage [see and Dosage Administration]. and Administration].

Hepatic Toxicity Hepatic andToxicity Hepaticand Failure.

Hepatic Cases Failure. of hepatic Cases failure, of hepatic including failure, fatalincluding cases, have fatalbeen cases, have been (continued) (continued)

ASCOPost.com | APRIL 10, 2015

PAGE 61

Announcements

B:16.75” T:16.25” S:14.625”

Thomas E. Merchant, DO, PhD

nervous system tumors is the basis for guidelines used in most of the national cooperative group pediatric brain tumor trials. He has led the development of treatment guidelines for intensitymodulated radiation therapy and proton therapy in all types of pediatric brain and solid tumors.

Dr. Merchant also played a key role

in creating the St. Jude Red Frog Events Proton Therapy Center, the world’s first proton therapy center designed for and dedicated solely to the treatment of children.

Dr. Merchant will be Chair of a department that was previously a division of St. Jude Radiological Sciences. As operations have grown in complexity,

resources, and space, St. Jude divided its radiological sciences area into two departments—Radiation Oncology and Diagnostic Imaging. Larry Kun, MD, St. Jude Clinical Director and Executive Vice President, will head Diagnostic Imaging until a Chair is appointed. n

Contact

The ASCO Post

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

B:11.25”

T:10.875”

S:10” B:11.25”

Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 S:10”

One event wasbOne Grade event 5 severity. was Grade 5 severity.

b

—James R. Downing, MD

T:10.875”

reported (< 1%). reported KYPROLIS (< 1%).can KYPROLIS cause elevations can causeof elevations serum transaminases of serum transaminases and bilirubin.and Withhold bilirubin.Description Withhold Description of SelectedofAdverse Selected Drug Adverse Reactions.

Drug Renal Reactions.

Events: Renal The Events: most common The most renal common renal KYPROLIS in KYPROLIS patients experiencing in patients experiencing Grade 3 or greater Gradeelevations 3 or greater of elevations transaminases, of transaminases, bilirubin, or other bilirubin,adverse or otherreactions adverse were reactions increasewere in blood increase creatinine in blood (24%) creatinine and renal (24%) failure and (9%), renal which failurewere (9%),mostly which were mostly liver abnormalities liver abnormalities until resolveduntil or returned resolved to or baseline. returned to After baseline. resolution, Afterconsider resolution, if restarting consider if restarting Grade 1 or Grade Grade 21 inorseverity.

Grade 2Grade in severity.

3 renalGrade adverse 3 renal reactions adverse occurred reactions in 6% occurred of patients in 6%and of patients and KYPROLIS is KYPROLIS appropriate. is appropriate.

Monitor liver Monitor enzymesliver frequently enzymes[see frequently Dosage [see and Dosage Administration and Administration and Gradeand 4 events Grade occurred 4 events in 1%. occurred Discontinuations in 1%. Discontinuations due to increased due to blood increased creatinine blood andcreatinine acute renal and acute renal Adverse Reactions].

AdverseEmbryo-fetal Reactions]. Embryo-fetal Toxicity. KYPROLIS Toxicity. canKYPROLIS cause fetal canharm cause when fetaladministered harm when administered to a failuretowere a 1% failure each. were In 1% one each. patient, In death one patient, occurred death withoccurred concurrent withsepsis concurrent and worsening sepsis andrenal worsening renal pregnant woman pregnant basedwoman on its mechanism based on itsofmechanism action and of findings actioninand animals. findings There in animals. are no adequate There are and no adequate and[see function function Dosage and [seeAdministration].

Dosage and Administration].

Peripheral Neuropathy: Peripheral Neuropathy: Peripheral neuropathy Peripheral(including neuropathy (including well‑controlledwell‑controlled studies in pregnant studieswomen in pregnant usingwomen KYPROLIS. using Carfilzomib KYPROLIS.caused Carfilzomib embryo‑fetal caused toxicity embryo‑fetal in all toxicity in of all events peripheral events ofsensory peripheral neuropathy sensoryand neuropathy peripheral andmotor peripheral neuropathy) motor occurred neuropathy) in 14% occurred of in 14% of pregnant rabbits pregnant at doses rabbits that were at doses lower thatthan were in patients lower than receiving in patients the recommended receiving the recommended dose. Femalesdose. of Females patientsofenrolled patients in clinical enrolled trials. in clinical Grade 3trials. peripheral Grade neuropathy 3 peripheraloccurred neuropathy in 1% occurred of patients. in 1%Serious of patients. Serious reproductive potential reproductive should potential be advised should to be avoid advised becoming to avoid pregnant becoming whilepregnant being treated while being with KYPROLIS. treated with KYPROLIS. peripheral neuropathy peripheralevents neuropathy occurred events in <occurred 1% of patients, in < 1%which of patients, resulted which in dose resulted reduction in dose in <reduction 1% in < 1% If this drug isIfused this drug duringis pregnancy, used duringorpregnancy, if the patient or ifbecomes the patient pregnant becomes while pregnant taking this whiledrug, taking thethis and drug,treatment the and discontinuation treatment discontinuation in < 1%. Withhold in < 1%. or discontinue Withhold or treatment discontinue as treatment recommended as recommended [see [see patient shouldpatient be apprised shouldofbethe apprised potential of hazard the potential to the hazard fetus [see to the Usefetus in Specific [see Use Populations]. in Specific Populations].

Dosage and Administration].

Dosage and Administration].

Herpes VirusHerpes Infection: Virus Herpes Infection: zosterHerpes reactivation zosterwas reactivation reportedwas in 2% reported in 2% ADVERSE REACTIONS: ADVERSE REACTIONS: The following adverse The following reactions adverse are discussed reactions are in greater discussed detail in in greater other detail sections in otherofsections patients. Consider of patients. antiviral Consider prophylaxis antiviralfor prophylaxis patients who for patients have a history who have of herpes a history zoster of herpes infection. zoster infection. of the labeling:of the labeling: DRUG INTERACTIONS: DRUG INTERACTIONS: Carfilzomib isCarfilzomib primarily metabolized is primarily via metabolized peptidasevia andpeptidase epoxide and hydrolase epoxide hydrolase • Cardiac Arrest, • Cardiac Congestive Arrest,Heart Congestive Failure,Heart Myocardial Failure,Ischemia Myocardial [seeWarnings Ischemia [see andWarnings Precautions] and Precautions] activities, andactivities, as a result, and the as apharmacokinetic result, the pharmacokinetic profile of carfilzomib profile ofiscarfilzomib unlikely toisbeunlikely affectedto by be affected by • Pulmonary •Hypertension Pulmonary Hypertension [seeWarnings [see andWarnings Precautions] and Precautions] concomitant administration concomitant administration of cytochromeofP450 cytochrome inhibitors P450 andinhibitors inducers.and Carfilzomib inducers.isCarfilzomib not expected is not expected • Pulmonary •Complications Pulmonary Complications [seeWarnings [see andWarnings Precautions] and Precautions] to influence exposure to influence of other exposure drugsof[see otherClinical drugs Pharmacology [see Clinical Pharmacology section of fullsection PI]. of full PI].

• Infusion Reactions • Infusion [see Reactions Warnings [see andWarnings Precautions] and Precautions] USE IN SPECIFIC USE IN POPULATIONS: SPECIFIC POPULATIONS: Pregnancy. Pregnancy.

Pregnancy Category PregnancyD Category [see Warnings D [seeand Warnings and • Tumor Lysis•Syndrome Tumor Lysis [see Syndrome Warnings [see andWarnings Precautions] and Precautions] Females of potential reproductive potential shouldtobe advised to avoid becoming pregnant while Precautions].Precautions].

Females of reproductive should be advised avoid becoming pregnant while • Thrombocytopenia • Thrombocytopenia [seeWarnings [see andWarnings Precautions] and Precautions] treated withBased KYPROLIS. on itsofmechanism action and findingsKYPROLIS in animals, KYPROLIS being treatedbeing with KYPROLIS. on its Based mechanism action andoffindings in animals, • Hepatic Toxicity • Hepatic and Hepatic Toxicity Failure and Hepatic [seeWarnings Failure [see andWarnings Precautions] and Precautions] can harm causewhen fetal administered harm when administered a pregnant woman.caused Carfilzomib caused embryo‑fetal can cause fetal to a pregnanttowoman.

Carfilzomib embryo‑fetal The most common The most adverse common reactions adverse (incidence reactions of (incidence 30% or greater) of 30%toorKYPROLIS greater) to observed KYPROLIS in clinical observed toxicity in clinical toxicity rabbits in pregnant rabbits doses thatthan wereinlower thanreceiving in patients the recommended in pregnant at doses thatatwere lower patients thereceiving recommended trials of patients trialswith of patients multiple with myeloma multiple were myeloma fatigue,were anemia, fatigue, nausea, anemia, thrombocytopenia, nausea, thrombocytopenia, dyspnea, dose. dyspnea, dose. Ifis KYPROLIS is pregnancy, used duringorpregnancy, or ifbecomes the patient becomes pregnant If KYPROLIS used during if the patient pregnant while taking while this taking this diarrhea, anddiarrhea, pyrexia. and Clinical pyrexia.

Trials Clinical SafetyTrials Experience.

Safety Experience.

Because clinical Because trials clinical are conducted trials are conducted drug,should the patient shouldofbethe apprised of hazard the potential to the fetus.was Carfilzomib was administered drug, the patient be apprised potential to the hazard fetus. Carfilzomib administered under widely under varyingwidely conditions, varyingadverse conditions, reaction adverse ratesreaction observed rates in the observed clinicalintrials the of clinical a drugtrials cannot of a drug cannot intravenously to pregnant ratsduring and rabbits during period of organogenesis at doses intravenously to pregnant rats and rabbits the period of the organogenesis at doses of 0.5, 1, andof 0.5, 1, and be directly compared be directlywith compared rates in with the clinical rates intrials the clinical of another trialsdrug, of another and may drug, not and reflect maythenotrates reflect 2themg/kg/day rates 2inmg/kg/day in rats and 0.8inmg/kg/day in rabbits.was Carfilzomib was notatteratogenic at rats and 0.2, 0.4,and and0.2, 0.8 0.4, mg/kg/day rabbits. Carfilzomib not teratogenic observed in medical observed practice. in medical A total practice. of 526Apatients total of with 526 relapsed patients with and/or relapsed refractory and/or multiple refractory myeloma multiple any myeloma any dose tested.there In rabbits, was in an pre‑implantation increase in pre‑implantation at ≥ 0.4 mg/kg/day dose tested.

In rabbits, was anthere increase loss at ≥ 0.4loss mg/kg/day received KYPROLIS received as KYPROLIS monotherapy as monotherapy or with pre‑dose or with dexamethasone. pre‑dose dexamethasone.

Patients received Patients a median received of a median and in anearly increase in earlyand resorptions and post‑implantation loss andina fetal decrease in at fetal weight at and an ofincrease resorptions post‑implantation loss and a decrease weight four treatment fourcycles treatment with acycles median withcumulative a medianKYPROLIS cumulativedose KYPROLIS of 993.4 dose mg.ofDeaths 993.4 due mg. to Deaths all due to all thetoxic maternally of 0.8The mg/kg/day. of 0.4 and 0.8inmg/kg/day the maternally dose oftoxic 0.8 dose mg/kg/day. doses ofThe 0.4doses and 0.8 mg/kg/day rabbits arein rabbits are causes withincauses 30 days within of the30last days dose of the of KYPROLIS last dose of occurred KYPROLIS in 37/526 occurred (7%) in 37/526 of patients.

(7%)Deaths of patients. not Deaths not approximately 20% and 40%, of respectively, of the recommended doseof in27humans 27 mg/m2 based approximately 20% and 40%, respectively, the recommended dose in humans mg/m2 of based attributed to disease attributed progression to diseasewere progression cardiac were in 5 patients cardiac (acute in 5 patients coronary (acute syndrome, coronary cardiac syndrome, arrest,cardiac on arrest, body surface on body area.surface Nursing area.

Mothers.

Nursing It isMothers. not known It iswhether not known KYPROLIS whetheris KYPROLIS excreted inishuman excreted in human cardiac disorder), cardiac end‑organ disorder),failure end‑organ in 4 patients failure in(multi‑organ 4 patients (multi‑organ failure, hepatic failure, failure, hepatic renal failure, failure),renalmilk. failure), Since many milk.drugs Since are many excreted drugs are in human excreted milkin and human because milk and of the because potential of for the serious potentialadverse for serious adverse infection in infection 4 patientsin (sepsis, 4 patients pneumonia, (sepsis, pneumonia, respiratory tract respiratory bacterial tract infection), bacterialdyspnea infection), anddyspnea and in nursing reactions reactions infants in nursing from KYPROLIS, infants from a decision KYPROLIS, should a decision be made should whether be made to discontinue whether tonursing discontinue nursing intracranial hemorrhage intracranial in hemorrhage 1 patient each, in 1 patient and 1 each, patientand found 1 patient dead offound unknown dead causes. of unknown Serious causes.orSerious to discontinue or tothe discontinue drug, taking the into drug,account taking into the importance account theofimportance the drug toofthe themother. drug toPediatric the mother. Pediatric adverse reactions adverse were reactions reportedwere in 45% reported patients. in 45% The patients. most common The most serious common adverse serious reactions adverse were reactions Use.were The safety Use.and Theeffectiveness safety and effectiveness of KYPROLISofin KYPROLIS pediatric patients in pediatric havepatients not been have established. not been established. pneumonia (10%), pneumonia acute (10%), renal failure acute (4%), renal pyrexia failure (4%), (3%),pyrexia and congestive (3%), andheart congestive failure (3%). heart Adverse failure (3%).Geriatric Adverse Use. Geriatric In studies Use. of KYPROLIS In studies there of KYPROLIS were nothere clinically weresignificant no clinically differences significantobserved differences in safety observed in safety reactions leading reactions to discontinuation leading to discontinuation of KYPROLIS occurred of KYPROLIS in 15% occurred of patients in 15% and of included patients and congestive included congestive and efficacy between and efficacy patients between less than patients 65 years less than of age 65 and yearspatients of age 65 andyears patients of age 65 and yearsolder. of age Renal and older. Renal heart failure (2%), heart failure cardiac(2%), arrest, cardiac dyspnea, arrest, increased dyspnea, blood increased creatinine, bloodand creatinine, acute renal andfailure acute (1% renal failure (1% Impairment.

Impairment.

The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS evaluated were in evaluated a Phase 2intrial a Phase in 2 trial in each). Adverse each). reactions Adverse occurring reactions at aoccurring rate of 10% at a or rate greater of 10% areorpresented greater are in Table presented 4. in Table 4. patients withpatients normal with renal normal functionrenal and function those with andmild, thosemoderate, with mild,and moderate, severe renal and severe impairment renal impairment on chronic patientsdialysis. on chronic On average, dialysis. patients On average, werepatients treated were for 5.5 treated cyclesforusing 5.5 cycles KYPROLIS using KYPROLIS Table 4: Incidence Table 4:ofIncidence Adverse Reactions of AdverseOccurring ReactionsinOccurring ≥ 10% of in Multiple ≥ 10% Myeloma of Multiple Myelomaand patients and 2 doses of 15 doses mg/m2ofon15Cycle mg/m 1,2 20 on mg/m Cycle 21,on20Cycle mg/m 2,2 and on Cycle 27 mg/m 2, and on27Cycles mg/m32 on andCycles beyond.

3 and beyond.

Patients Treated Patients withTreated KYPROLIS with KYPROLIS The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS not influenced were notbyinfluenced the degreebyofthe baseline degreerenal of baseline renal Patients Patients (N = 526) (N = 526) impairment, including impairment, the including patients on thedialysis. patientsSince on dialysis. dialysisSince clearance dialysis of clearance KYPROLIS ofconcentrations KYPROLIS concentrations [n (%)] [n (%)] has not beenhas studied, not been the studied, drug should the drug be administered should be administered after the dialysis after procedure the dialysis[see procedure Clinical [see Clinical Grade Grade 3 4 GradePharmacology 4 All Grade 3 All Pharmacology section of fullsection PI]. Hepatic of full Impairment.

PI]. Hepatic Impairment.

The safety, efficacy The safety, and pharmacokinetics efficacy and pharmacokinetics of of a a EventsEvents Events Event GradesEvents Event Grades KYPROLIS have KYPROLIS not been have evaluated not been in evaluated patients with in patients baselinewith hepatic baseline impairment. hepatic Patients impairment. withPatients the with the following laboratory following values laboratory were excluded values were fromexcluded the KYPROLIS from theclinical KYPROLIS trials:clinical ALT/AST trials: ≥ 3ALT/AST × upper ≥ 3 × upper Fatigue Fatigue 292 (55.5) 292 (55.5) 38 (7.2) 38 (7.2)2 (0.4) 2 (0.4) limit of normallimit (ULN) of normal and bilirubin (ULN) ≥ and 2× bilirubin ULN [see ≥ 2Clinical × ULN Pharmacology [see Clinical Pharmacology section of fullsection PI]. Cardiac of full PI]. Cardiac Anemia Anemia 246 (46.8) 246 (46.8) 111 (21.1) 111 (21.1)7 (1.3) 7 (1.3) Impairment.Impairment.

Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and IV Class heartIII failure and IV were heartnot failure eligible were not eligible Nausea Nausea 236 (44.9) 236 (44.9)7 (1.3) 7 (1.3) 0 0 for the clinicalfortrials. the clinical Safety in trials. this Safety population in thishas population not beenhas evaluated. not been evaluated.

Thrombocytopenia Thrombocytopenia 191 (36.3) 191 (36.3) 69 (13.1) 69 (13.1) 54 (10.3) 54 (10.3) OVERDOSAGE: OVERDOSAGE: There is no known There isspecific no known antidote specific for KYPROLIS antidote foroverdosage.

KYPROLIS In overdosage. the event of In the an event of an b overdosage, monitor overdosage, the patient monitorand theprovide patientappropriate and providesupportive appropriatecare. supportive care.

Dyspnea Dyspnea 182 (34.6) 182 (34.6) 25 (4.8) 25 (4.8)1 (0.2)b 1 (0.2) NONCLINICAL NONCLINICAL TOXICOLOGY: TOXICOLOGY: Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, and Impairment and Impairment of Fertility. of Fertility.

Diarrhea Diarrhea 172 (32.7) 172 (32.7)4 (0.8) 4 (0.8)1 (0.2) 1 (0.2) Carcinogenicity Carcinogenicity studies have studies not beenhave conducted not beenwith conducted carfilzomib. withCarfilzomib carfilzomib.was Carfilzomib clastogenic wasinclastogenic the in the Pyrexia Pyrexia 160 (30.4) 160 (30.4)7 (1.3) 7 (1.3)2 (0.4) 2 (0.4) in vitro chromosomal in vitro chromosomal aberration testaberration in peripheral test in blood peripheral lymphocytes. blood lymphocytes.

Carfilzomib was Carfilzomib not mutagenic was not mutagenic in the in vitro in bacterial the in vitro reverse bacterial mutation reverse (Ames) mutation test and (Ames) was test not and clastogenic was not in clastogenic the in vivo in the in vivo mouse mouse Upper respiratory Uppertract respiratory infectiontract infection 149 (28.3) 149 (28.3) 17 (3.2) 17 (3.2) 0 0 marrow micronucleus Fertility withhave carfilzomib have not beenNo conducted. No micronucleus assay. Fertilityassay. studies with studies carfilzomib not been conducted.

Headache Headache 145 (27.6) 145 (27.6)7 (1.3) 7 (1.3) 0 0 bone marrowbone effects on reproductive were noted during 28‑day repeat‑dose rat and monkey toxicity effects on reproductive tissues weretissues noted during 28‑day repeat‑dose rat and monkey toxicity Cough Cough 137 (26.0) 137 (26.0)1 (0.2) 1 (0.2) 0 0 studies or in studies in and 6‑month rat and 9‑month monkey chronic toxicity studies.

Animal and/ Toxicology and/ 6‑monthorrat 9‑month monkey chronic toxicity studies.

Animal Toxicology Blood creatinine Blood increased creatinine increased 127 (24.1) 127 (24.1) 13 (2.5) 13 (2.5)1 (0.2) 1 (0.2) or Pharmacology.

Monkeys administered single bolusdose intravenous dose ofatcarfilzomib or Pharmacology.

Monkeys administered a single bolusa intravenous of carfilzomib 3 mg/kg at 3 mg/kg 2 2 1.3 times recommended doseofin27humans 27 mg/m (approximately(approximately 1.3 times recommended dose in humans mg/m ofbased on body based surface on body area) surface area) LymphopeniaLymphopenia 126 (24.0) 126 (24.0) 84 (16.0) 84 (16.0) 11 (2.1) 11 (2.1) experienced hypotension, experienced increased hypotension, heart increased rate, andheart increased rate, and serum increased levels of serum troponin‑T. levels ofThe troponin‑T. repeated The repeated Edema peripheral Edema peripheral 126 (24.0) 126 (24.0)3 (0.6) 3 (0.6) 0 0 bolus intravenous bolus administration intravenous administration of carfilzomibofatcarfilzomib ≥ 2 mg/kg/dose at ≥ 2 in mg/kg/dose rats and in 2 mg/kg/dose rats and 2 mg/kg/dose in in Vomiting Vomiting 117 (22.2) 117 (22.2)5 (1.0) 5 (1.0) 0 0 monkeys using monkeys dosingusing schedules dosingsimilar schedules to those similar usedto clinically those used resulted clinically in mortalities resulted inthat mortalities were that were due occurring to toxicities in occurring the cardiovascular in the cardiovascular (cardiac failure, (cardiac cardiac failure, fibrosis, cardiac pericardial fibrosis,fluid pericardial fluid Constipation Constipation 110 (20.9) 110 (20.9)1 (0.2) 1 (0.2) 0 0 due to toxicities accumulation,accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal Neutropenia Neutropenia 109 (20.7) 109 (20.7) 50 (9.5) 50 (9.5)4 (0.8) 4 (0.8) (glomerulonephropathy, tubular necrosis, and pulmonary (glomerulonephropathy, tubulardysfunction), necrosis, dysfunction), and(hemorrhage/inflammation) pulmonary (hemorrhage/inflammation) Back pain Back pain 106 (20.2) 106 (20.2) 15 (2.9) 15 (2.9) 0 0 systems. The systems. dose of 2inmg/kg/dose in rats is approximately half the recommended dose in humans dose of 2The mg/kg/dose rats is approximately half the recommended dose in humans 2 Insomnia Insomnia 94 (17.9) 94 (17.9) 0 0 0 0 of 27 mg/m2ofbased 27 mg/m on body based surface on body area.surface The dose area. of 2The mg/kg/dose dose of 2 in mg/kg/dose monkeys isinapproximately monkeys is approximately equivalent to equivalent the recommended to the recommended dose in humans dose based in humans on body based surface on body area. surface area.

Chills Chills 84 (16.0) 84 (16.0)1 (0.2) 1 (0.2) 0 0 PATIENT COUNSELING INFORMATION: INFORMATION: Discuss the following Discuss the withfollowing patients with priorpatients to treatment prior with to treatment with Arthralgia Arthralgia 83 (15.8) 83 (15.8)7 (1.3) 7 (1.3) 0 0 PATIENT COUNSELING KYPROLIS: Instruct KYPROLIS: patients Instruct to contact patients their to contact physiciantheir if they physician develop if they any of develop the following any of the symptoms: following symptoms: Muscle spasms Muscle spasms 76 (14.4) 76 (14.4)2 (0.4) 2 (0.4) 0 0 fever, chills, rigors, fever, chills, chest rigors, pain, cough, chest or pain, swelling cough,oforthe swelling feet oroflegs. the Advise feet or patients legs. Advise that patients KYPROLIS that KYPROLIS HypertensionHypertension 75 (14.3) 75 (14.3) 15 (2.9) 15 (2.9)2 (0.4) 2 (0.4) may cause fatigue, may cause dizziness, fatigue, fainting, dizziness, and/or fainting, drop inand/or blooddrop pressure. in blood Advise pressure. patients Advise not topatients drive ornot to drive or operate machinery operate if they machinery experience if theyany experience of these symptoms. any of theseAdvise symptoms. patients Advise that they patients maythat experience they may experience Asthenia Asthenia 73 (13.9) 73 (13.9) 12 (2.3) 12 (2.3)1 (0.2) 1 (0.2) shortness of shortness breath (dyspnea) of breath during (dyspnea) treatment during with treatment KYPROLIS. withThis KYPROLIS. most commonly This mostoccurs commonly withinoccurs within Hypokalemia Hypokalemia 72 (13.7) 72 (13.7) 14 (2.7) 14 (2.7)3 (0.6) 3 (0.6) a day of dosing. a day Advise of dosing. patients Advise to contact patientstheir to contact physicians theirif physicians they experience if theyshortness experience of shortness breath. of breath.

Hypomagnesemia Hypomagnesemia 71 (13.5) 71 (13.5)2 (0.4) 2 (0.4) 0 0 Counsel patients Counsel to avoid patients dehydration, to avoid dehydration, since patientssince receiving patients KYPROLIS receivingtherapy KYPROLIS may therapy experience may experience vomiting and/or vomiting diarrhea. and/or Instruct diarrhea. patients Instruct to seek patients medical to seek advice medical if theyadvice experience if theysymptoms experience symptoms Leukopenia Leukopenia 71 (13.5) 71 (13.5) 27 (5.1) 27 (5.1)1 (0.2) 1 (0.2) lightheadedness, dizziness, lightheadedness, or fainting spells. or fainting Counsel spells. females Counsel of reproductive females of reproductive potential to use potential to use Pain in extremity Pain in extremity 70 (13.3) 70 (13.3)7 (1.3) 7 (1.3) 0 0 of dizziness, of effective contraceptive effective contraceptive measures to measures prevent pregnancy to preventduring pregnancy treatment during with treatment KYPROLIS. withAdvise KYPROLIS. the Advise the b Pneumonia Pneumonia 67 (12.7) 67 (12.7) 52 (9.9) 52 (9.9)3 (0.6)b 3 (0.6) patient that ifpatient she becomes that if she pregnant becomes during pregnant treatment, duringto treatment, contact hertophysician contact her immediately. physician immediately.

Advise Advise Aspartate aminotransferase Aspartate aminotransferase increased increased 66 (12.5) 66 (12.5) 15 (2.9) 15 (2.9)1 (0.2) 1 (0.2) patients not topatients take KYPROLIS not to take treatment KYPROLIS while treatment pregnant while or breastfeeding. pregnant or breastfeeding.

If a patient wishes If a patient to restart wishes to restart breastfeeding breastfeeding after treatment, after advise treatment, her to advise discuss her the to appropriate discuss the timing appropriate with her timing physician. with her Advise physician.

Advise Dizziness Dizziness 66 (12.5) 66 (12.5)5 (1.0) 5 (1.0)1 (0.2) 1 (0.2) patientswith to discuss their physician with their anyphysician medication anythey medication are currently they are taking currently prior to taking starting prior to starting HypoesthesiaHypoesthesia 64 (12.2) 64 (12.2)3 (0.6) 3 (0.6) 0 0 patients to discuss treatment withtreatment KYPROLIS, withorKYPROLIS, prior to starting or prior anytonew starting medication(s) any new medication(s) during treatment during withtreatment KYPROLIS. with KYPROLIS. Anorexia Anorexia 63 (12.0) 63 (12.0)1 (0.2) 1 (0.2) 0 0 Pain Pain 63 (12.0) 63 (12.0) 12 (2.3) 12 (2.3) 0 0 Hyperglycemia Hyperglycemia 62 (11.8) 62 (11.8) 16 (3.0) 16 (3.0)3 (0.6) 3 (0.6) Chest wall pain Chest wall pain 60 (11.4) 60 (11.4)3 (0.6) 3 (0.6) 0 0 Hypercalcemia Hypercalcemia 58 (11.0) 58 (11.0) 13 (2.5) 13 (2.5)8 (1.5) 8 (1.5) Manufactured Manufactured for: Onyx Pharmaceuticals, for: Onyx Pharmaceuticals, Inc., 249 EastInc., Grand 249Avenue, East Grand Avenue, Hypophosphatemia Hypophosphatemia 55 (10.5) 55 (10.5) 24 (4.6) 24 (4.6)3 (0.6) 3 (0.6) South San Francisco, South San CAFrancisco, 94080 CA 94080 HyponatremiaHyponatremia 54 (10.3) 54 (10.3) 31 (5.9) 31 (5.9)3 (0.6) 3 (0.6) U.S. Patent Numbers: U.S. Patent7,232,818; Numbers:7,417,042; 7,232,818;7,491,704; 7,417,042;7,737,112 7,491,704; 7,737,112 05‑1088‑00 05‑1088‑00 a National CanceraNational InstituteCancer Common Institute Terminology Common Criteria Terminology for Adverse Criteria Events for Adverse (NCI CTCAE) Events Version (NCI CTCAE) 3.0. Version 3.0. ©2014 Onyx©2014 Pharmaceuticals, Onyx Pharmaceuticals, Inc. TROPIC‑KYPR‑100826J Inc. TROPIC‑KYPR‑100826J November 2014 November 2014

Dr. Merchant is a proven leader in pediatric radiotherapy and will be instrumental in helping St. Jude define the next generation of treatments.

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The ASCO Post | APRIL 10, 2015

PAGE 62

State of the Art Gastrointestinal Oncology

The Emerging Role of Radiation Therapy in Gastrointestinal Cancers A Conversation With Theodore S. Hong, MD

By Ronald Piana

T

he use of radiation therapy in the treatment of gastrointestinal cancer has evolved over the past several decades, in a gradual, stepwise fashion.

Since most gastrointestinal cancers are diagnosed at a locally advanced stage, coupled with the inherent sensitivity of most parts of the gastrointestinal tract to high-dose radiation, radiation therapy is most often used as part of multimodality therapy, instead of as a sole curative modality. New developments may change the approach of radiation therapies in these highly complex gastrointestinal cancers. To shed light on the emerging role of radiation in gastrointestinal cancers, The ASCO Post recently spoke with Theodore S. Hong, MD, Associate Professor, Department of Radiation Oncology, Harvard Medical School.

Greatest Advance in Liver Tumors Over the course of your career, what has been the greatest advance(s) in gastrointestinal radiation oncology?

I think the greatest advance in gastrointestinal radiation oncology has occurred in the treatment of liver tumors. The improved technology both in terms of delivery as well as localization has allowed for a new generation of therapeutic options, in which a small number of high-dose fractions can be accurately targeted to the liver in an ablative fashion.

This advance has led to a number of institutional trials, which have demonstrated that patients with unresectable primary or metastatic liver tumors can have durable local control with highdose radiation (stereotactic body radiation). And the promising local control and survival that we see in hepatocellular carcinoma and intrahepatic cholangiocarcinoma have led to two randomized clinical trials that are currently open for enrollment.

For hepatocellular carcinoma, RTOG-1112 is looking at sorafenib (Nexavar) plus or minus high-dose

liver radiation, and NRG-GI001 is a randomized trial evaluating the addition of liver-directed radiation therapy to chemotherapy with respect to overall survival for patients with unresectable, localized intrahepatic cholangiocarcinoma. Both trials will give us valuable results that will translate to the clinic.

Progress in Limiting Toxicity The luminal gastrointestinal tract is sensitive to high-dose radiation. Have we progressed in our ability to target tumors in this complex anatomic region?

I believe we’ve made progress in this area, certainly in anal cancer, in which previously all the radiation was delivered from the front and back; this approach led to a fair amount of gastro-

Proton-Beam Therapy Advocates of proton-beam therapy contend that it is more tumor-specific than intensity-modulated radiation therapy, leading to less morbidity. Where are we in this debate?

I believe that one of the most important questions in gastrointestinal radiation oncology is determining what is the comparative benefit of protons over intensity-modulated radiation therapy. As we know, protons have a theoretic benefit due to the lack of an exit dose, giving greater tissuesparing efficacy.

There are very robust data from Japan as well as Loma Linda Cancer Center evaluating proton-beam therapy in primary liver tumors. But there have

One of the most important questions in gastrointestinal radiation oncology is determining what is the comparative benefit of protons over intensity-modulated radiation therapy.

—Theodore S. Hong, MD

intestinal toxicity, which manifested as problematic diarrhea.

Also, the development of intensitymodulated radiation therapy (looked at prospectively through the RTOG) was able to demonstrate that with improved radiation targeting, we could substantially decrease the rate of gastrointestinal toxicity. And this development has led to a wide rate of acceptance for intensity-modulated radiation therapy in anal cancer.

In addition, in treating both liver tumors as well as pancreatic tumors, there was always a risk of damaging the luminal gastrointestinal tract. However, multiple publications now suggest that we are indeed getting better at protecting the patient from the acute side effects of nausea and vomiting in upper gastrointestinal cancers and also preventing long-term side effects such as gastrointestinal bleeding.

been no direct comparisons of protonbeam vs intensity-modulated radiation therapy. Currently, we at Mass General, in collaboration with MD Anderson, are designing a proton vs intensitymodulated radiation therapy study to try to determine which one has more benefit in liver cancer.

The other gastrointestinal site where we’ve looked at proton-beam therapy is anal cancer. We are currently conducting a prospective trial evaluating patient-reported qualityof-life metrics, both during and after completion of proton-beam therapy.

Given the toxicity profile of chemoradiotherapy, we want to see whether protons offer a better option in this disease. Once we have these prospective data to evaluate, it might help us move to a randomized trial looking at proton-beam therapy against intensity-modulated radiation therapy.

Preoperative Chemoradiotherapy Is there a role for preoperative chemoradiotherapy in certain gastrointestinal malignancies?

There certainly is. Preoperative chemoradiotherapy is standard of care in esophageal and gastroesophageal cancers. This is largely based on the CROSS trial, which demonstrated a substantial benefit to preoperative chemoradiotherapy with carboplatin and paclitaxel followed by surgery. The trial confirmed that preoperative chemoradiotherapy for resectable esophageal cancer is safe and, compared with surgery alone, is associated with pathologic complete responses and prolonged survival.

Another disease site in which neoadjuvant or preoperative chemoradiotherapy is the standard of care is in rectal cancer. There have been two randomized trials that have demonstrated improved clinical outcomes when chemoradiotherapy is given before surgery as opposed to after surgery.

There is an increasing movement toward preoperative therapy in pancreatic cancer; however, the role of radiation in pancreatic disease remains highly ­controversial.

A Glimpse at Clinical Trials What is ongoing or planned in the clinical trial setting for gastrointestinal ­radiation?

Along with the trials I’ve already mentioned, RTOG is also looking at radiation in the context of different chemotherapy regimens for locally advanced pancreatic cancer. One interesting study is going to evaluate outcomes based on whether a patient’s tumor has preserved DPC-4, which seems to be a predictor of patterns of failure.

Another interesting ongoing trial is RTOG-1010, which is a randomized phase III study evaluating the addition of trastuzumab (Herceptin) to neoadjuvant chemoradiotherapy in esophageal or gastrointestinal junction cancer. I

ASCOPost.com | APRIL 10, 2015

PAGE 63

State of the Art

think both of these trials highlight that radiation, which has historically been used in a homogeneous way in a given disease, is now moving in the personalized direction that we see in medical oncology. Hence, the integration of targeted therapies and appropriately selected patients to evaluate which patients may benefit from aggressive treatment based on potential patterns of failure.

There’s also a lot of excitement in work that shows the potential of radiation to enhance the ability of the immune system to recognize cancer cells.

Closing Thoughts Do you have any final thoughts?

This is an exciting time for radia-

tion oncology. The ability to treat liver tumors, which has arisen over the past 10 years, opens up many opportunities for our patients who previously had no curative options.

Moreover, I think our community remains interested in the integration of new drugs with radiation. Even beyond classic radiosensitization, in which we

are just trying to enhance the radiospecific site, the idea of enhancing the abscopal effect, which might trigger a widespread immune response to cancer, is very exciting. The field of radiation oncology is exploring new ways to use our powerful tools. n Disclosure: Dr. Hong has received research support from Novartis.

Active Research Areas Are any of the newer targeted therapies showing a synergistic benefit with radiation therapy?

Many of the newer targeted therapies have been looked at in gastrointestinal cancers, but unfortunately, no biologic in combination with radiation has been shown to improve clinical outcomes.

That said, we have high hopes for the trastuzumab trial, so it remains an active research area. In rectal cancer, we are looking at a drug called midostaurin (a multitarget kinase inhibitor) in a phase I trial.

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.

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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

The ASCO Post | APRIL 10, 2015

PAGE 64

Journal Spotlight Hematology

Increased Progression-Free Survival With Addition of Carfilzomib to Lenalidomide/Dexamethasone in Relapsed Multiple Myeloma

By Matthew Stenger

I

n a planned interim analysis of the phase III ASPIRE trial reported in The New England Journal of Medicine, A. Keith Stewart, MB, ChB, of the Mayo Clinic, Scottsdale, Arizona, and colleagues found that the addition of the proteasome inhibitor carfilzomib (Kyprolis) to lenalidomide (Revlimid)/ dexamethasone significantly increased progression-free survival.1 The interim analysis suggested a survival benefit with the three-drug regimen, which was also associated with a significantly higher response rate and improvement in healthrelated quality of life.

treatment if lenalidomide/dexamethasone was the most recent treatment.

The carfilzomib and control groups were generally balanced for age (median 64 and 65 years, 47% and 53% ≥ 65 years), gender (54% and 59% male), Eastern Cooperative Oncology Group

Carfilzomib combined with lenalidomide and dexamethasone led to a significant improvement in progression-free survival, as compared with lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma.

Study Details In this open-label trial, 792 patients from North America, Europe, and the Middle East with relapsed multiple myeloma and receipt of 1 to 3 prior treatments were randomized to receive carfilzomib plus lenalidomide/dexamethasone (n = 396) or lenalidomide/ dexamethasone (n = 396) between July 2010 and March 2012. The primary endpoint was progression-free survival.

Treatment consisted of 28-day cycles, with carfilzomib given via 10-minute infusion on days 1, 2, 8, 9, 15, and 16 (starting dose = 20 mg/m2 on days 1 and 2 of cycle 1 and target dose = 27 mg/m2 for all subsequent treatment) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, after which carfilzomib was discontinued. Lenalidomide (25 mg) was given on days 1 through 21. Dexamethasone (40 mg) was given on days 1, 8, 15, and 22.

Patients previously treated with bortezomib (Velcade) were eligible if they had not progressed during bortezomib treatment. Patients previously treated with lenalidomide and dexamethasone were eligible if they did not discontinue treatment due to adverse effects, did not have disease progression during the first 3 months of treatment, and did not have disease progression at any time during

survival was also performed, after occurrence of 60% of the 510 events prespecified for final overall survival analysis. The median follow-up was 32.3 months in the carfilzomib group and 31.5 months in the control group.

Survival at 24 months was 73.3%

—A. Keith Stewart, MB, ChB, and colleagues

performance status (0 or 1 for 90% and 91%), cytogenetic risk (high in 12% and 13%, standard in 37% and 43%, unknown in 51% and 44%), creatinine clearance (≥ 50 mL/min, required at screening, in 93% and 90%), serum β2 microglobulin (≥ 2.5 mg/L in 81% in both), number of previous regimens (1 in 47% and 40%, 2 or 3 in 53% and 60%), and previous therapies (bortezomib in 66% in both, lenalidomide in 20% in both).

Progression-Free Survival At the time of the interim analysis, the median progression-free survival was 26.3 months (95% confidence interval [CI] = 23.3–30.5 months) in the carfilzomib group vs 17.6 months (95% CI = 15.0–20.6); the hazard ratio [HR] was 0.69 (95% CI = 0.57–0.83, P = .0001), which crossed the prespecified stopping boundary. The benefit of carfilzomib was observed across all predefined subgroups.

Interim Analysis of Overall Survival Since the primary study objective was met, an interim analysis of overall

Carfilzomib and Lenalidomide/Dexamethasone in Relapsed Myeloma ■■ The addition of carfilzomib to lenalidomide/dexamethasone significantly increased progression-free survival, with a trend toward an overall survival benefit on interim analysis.

■■ The three-drug regimen was associated with greater response rates and an improvement in health-related quality of life.

(95% CI = 68.6%–77.5%) in the carfilzomib group vs 65.0% (95% CI = 59.9%–69.5%) in the control group. The median overall survival was not reached in either group, with a trend favoring the carfilzomib group (HR = 0.79, P = .04), but the difference did not cross the prespecified stopping boundary.

Responses and Quality of Life Overall response rates were 87.1% vs 66.7% (P < .001), including complete response or better in 31.8% vs 9.3% (P < .001) and stringent complete response in 14.1% vs 4.3%. The mean time to response was 1.6 vs 2.3 months, and the median duration of response was 28.6 vs 21.2 months.

Health-related quality of life, assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Core Module (QLQC30) questionnaire, was significantly improved in the carfilzomib group vs the control group during 18 cycles of treatment (P < .001). The minimal clinically important between-group difference on the QLQ-C30 Global Health Status and Quality-of-Life scale is 5.0 points, which was met at cycle 12 (difference = 5.6 points) and approached at cycle 18 (difference = 4.8 points).

Adverse Events The median duration of treatment was 88.0 weeks in the carfilzomib group and 57.0 weeks in the control group.

Adverse events of any grade that were at

least 5% more frequent in the carfilzomib group included hypokalemia (28% vs 13%), cough (29% vs 17%), upper respiratory tract infection (29% vs 19%), diarrhea (42% vs 34%), pyrexia (29% vs 21%), hypertension (14% vs 7%), and muscle spasms (27% vs 21%), with rates of treatment discontinuation due to these events being less than 1% in both groups. Peripheral neuropathy occurred in 17% of both groups.

Adverse events of grade 3 or higher occurred in 84% vs 81%, and serious adverse events occurred in 60% vs 54%.

Grade 3 or higher adverse events of specific interest included dyspnea (2.8% vs 1.8%), cardiac failure (3.8% vs 1.8%), ischemic heart disease (3.3% vs 2.1%), hypertension (4.3% vs 1.8%), and acute renal failure (3.3% vs 3.1%).

Adverse events led to carfilzomib dose reduction in 11.0% and lenalidomide dose reduction in 43% of the carfilzomib group, lenalidomide dose reduction in 39% of the control group, and discontinuation of treatment in 15.3% and 17.7% of patients. Adverse events led to death in 6.9% of patients in each group, with six deaths in the carfilzomib group and eight deaths in the control group considered related to treatment. The most common causes of toxicity-related death were myocardial infarction (three patients in the carfilzomib group and one in the control group), cardiac failure (one and three patients), and sepsis (three and two patients).

The investigators concluded: “Carfilzomib combined with lenalidomide and dexamethasone led to a significant improvement in progression-free survival, as compared with lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma. These findings were bolstered by higher response rates, more robust responses, a favorable risk-benefit profile, improved health-related quality of life, and a trend toward improved overall survival with the three-drug regimen.” n

Disclosure: This study was funded by Onyx Pharmaceuticals. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372:142152, 2015.

ASCOPost.com | APRIL 10, 2015

PAGE 65

Perspective

The ASPIRE Trial of Carfilzomib in Relapsed Myeloma: A Major Step Forward

By Sagar Lonial, MD

C

urrently in myeloma, there are at least five new agents that are either approved or in the late-stage of development with impending approval. Major questions in the field relate to how we, as clinicians, will use these new agents and where they will fit in the overall treatment schema.

The phase III ASPIRE trial— recently reported by Stewart and colleagues1 and reviewed in this issue of The ASCO Post—evaluated the benefit of adding the second-generation proteasome inhibitor carfilzomib (Kyprolis) to a standard two-drug salvage regimen of lenalidomide (Revlimid) and dexamethasone. A number of lessons that may help us plan our way forward can be drawn from this very important clinical trial.

study of carfilzomib in the relapsed and refractory myeloma setting about potential cardiac issues associated

with the agent. The adverse-event profile presented from ASPIRE indicated no significant difference in cardiac-

related adverse events between the carfilzomib and control arms, procontinued on page 66

Impressive Outcomes First, the trial showed that the addition of carfilzomib resulted in significant improvement in progression-free survival, overall response rate, and depth of response, as well as in patient-reported quality-of-life metrics. Strikingly, the improvement in progressionfree survival was 9 months, and the aggregate progression-free survival of 27 months represents the longest progression-free survival reported to date in a phase III clinical trial in this setting—a major achievement. Although the patient population was predominately a relapsed and early-relapse population—both features that favor better outcomes—the duration of remission for the experimental arm is nevertheless unprecedented.

Tolerable Toxicity Second, we learned that a carfilzomib-based combination could be safely used in the relapsed setting for a large number of patients. There were lingering questions following a phase II Dr. Lonial is Professor and Vice Chair of Clinical Affairs in the Department of Hematology and Medical Oncology at the Winship Cancer Institute, Emory University, Atlanta.

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The ASCO Post | APRIL 10, 2015

PAGE 66

Perspective

Sagar Lonial, MD continued from page 65

viding reassurance in this regard. The carfilzomib group had an increased incidence of dyspnea, but in most cases, this did not result in dose modification or discontinuation.

Other adverse events were similar between the two treatment groups, further supporting the safety profile of the three-drug combination and countering one of the major arguments against combination therapy (i.e., toxicity of the therapy). It seems clear from both patient-reported outcomes and objective assessment of adverse events that toxicity associated with the addition of the third agent to the standard lenalidomide/dexamethasone salvage approach did not limit the potential benefit of the three-drug approach.

Time to Reevaluate the Benign Approach?

Third, the impressive results from this trial also begin to address a larger question currently being asked in the myeloma community. Should patients with early relapse be preferentially treated with a three-drug salvage regimen, or should we continue to use two drugs as we have traditionally done?

In the context of newly diagnosed myeloma, it is almost universally accepted now that a three-drug induction is preferable to a two-drug

regimen in terms of overall response rate and depth of response and that better pretransplant response translates to improved post-transplant duration and depth of response. We are beginning to target not just conventional complete response, but minimal residual disease–negative complete response as a goal of ther-

the progression-free survival curve in ASPIRE, but is that benefit strictly in patients with early relapse?

In a subset analysis of the trial, it appears that one group that perhaps did not get the same magnitude of benefit from the three-drug regimen was the group older than age 65. These patients tend to be frailer than younger

There are patients who can clearly benefit from a more-intensive approach, as we see from the progression-free survival curve in ASPIRE, but is that benefit strictly in patients with early relapse?

—Sagar Lonial, MD

apy for newly diagnosed patients.

Should we think about early relapse in the same fashion?

The arguments against this moreaggressive approach come from the “myeloma is an indolent disease” line of thought, in which it is typically proposed to “gently” treat patients, with the goal of pushing the ball forward one step at a time. Given the impressive results from the ASPIRE trial, is it time to reevaluate that ‘benign’ approach? There are patients who can clearly benefit from a moreintensive approach, as we see from

patients, so a better understanding of this group of patients is an important step as we begin to individualize treatment recommendations.

Who Is Likely to Derive the Most Benefit?

However, with results of many more phase III trials evaluating threevs two-drug combinations in the early relapse setting on the horizon, this question about who is likely to derive the most benefit will come up more and more. As we consider the intensity of therapy, the impact of combina-

tions, and how to approach a relapsed patient, we should begin to think more about biology and less about “populations.” What happened at the time of relapse that allowed the clone to grow back, and is this an event that requires two or three drugs for control?

As we amass new phase III trial results, in the context of the ASPIRE trial, we must carefully consider the characteristics of the patients who were treated, the magnitude of benefits achieved, and the patient and disease characteristics associated with the differential benefit: Who are the patients who derive no or little benefit, and who are the patients who derive the greatest benefit, perhaps even “cure”?

The outstanding results reported

by Stewart and colleagues represent a major step forward for our patients.

But now, as clinicians and scientists, we must find a way to apply their data and forthcoming data in a way that results in meaningful long-term benefit for our patients as part of an overall long-term treatment strategy. n

Disclosure: Dr. Sagar is on the scientific advisory boards of Millennium, Celgene, Novartis, Onyx, BMS, and Janssen.

Reference 1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372:142-152, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Lee M. Krug, MD, on Clinical Trial Participation see page 1

Hope S. Rugo, MD, on Genome Sequencing for Breast Cancers see page 4

Abdenour Nabid, MD, on Androgen-Deprivation Therapy in Intermediate-Risk Prostate Cancer see page 10

Matthew R. Smith, MD, PhD, on Cabozantinib in Metastatic Castration-Resistant Prostate Cancer see page 16

James N. Frame, MD, FACP, on SGR Formula Replacement see page 17

Jeffrey D. Bradley, MD, on Unsuccessful Treatment Additions to Stage IIIA/IIIB NSCLC see page 23

Jame Abraham, MD, FACP, on Breast Cancer in 2014 and Beyond see page 29

Cora N. Sternberg, MD, FACP, on Chemotherapy After Radical Cystectomy in Bladder Cancer see page 40

Gregory A. Masters, MD, FACP, FASCO, on Cancer Advances in the Last Decade and What Lies Ahead see page 45

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | APRIL 10, 2015

PAGE 67

FDA Update

FDA Approves Isavuconazonium Sulfate for the Treatment of Invasive Aspergillosis and Invasive Mucormycosis

T

he U.S. Food and Drug Administration (FDA) has approved Astellas’ New Drug Application for the use of isavuconazonium sulfate (Cresemba), the prodrug for isavuconazole, for patients 18 years of age and older in the treatment of invasive aspergillosis and invasive mucormycosis (also known as zygomycosis). These are life-threatening fungal infections predominantly occurring in immunocompromised patients.

The safety and efficacy profile of isavuconazonium sulfate in patients with invasive aspergillosis and invasive mucormycosis was demonstrated based on data from the Cresemba development program. The safety and efficacy profile

of isavuconazonium sulfate in patients with invasive aspergillosis was demonstrated based on data from two phase III clinical trials in adult patients with invasive fungal infections: SECURE, a randomized, double-blind, active-control study of adult patients with invasive aspergillosis; and VITAL, an open-label noncomparative study of isavuconazonium sulfate in adult patients with invasive aspergillosis and renal impairment or in patients with invasive fungal disease caused by other rare fungi.

Study Details In the SECURE study (a study of 516 patients), isavuconazonium sulfate demonstrated noninferiority to voriconazole on the primary endpoint of all-cause mortality at day 42 for the treatment of adult patients with invasive aspergillosis or other filamentous fungi. All-cause mortality through day 42 was 18.6% in the isavuconazonium sulfate treatment group and 20.2% in the voriconazole treatment group.

The safety and efficacy profile of isavuconazonium sulfate in patients with invasive mucormycosis was demonstrated based on data from the VITAL study, which included a subpopulation of 37 patients with invasive mucormycosis treated with isavuconazonium sulfate. All-cause mortality in isavuconazonium sulfate–treated patients was 38%.

The efficacy of isavuconazonium sulfate for the treatment of invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.

Safety Profile In the SECURE study, the overall safety profile for isavuconazonium sulfate demonstrated similar rates of mortality and nonfatal adverse events as the

comparator, voriconazole. The most frequent adverse events for patients treated with isavuconazonium sulfate in clinical trials were: nausea (26%), vomiting (25%), diarrhea (22%), headache

(17%), elevated liver chemistry tests (17%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%). n

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PAGE 68

In the Clinic Thoracic Oncology

Nivolumab in Metastatic Squamous Non–Small Cell Lung Cancer After Platinum Therapy

By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n March 4, 2015, the anti–programmed cell death protein 1 (PD1) monoclonal antibody nivolumab (Opdivo) was granted approval for treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC) with progression on or after platinumbased chemotherapy.1,2 Nivolumab was previously approved in December 2014 for treatment of previously treated unresectable or metastatic melanoma.

Supporting Studies Approval was based on improved overall survival with nivolumab treatment in a phase III open-label trial in which 272 patients with metastatic squamous NSCLC with disease progression during or after one prior platinum doublet–based chemotherapy regimen were randomly assigned to receive nivolumab at 3 mg/kg every 2 weeks (n = 135) or docetaxel at 75

OF NOTE Nivolumab is a human IgG4 monoclonal antibody that binds the PD-1 receptor on T cells and prevents its interaction with its ligands, thereby blocking PD-1 pathway–mediated inhibition of immune response.

mg/m2 every 2 weeks (n = 137).2 Patients were included regardless of PD-L1 [PD1 ligand] status; those with symptomatic interstitial lung disease or untreated brain metastasis were excluded.

Patients had a median age of 63 years (range = 39–85 years, 44% ≥ 65 years, 11% ≥ 75 years). Most were white (93%) and male (76%). Baseline Eastern Cooperative Oncology Group performance status was 0 (24%) or 1 (76%).

On interim analysis, median overall survival was 9.2 months (95% confidence interval [CI] = 7.3–13.3 months) in the nivolumab group vs 6 months (95% CI = 5.1–7.3 months) in the docetaxel group (hazard ratio = 0.59%, P = .00025).

Response and safety data are from a single-arm study of nivolumab at

3 mg/ kg in 117 patients who had disease progression after platinum-based therapy and at least one additional systemic regimen.3 Patients had a median age of 65 years (range = 37–87, 50% ≥ 65 years, 14% ≥ 75 years), most were male (73%) and white (85%), all had received at least two prior systemic treatments (2 in 35%), 94% had stage IV disease, 2% had brain metastasis, and performance status was 0 (22%) or 1 (78%).

The overall response rate in the single-arm study was 15% (95% CI = 9%– 22%), with 10 (59%) of 17 responding patients having response durations ≥ 6 months at the time of analysis.

How It Works Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking PD-1 pathway–mediated inhibition of immune response, including antitumor immune response.

Binding of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse tumor models, blocking PD-1 activity results in decreased tumor growth.

How It Is Given The recommended dose of nivolumab is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Nivolumab treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, alanine transaminase or aspartate transaminase > 3 to 5 times upper limit of normal or total bilirubin > 1.5 to 3 times upper limit of normal, serum creatinine > 1.5 to 6 times upper limit of normal or > 1.5 times baseline

OF NOTE Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism and hyperthyroidism, and embryofetal toxicity.

level, and any other severe or grade 3 treatment-related adverse reactions.

Nivolumab can be resumed when adverse reactions resolve to grade 0 or 1.

There are no recommended dose modifications for hypothyroidism or hyperthyroidism. No dose modifications are required in patients with renal impairment or mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment.

Nivolumab should be discontinued for any life-threatening or grade 4 adverse reaction, grade 3 or 4 pneumonitis, grade 4 colitis, alanine transaminase or aspartate transaminase > 5 times upper limit of normal, total bilirubin > 3 times upper limit of normal, serum creatinine > 6 times upper limit of normal, any recurring severe or grade 3 treatment-related adverse reaction, inability to reduce corticosteroid dose to ≤ 10 mg/d of prednisone or equivalent within 12 weeks, and persistent grade 2 or 3 treatment-related adverse reactions that do not recover to grade 0 or 1 within 12 weeks after the last dose.

Safety Profile In the single-arm trial in 117 patients, the most common adverse events of any grade were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), and cough (32%). The most frequent grade 3 or 4 adverse events were dyspnea (9%), fatigue (7%), musculoskeletal pain (6%), and pneumonia (5%). Clinically significant immune-mediated adverse events included pneumonitis, colitis, hepatitis,

Expanded Indication for Nivolumab ■■ Nivolumab (Opdivo) was granted approval for treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

■■ The recommended dose of nivolumab is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

nephritis/renal dysfunction, hypothyroidism, and hyperthyroidism.

Serious adverse events occurred in 59% of patients, with the most common being dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Adverse events led to treatment interruption in 29% and discontinuation in 27%.

Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism and hyperthyroidism, and embryo-fetal toxicity. Patients should receive corticosteroid treatment for immune-mediated adverse reactions based on reaction severity.

Patients should be monitored for liver and kidney function and thyroid function.

Thyroid hormone replacement should be used as needed. Breastfeeding women should discontinue breastfeeding. n References 1. U.S. Food and Drug Administration: Nivolumab. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm436566.htm. Accessed March 20, 2015.

2. Opdivo® (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, March 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/2015/125527s000lbl.pdf. Accessed March 20, 2015.

3. Rizvi NA, Mazières J, Planchard D, et al: Activity and safety of nivolumab, an antiPD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol 16:257-265, 2015.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

BECAUSE YOU CAN’T DO THIS TO FL…

THERE’S ZYDELIG

®

A first-in-class selective inhibitor of PI3Kδ, a protein that is expressed in normal and malignant B cells

ZYDELIG is a PI3Kδ inhibitor indicated for Relapsed FL after ≥2 systemic therapies The FL indication was granted accelerated approval based on ORR; improvement in patient survival or disease-related symptoms has not been established.

FL=follicular B-cell non-Hodgkin lymphoma; ORR=overall response rate; PI3Kδ=phosphatidylinositol 3-kinase delta.

IMPORTANT SAFETY INFORMATION BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended • Fatal and serious intestinal perforation can occur in ZYDELIG-treated patients. Discontinue ZYDELIG for intestinal perforation

FL

Please see the following pages for additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING.

IMAGINE WHAT’S POSSIBLE

FDA approved in relapsed FL after ≥2 systemic therapies

Imagine what’s possible: ZYDELIG®—A first-in-class PI3Kδ inhibitor ZYDELIG is the FIRST AND ONLY

KINASE INHIBITOR APPROVED IN FL.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) RECOMMEND IDELALISIB MONOTHERAPY AS AN OPTION for appropriate patients with relapsed/refractory FL.1*

ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCCN®=National Comprehensive Cancer Network®. *Please see the complete version of the NCCN Guidelines® for Non-Hodgkin’s Lymphomas available on NCCN.org for specific recommendations.

IMPORTANT SAFETY INFORMATION (cont'd) Contraindications • History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN) Warnings and Precautions • Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients.

In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3× upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5× ULN, withhold ZYDELIG and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs • Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents.

Avoid concurrent use with other drugs that cause diarrhea • Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5% • Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting • Severe cutaneous reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development

of severe cutaneous reactions and discontinue ZYDELIG if a reaction occurs • Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue ZYDELIG permanently and institute appropriate supportive measures if a reaction occurs • Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31% of ZYDELIG-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months.

In patients with neutrophil counts <1.0 Gi/L, monitor weekly • Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ZYDELIG and to use effective contraception during and at least 1 month after treatment with ZYDELIG Adverse Reactions • Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash • Most frequent serious adverse reactions (SAR) were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients and 53% of patients discontinued or interrupted therapy due to adverse reactions • Most common lab abnormalities (incidence ≥30%; all grades) were neutrophils decreased and ALT/AST elevations

Median time— the first follow-up, per protocol

Powerful efficacy, chemotherapy free 0

1.9

months 1

2

3

Demonstrated single-agent efficacy in an open-label, pivotal, phase 2 trial2† Range=1.6 to 8.3 months ZYDELIG in FL (n=72)

ORR

Response (%)

60

POWER of response

40

20

0

54

%

(95% CI, 42%-66%) 8% CR, 46% PR

Median DoR

Not reached

DURATION of response 0

3

6

9

12

15

Range=0.0+ to 14.8+ months CI=confidence interval; CR=complete response; DoR=duration of response; PR=partial response. †Results of a single-arm, open-label trial of ZYDELIG (150 mg, twice daily) in patients with FL who failed to respond or relapsed after ≥2 prior therapies (which must have included both rituximab and an alkylating agent). Primary end point was ORR, as assessed by an independent review committee. ORR was defined as the proportion of subjects who achieved CR or PR. Secondary end point was DoR. DoR was measured from the onset of first documented response (CR or PR) to disease progression or death.2

• Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash; 53% of patients discontinued or interrupted therapy due to adverse reactions Drug Interactions • CYP3A inducers: Avoid coadministration with strong CYP3A inducers • CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for ZYDELIG toxicity • CYP3A substrates: Avoid coadministration with CYP3A substrates Dosage and Administration • Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food.

Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown • Dose modification: Consult the ZYDELIG full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations,

bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, ZYDELIG should be permanently discontinued Please see the following pages for Brief Summary of full Prescribing Information, including BOXED WARNING. VISIT ZYDELIG.COM

IMAGINE WHAT’S POSSIBLE

S:9.5” ZYDELIG® (idelalisib) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only.

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions].

• Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions].

• Fatal and serious pneumonitis can occur in ZYDELIG-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions].

• Fatal and serious intestinal perforation can occur in ZYDELIGtreated patients. Discontinue ZYDELIG for intestinal perforation [See Warnings and Precautions].

INDICATIONS AND USAGE: • ZYDELIG is indicated in combination with rituximab for the treatment of adults with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other comorbidities.

• ZYDELIG is indicated for the treatment of adults with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received ≥2 prior systemic therapies.

• ZYDELIG is indicated for the treatment of adults with relapsed small lymphocytic lymphoma (SLL) who have received ≥2 prior systemic therapies.

• Accelerated approval was granted for FL and SLL based on overall response rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

See Warnings and Precautions, Adverse Reactions, and Use in Specific Populations for additional information.

Adult Starting Dose: One 150 mg tablet taken orally twice daily (BID), swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who required treatment longer than several months is unknown.

Severe diarrhea or colitis (≥Grade 3) occurred in 14% of ZYDELIG-treated patients across clinical trials. ZYDELIG-induced diarrhea can occur at any time and responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month following ZYDELIG interruption with or without enteric or systemic corticosteroids. Avoid concurrent use of ZYDELIG with drugs that cause diarrhea. [See Dosage and Administration].

Fatal and serious pneumonitis occurred in ZYDELIG-treated patients.

Patients taking ZYDELIG who present with pulmonary symptoms (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, >5% decrease in oxygen saturation) should be evaluated for pneumonitis. If pneumonitis is suspected, withhold ZYDELIG until etiology of pulmonary symptoms has been determined. Patients thought to have ZYDELIG-induced pneumonitis were treated with ZYDELIG discontinuation and corticosteroids.

Fatal and serious intestinal perforation occurred in ZYDELIG-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Permanently discontinue ZYDELIG in patients who experience intestinal perforation.

Severe Cutaneous Reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions (dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, skin disorder) have been reported. Monitor patients for severe cutaneous reactions and discontinue ZYDELIG. Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported in ZYDELIG-treated patients. Permanently discontinue ZYDELIG and institute appropriate supportive measures in patients who develop serious allergic reactions.

Neutropenia: Treatment-emergent neutropenia (Grade 3 or 4) occurred in 31% of ZYDELIG-treated patients across clinical trials. Monitor blood counts every 2 weeks for the first 3 months, and weekly when neutrophils are <1 Gi/L [See Dosage and Administration].

Embryo-fetal Toxicity: Idelalisib is teratogenic in rats and may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after treatment [See Use in Specific Populations].

ADVERSE REACTIONS: See BOXED WARNING and Warnings and Precautions for additional serious adverse reactions.

Dose Modifications:

Subjects with Relapsed CLL:

• Pneumonitis: discontinue ZYDELIG for any symptomatic pneumonitis

The safety assessment of ZYDELIG 150 mg BID + rituximab (up to 8 doses) is based on data from 110 adult subjects with relapsed CLL (Study 1). The median duration of exposure to ZYDELIG was 5 months.

• Hepatotoxicity: – ALT/AST >3 to 5x ULN or bilirubin >1.5 to 3x ULN: maintain ZYDELIG dose; monitor weekly until ≤1x ULN – ALT/AST >5 to 20x ULN or bilirubin >3 to 10x ULN: withhold ZYDELIG; monitor weekly until ≤1x ULN then resume ZYDELIG 100 mg BID – ALT/AST >20x ULN or bilirubin >10x ULN: permanently discontinue ZYDELIG • Diarrhea: – Moderate (increase of 4-6 stools/day over baseline): maintain ZYDELIG dose; monitor weekly until resolved – Severe (increase of ≥7 stools/day over baseline) or hospitalization: withhold ZYDELIG; monitor weekly until resolved then resume ZYDELIG 100 mg BID – Life-threatening: permanently discontinue ZYDELIG • Neutropenia: – ANC 1 to <1.5 Gi/L: maintain ZYDELIG dose – ANC 0.5 to <1 Gi/L: maintain ZYDELIG dose; monitor weekly – ANC <0.5 Gi/L: withhold ZYDELIG; monitor weekly until ≥0.5 Gi/L then resume ZYDELIG 100 mg BID • Thrombocytopenia: – Platelets 50 to <75 Gi/L: maintain ZYDELIG dose – Platelets 25 to <50 Gi/L: maintain ZYDELIG dose; monitor weekly – Platelets <25 Gi/L: withhold ZYDELIG; monitor weekly until ≥25 Gi/L then resume ZYDELIG 100 mg BID • For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce dose to 100 mg BID if resuming treatment.

Permanently discontinue ZYDELIG if severe or life-threatening toxicities recur upon rechallenge.

CONTRAINDICATIONS: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis (TEN).

WARNINGS AND PRECAUTIONS: Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. ALT or AST >5x ULN have occurred, usually within the first 12 weeks of treatment and were reversible with dose interruption. Upon resuming

• Adverse Reactions: Most common (≥2%) serious adverse reactions reported in 49% of subjects were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%). Most common adverse reactions (incidence ≥5% and occurring at ≥2% higher incidence in ZYDELIG-treated subjects; all Grades) were pyrexia (35%), nausea (25%), pneumonia (23%), diarrhea (21%), chills (21%), rash (18%), vomiting (13%), headache (10%), sepsis (8%), sinusitis (8%), pain (7%), arthralgia (7%), GERD (6%), stomatitis (6%), bronchitis (6%), nasal congestion (5%), and urinary tract infection (5%). Most common adverse reactions leading to dose reductions in 15% of subjects were elevated transaminases, diarrhea or colitis, and rash. Most common adverse reactions leading to discontinuation in 10% of subjects were hepatotoxicity and diarrhea/colitis.

• Laboratory Abnormalities: Treatment emergent laboratory abnormalities (incidence ≥10% and occurring at ≥5% higher incidence in ZYDELIG-treated subjects; all Grades) were decreased neutrophils (60%), hypertriglyceridemia (56%), hyperglycemia (54%), increased ALT (35%), increased GGT (26%), increased lymphocytes (25%), increased AST (25%), decreased lymphocytes (20%), hyponatremia (20%), and hypoglycemia (11%).

Subjects with Indolent Non-Hodgkin Lymphoma (iNHL):

• Laboratory Abnormalities: Treatment emergent laboratory abnormalities (all Grades) were decreased neutrophils (53%), increased ALT (50%), increased AST (41%), decreased hemoglobin (28%), and decrease platelets (26%).

DRUG INTERACTIONS: • CYP3A Inducers: Strong CYP3A inducers decreased idelalisib AUC by 75%. Avoid coadministration with strong CYP3A inducers (e.g., rifampin, phenytoin, St. John’s wort, carbamazepine).

• CYP3A Inhibitors: Strong CYP3A inhibitors increased idelalisib AUC 1.8-fold. Monitor for signs of ZYDELIG toxicity during coadministration and follow dose modifications for adverse reactions [See Dosage and Administration].

• CYP3A Substrates: ZYDELIG is a strong CYP3A inhibitor. Avoid coadministration with CYP3A substrates as AUC of sensitive CYP3A substrates increased 5.4-fold when coadministered.

USE IN SPECIFIC POPULATIONS: Pregnancy: ZYDELIG is Pregnancy Category D and may cause fetal harm.

In pregnant rats, embryo-fetal toxicities were observed, including decreased fetal weights, external malformations (short tail), skeletal variations (delayed ossification and/or unossification of the skull, vertebrae and sternebrae), urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, microphthalmia/anophthalmia). Women who are or become pregnant during ZYDELIG treatment should be apprised of the potential hazard to the fetus [See Warnings and Precautions].

Nursing Mothers: It is not known whether idelalisib 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 ZYDELIG, a decision should be made whether to discontinue nursing or ZYDELIG, taking into account the importance of ZYDELIG to the mother.

Pediatric Use: Safety and effectiveness of ZYDELIG in children <18 years of age have not been established.

Geriatric Use: In clinical trials of ZYDELIG in patients with FL, SLL, and CLL, 63% of patients were ≥65 years old; no major differences in effectiveness were observed.

• In patients with iNHL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (28% vs. 20%), serious adverse reactions (64% vs. 37%), and death (11% vs. 5%).

• In patients with CLL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (11% vs. 5%), serious adverse reactions (51% vs. 43%), and death (3% vs. 0%).

Contraception in Females of Reproductive Potential: ZYDELIG may cause fetal harm. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after taking the last dose of ZYDELIG. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking ZYDELIG [See Warnings and Precautions].

Renal Impairment: No dose adjustment of ZYDELIG is necessary for patients with creatinine clearance ≥15 mL/min.

Hepatic Impairment: Idelalisib AUC increased up to 1.7-fold in subjects with ALT, AST, or bilirubin >ULN compared to healthy subjects with normal ALT, AST, or bilirubin. Safety and efficacy data are not available in patients with baseline ALT or AST >2.5x ULN or bilirubin >1.5x ULN as these patients were excluded from Studies 1 and 2. Monitor patients with baseline hepatic impairment for signs of ZYDELIG toxicity and follow dose modifications for adverse reactions [See Warnings and Precautions, Dosage and Administration].

205858-GS-000-PI July 2014

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.1.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed January 7, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018.

The safety assessment of ZYDELIG 150 mg BID is based on data from 146 adult subjects with iNHL. The median duration of exposure to ZYDELIG was 6.1 months (range: 0.3 to 26.4 months).

• Adverse Reactions: Most common serious adverse reactions reported in 50% of subjects were pneumonia (15%), diarrhea (11%), and pyrexia (9%). Most common adverse reactions (incidence ≥10%; all Grades) were diarrhea (47%), fatigue (30%), cough (29%), nausea (29%), pyrexia (28%), abdominal pain (26%), pneumonia (25%), rash (21%), dyspnea (17%), decreased appetite (16%), vomiting (15%), upper respiratory tract infection (12%), asthenia (12%), night sweats (12%), insomnia (12%), headache (11%), and peripheral edema (10%). Most common adverse reactions leading to dose interruption or discontinuation in 53% of subjects were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

Gilead, the Gilead logo, and ZYDELIG are trademarks of Gilead Sciences, Inc., or one of its related companies. All other trademarks referenced herein are the property of their respective owners. © 2015 Gilead Sciences, Inc. All rights reserved.

ZYDP0068 02/2015

S:13”

DOSAGE AND ADMINISTRATION:

treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use of ZYDELIG with hepatotoxic drugs. In all patients, monitor ALT and AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. If ALT or AST >3x ULN, monitor weekly until elevation resolves; if ALT or AST >5x ULN, withhold ZYDELIG and monitor AST, ALT and total bilirubin weekly until elevation resolves [See Dosage and Administration].

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PAGE 73

Palliative Care in Oncology Clinician-Patient Communication

Why Just Having ‘Good’ Communication Skills Is Not Enough for Talking With Seriously Ill Patients A Conversation With Anthony L. Back, MD

By Jo Cavallo

I

T:13.75”

n the Institute of Medicine’s 2014 report Dying in America,1 the report’s authors found that while frequent clinician-patient conversations about end-of-life care, goals, and preferences are necessary to avoid unwanted treatment, most patients do not have those conversations with their physicians.

As a result, “Clinicians need to initiate conversations about end-of-life care choices and work to ensure that patient and family decision-making is based on adequate information and understanding,” concluded the study authors.

Incorporating precise language and good communication skills into his oncology practice to ensure that his patients understand their prognosis and treatment options and teaching other oncologists how to become good communicators in their practices is the lifework of Anthony L. Back, MD, Professor of Medicine at the University

nication strategies to physicians.

The ASCO Post talked with Dr. Back about what constitutes good communication skills, the barriers impeding communication and decision-making about goals of care with seriously ill patients, and how oncologists can become more effective communicators.

Emotionally Loaded Conversations Please discuss the importance of having good communication and listening skills when talking with patients, especially when addressing difficult issues like advance care planning and end-of-life care.

A study in JAMA Internal Medicine looked at barriers to goals of care conversations with seriously ill hospitalized patients and their families.2 The study surveyed hospital-based clinicians on the importance of 21 barriers to goals of care discussions rated on a 7-point scale. The

It is our responsibility as oncologists to find a way to individualize the way we talk to patients about things like advance directives, based on the patient’s ability to cope with the information at a particular time.

—Anthony L. Back, MD

of Washington and the Fred Hutchinson Cancer Research Center and CoDirector of the Cambia Palliative Care Center of Excellence at the University of Washington, Seattle.

In addition to his clinical practice, Dr. Back conducts research on patient/ clinician communication and interventions to help make oncologists and nurse practitioners more effective oncology care providers. He is the recipient of the American Cancer Society’s Pathfinder in Palliative Care Award and the American Academy for Hospice and Palliative Medicine’s National Leadership Award and the coauthor of Mastering Communication With Seriously Ill Patients: Balancing Honesty With Empathy and Hope (Cambridge University Press, 2009). Two years ago, Dr. Back and his colleagues launched VitalTalk.org, a nonprofit website dedicated to disseminating effective research-based commu-

study found that the clinicians perceive family member–related and patient-related factors as the most important barriers to goals of care discussions.

That’s fine, but I am concerned that the study finding encapsulates a worldview many clinicians have that patients—and not physicians—are the problem when it comes to effective end-of-life discussions. These conversations with patients are emotionally loaded, and just being good at giving information isn’t enough.

Physicians feel that patients don’t want to know about the seriousness of their illness and resist talking about it, and a lot of oncologists find the problem frustrating. But the approach that I try to embody when a patient is reluctant to discuss end-of-life care is to ask myself, what could I do differently to engage this patient in this difficult conversation? Effectively engaging patients

in these difficult discussions takes a repertoire of different kinds of communication skills.

Instead of blaming the patient, it is our responsibility as oncologists to find a way to individualize the way we talk to patients about things like advance directives, based on the patient’s ability to cope with the information at a particular time. If the patient says, “I don’t want to talk about advance directives,” you have to find another way to engage the patient. That is our responsibility.

If the patient is distressed and nervous, starting with an acknowledgement that this is a difficult conversation to have can help give patients time to gather their emotional bearings and hear what you are saying. Or asking patients about how other family members coped with a similar situation or what patients said to their spouses about the situation might give clinicians a clue to how to start the conversation.

So some of the skills in being a great communicator—not just a good one— are the ability to listen for emotional cues, to pick up on stories patients are telling you about their experience with cancer, what their family members’ or friends’ experiences with cancer or other life-threatening diseases were, and knowing when to slow down or stop the conversation temporarily if the patient is getting so upset he can’t hear you anymore.

Clinicians also have to have the ability to summarize patients’ clinical situation in language they can understand.

Benefits to Patients What are some of the benefits to patients when they are clear about what their desires are for end-of-life care?

Good communication between clinicians and patients helps patients understand the reality of their situation and helps them make better decisions about their treatment, meaning that their treatments will match their values and goals for quality of life over aggressive care. It also helps ensure that they will have fewer regrets about their ­decisions.

When clinicians and patients have strong communication, patients will weigh their doctors’ recommendations more carefully. They will also have a sense of being cared for, and that alone can have a therapeutic effect on ­patients.

GUEST EDITOR

Jamie H. Von Roenn, MD

A

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

Benefits to Physicians How does having great communication skills benefit oncologists?

The reality is that providing oncology care is pretty stressful. Studies show that having communication skills training is associated with less physician burnout. I think having a repertoire of great communication skills helps physicians feel they can be more effective providers by helping their patients make the best-­ informed medical decisions, whether that means matching up a patient’s clinical needs with the most effective therapies or being okay with a patient’s decision to try something else.

Improving Communication Skills Please give some suggestions on how oncologists can become more effective ­communicators.

One important suggestion for physicians is simply to be attuned to the patient’s emotional state and to use that knowledge as data on how to navigate the course of the conversation. It can also be helpful to ask a member of the medical team—for example, a nurse or social worker—to critique your conversation with the patient and to tell you one thing that you did well and one area you could improve.

Pausing every few minutes during the conversation with patients to gauge how much they are absorbing of what continued on page 74

The ASCO Post | APRIL 10, 2015

PAGE 74

Announcements

American Association for Cancer Research Elects New Board of Directors, Nominating Committee Members

T

he members of the American Association for Cancer Research (AACR) have elected five members to serve on the AACR board of directors for the 2015–2018 term and four members to serve on the nominating committee for the 2015–2017 term. They will begin their terms at the AACR Annual Meeting 2015, to be held in Philadelphia, April 18–22.

Board of Directors The following five members were elected to the board of directors: George D. Demetri, MD, Professor of Medicine at Harvard Medical School, Director of the Ludwig Center at Harvard, Director of the Center for Sarcoma and Bone Oncology at DanaFarber Cancer Institute and Brigham

Anthony L. Back, MD continued from page 75

you are saying is another good communication skill to adopt. For example, stopping at different points during the conversation and asking, “What are you taking away from what I am saying so far?” Asking that question periodically gives physicians instant feedback.

We have designed an online guide on VitalTalk.org to help physicians navigate tough situations and sharpen their communication skills. The website has one-page guides that offer quick, actionable insights on various topics, including talking about dying, transitions/goals of care, conflicts, and discussing prognosis, which can

George D. Demetri, MD

and Women’s Hospital, Senior Vice President for Experimental Therapeutics and Staff Physician at Dana-Farber Cancer Institute, Coassociate Director of Clinical Science at Dana-Farber/ Harvard Cancer Center, Associate Physician at Brigham and Women’s Hospital, Affiliate Physician at Massachusetts General Hospital, and a Visiting Clinical Attending Physician at the be downloaded for free. The website also includes video demonstrations of conversations between oncologists and patients on such topics as establishing rapport, tracking and responding to emotion, disclosing serious news, and resetting goals of care.

Advice for Patients You recommend that patients write down any questions they may have about their care before the office visit. How does that help forge better physician-patient communication?

Patients who bring a list of questions to the office visit develop better comprehension of the information given about their cancer, such as prognosis.

National Cancer Institute.

Dr. Demetri is currently a member of the AACR Chemistry in Cancer Research Working Group.

Patricia M. LoRusso, DO, Professor of Medicine in the Division of Oncology at Yale University, and Associate Director of Innovative Medicine at Yale Cancer Center.

Dr. LoRusso is currently Chair-Elect

Designate of the AACR Women in Cancer Research Council, Cochair of the Annual Meeting Clinical Trials Committee, and an editorial board member of Molecular Cancer Therapeutics.

Richard M. Marais, MD, Director and Senior Group Leader of the Molecular Oncology Group at the Cancer Research UK Manchester Institute, Center

Patricia M. LoRusso, DO

Richard M. Marais, MD

What I find in my own practice is that asking patients to bring in a list of questions has two benefits.

First, patients come to the visit more focused—the fact that they thought about and wrote down their concerns enables the big issues to surface more quickly. And, second, I can read through the list and prioritize the most important questions that I need to answer and then triage other questions to a nurse, nutritionist, or other member of the medical team.

I also advise patients to bring someone with them to the office visit so they have another ear in case they miss something. I reassure patients not to worry if they missed some piece of the information discussed because there

will be more opportunities to go over the details of the discussion again in other meetings. n

continued on page 75

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

References 1. Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life. Institute of Medicine of the National Academies, September 17, 2014.

Available at www. iom.edu/endoflife. Accessed March 20, 2015.

2. You JJ, Downar J, Fowler RA, et al: Barriers to goals of care discussions with seriously ill hospitalized patients and their families. JAMA Intern Med. February 2, 2015 (early release online).

ASCOPost.com | APRIL 10, 2015

PAGE 75

Announcements AACR Elections

Nominating Committee

continued from page 75

The following four members were elected to the nominating committee: Kornelia Polyak, MD, PhD, Professor of Medicine at Harvard Medical School, Professor of Medical Oncology at Dana-Farber Cancer Institute, and Principal Faculty at the Harvard Stem Cell Institute.

Colead at the Cancer Research UK Lung Cancer Centre of Excellence, Scientific Codirector at the Belfast-Manchester Movember Centre of Excellence, and Professor of Molecular Oncology at the University of Manchester.

Dr. Marais is currently Cochair of the AACR Annual Meeting Education Committee and the Program Committee, a scientific editor of Cancer Discovery, a member of the Cancer Immunology Working Group, and Cochair of the Stand Up To Cancer-Cancer Research UK Translational Research Fellowship Joint Scientific Advisory Committee.

Elaine R. Mardis, PhD, Robert E. and Louise F. Dunn Distinguished Professor of Medicine, Codirector of the

Dr. Polyak is currently a member of the AACR Outstanding Investigator Award for Breast Cancer Research Committee and the Pediatric Cancer Working Group.

Charles L. Sawyers, MD, Chairperson of the Human Oncology and Pathogenesis Program at Memorial Kornelia Polyak, MD, PhD

continued on page 76

Elaine R. Mardis, PhD

Genome Institute, Professor in the Departments of Genetics and Molecular Microbiology, and Assistant Professor in the Department of Molecular Microbiology at the Washington University in St. Louis School of Medicine.

Dr. Mardis is currently Senior Editor of Molecular Cancer Research and a member of the Special Conferences Committee and the Clinical and Translational Cancer Research Steering Committee.

Edith A. Perez, MD, Deputy Director at Large at the Mayo Clinic Cancer Center, Serene M. and Frances C. Durling Professor of Medicine, Direc-

Edith A. Perez, MD

tor of the Breast Cancer Translational Genomics Program, and Chair of the Breast Cancer Specialty Council at the Mayo Clinic College of Medicine.

Dr. Perez is currently Chair-Elect of the AACR Minorities in Cancer Research Council and a member of the Science Policy and Government Affairs Committee and the Finance and Audit Committee.

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Announcements AACR Elections continued from page 75

Sloan Kettering Cancer Center, a Howard Hughes Medical Institute Investigator, and Professor in the Cell and Developmental Biology Program at the Weill Cornell Graduate School of Medical Sciences of Cornell University. He is also a fellow of the AACR Academy.

Charles L. Sawyers, MD

Dr. Sawyers served as AACR president from 2013 to 2014. He is currently a scientific editor of Cancer Discovery and Coleader of the Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team, “Precision Therapy of Advanced Prostate Cancer.”

William R. Sellers, MD, Vice President and Global Head of Oncol-

William R. Sellers, MD

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ASCOPost.com | APRIL 10, 2015

PAGE 77

Announcements

ogy at Novartis Institutes of BioMedical Research, Associate Professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute, Associate Member of the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, and Associate Physician at Brigham and Women’s Hospital.

Dr. Sellers served as Chair of the AACR special conference, “Translation of the Cancer Genome,” in 2009 and 2015, as well as Keynote Speaker in 2011, and as Chair of the Research Grant Review Committee.

Inder M. Verma, PhD, Professor in the Laboratory of Genetics at The Salk Institute and Adjunct Professor in the

Inder M. Verma, PhD

Department of Biology at the University of California, San Diego. He is also a fellow of the AACR Academy.

Dr. Verma served as a program committee member of the AACR international conference, “New Horizons in Cancer Research: Biology to Prevention and Therapy,” in India, and on the International Affairs Committee. n

ONS Lifetime Achievement Award

D

eborah K. Mayer, PhD, RN, Director of Cancer Survivorship at the UNC Lineberger Comprehensive Cancer Center has been named the recipient of the 2015 Oncology Nursing Society Lifetime Achievement Award.

Deborah K. Mayer, PhD, RN

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The award recognizes her contributions as an oncology nurse researcher, mentor, and educator, as well as her service to the Oncology Nursing Society and community.

“It is an honor to receive this award,” said Dr. Mayer, a UNC Lineberger Member and Professor in the UNC School of Nursing Adult and Geriatric Health Division. “As a member of the Oncology Nursing Society since 1975, I have grown professionally along with the organization and have learned as much from my volunteer activities as I have given. It has been a great way to extend my efforts to improve cancer care.”

Dr. Mayer is a charter member of the society. While serving as a Director-atLarge and then as the President of the organization, she was instrumental in developing a strategic planning process that continues today.

Dr. Mayer earned her bachelor’s of science degree in nursing from Excelsior College, her master’s of science degree in nursing from Yale University, her nurse practitioner certificate from the University of Maryland School of Nursing, and her PhD from the University of Utah, Salt Lake City. n

The ASCO Post | APRIL 10, 2015

PAGE 78

Journal Spotlight Gastrointestinal Oncology

Adding Cetuximab to First-Line FOLFIRI Does Not Benefit Metastatic Colorectal Cancer Patients With RAS Mutations

By Mathew Stenger

T

he phase III CRYSTAL trial showed that the addition of cetuximab (Erbitux) to first-line FOLFIRI (fluorouracil, leucovorin, and irinotecan) significantly improved overall survival, progression-free survival, and objective response rates in patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer.1,2 According to a post hoc analysis conducted in the CRYSTAL population and reported in the Journal of Clinical Oncology, Eric Van Cutsem, MD, PhD, of University Hospitals Gasthuisberg/Leuven, and colleagues found that cetuximab was not of benefit among patients in the trial with RAS mutations at exon 2 or other loci.3

Study Details In the CRYSTAL trial, patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer were randomly assigned to receive 14-day cycles of FOLFIRI plus weekly cetuximab or FOLFIRI alone as first-line treatment. In the current study, DNA samples from CRYSTAL patients with KRAS exon 2 wild-type tumors were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology; no tissue microdissection was performed.

In total, RAS mutation status was assessable in 430 (65%) of the 666 patients with KRAS exon 2 wild-type tumors, including 210 in the cetuximab/FOLFIRI group and 220 in the FOLFIRI-alone group. Other RAS mutations, using a 5% mutant/wild-type cutoff, were found in 63 (15%) of the 430 patients, including 32 patients in the cetuximab/FOLFIRI group and 31 in the FOLFIRI group.

Outcomes According to RAS Status Among all 430 RAS-assessable patients with wild-type KRAS exon 2 tumors, median overall survival was 26.1 months with cetuximab/FOLFIRI vs 20.2 months with FOLFIRI alone (hazard ratio [HR] = 0.75, P = .008), median progression-free survival was 11.3 vs 7.7 months (HR = 0.58, P < .001), and objective response rate was 61% vs 38% (P < .001).

Among the 367 patients with wildtype RAS at all loci, overall survival was 28.4 months with cetuximab/FOLFIRI vs 20.2 months with FOLFIRI

Cetuximab/FOLFIRI and RAS Mutation Status in Colorectal Cancer ■■ The addition of cetuximab to FOLFIRI was associated with significant improvements in overall survival and progression-free survival among patients with wild-type RAS at all loci.

■■ No benefit of adding cetuximab was observed among patients with any RAS mutation.

in the C ­ RYSTAL population, overall survival was 16.4 months with cetuximab/­FOLFIRI vs 17.7 months with ­FOLFIRI (HR = 1.05, P = .64), progression-free survival was 7.4 vs 7.5

[O]ur study supports the use of FOLFIRI plus cetuximab in patients with RAS wild-type tumors and, on the basis of a lack of observed benefit, suggests the exclusion of patients with other RAS mutations.

—Eric Van Cutsem, MD, PhD, and colleagues

(hazard ratio [HR] = 0.69, P = .0024), progression-free survival was 11.4 vs 8.4 months (HR = 0.56, P < .001), and objective response rate was 66% vs 39% (P < .001).

Among the 63 patients with RAS mutations, overall survival was 18.2 months with cetuximab/FOLFIRI vs 20.7 months with FOLFIRI (HR = 1.22, P = .50), progression-free survival was 7.2 vs 6.9 months (HR = 0.81, P = .56), and objective response rate was 34% vs 35% (P = .97).

Finally, in a population of 460 patients with any RAS mutation, consisting of the 63 patients with other RAS mutation and 397 previously identified with KRAS exon 2 mutation

months (HR = 1.10, P = .47), and objective response rate was 32% vs 36% (P = .40).

Conclusions The investigators concluded: “In the first-line treatment of [metastatic colorectal cancer], patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not…. [O]ur study supports the use of FOLFIRI plus cetuximab in patients with RAS wild-type tumors and, on the basis of a lack of observed benefit, suggests the exclusion of patients with other RAS mutations.

Reserving such first-line treatment for

a RAS wild-type population allows the definition of a subgroup more likely to benefit from the addition of cetuximab to FOLFIRI. Molecular testing of tumors for all activating mutations in KRAS and NRAS before considering anti-EGFR therapy is therefore essential in selecting the most effective treatment for patients with [metastatic colorectal cancer].” n Disclosure: The study was supported by Merck KGaA. Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly, Merck Serono, Novartis, Roche, and sanofi-aventis, all via his institution.

For full disclosures of the study authors, visit jco. ascopubs.org.

References 1. Van Cutsem E, Köhne CH, Hitre E, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408-1417, 2009.

2. Van Cutsem E, Köhne CH, 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 29:20112019, 2011.

3. Van Cutsem E, Lenz H-J, Köhne C-H, et al: Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 33:692-700, 2015.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | APRIL 10, 2015

PAGE 79

Perspective

Refining the ‘Right Patient, Right Drug’ Pairing in Cancer Care: RAS Profiling in Metastatic Colorectal Cancer

By Brandon G. Smaglo, MD

I

n an important post hoc analysis (reviewed in this issue of The ASCO Post), Van Cutsem and colleagues have further refined our knowledge of who are the “right” patients with metastatic colorectal cancer to receive treatment with cetuximab (Erbitux).1 This refinement was accomplished through the retrospective assessment of extended RAS profiling on the patients’ tumors from the original CRYSTAL study, to assess for a correlation between additional RAS mutations and cetuximab benefit.

First Foray Into ‘Personalized’ Therapy When the association was first identified between KRAS mutational status and tumor response to antiepidermal growth factor receptor antibody (antiEGFR) therapy, both cetuximab and panitumumab (Vectibix), it represented the first instance in which a therapy for patients with metastatic colorectal cancer could be recommended based upon unique characteristics of the individual tumor. In essence, it was the first foray into “personalized” therapy for colorectal cancer.2,3 This updated analysis from the CRYSTAL study further refines this personalization. In doing so, however, it also further reduces the percentage of patients available to benefit from this therapy.

As noted in the study article, a similar finding of extended RAS mutational analysis from the PRIME study tumors identified a corresponding lack of benefit with the use of panitumumab to extended RAS mutations.4 The immediate impact from this analysis of the CRYSTAL study, as well as the PRIME study analysis, is the need for extended RAS evaluation of all colorectal tumors in patients for whom treatment with either anti-EGFR monoclonal antibody is being considered.

The CRYSTAL authors do note that their patient numbers were insufficient to make a definitive statement for extended RAS testing, but the trend Dr. Smaglo is Assistant Professor of Medicine at The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC.

toward a lack of benefit is adequate to make this practice change. Although this will translate into fewer patients who are eligible to receive cetuximab, the corollary effect may be that the group selected is even more appropriate for such treatment, and thus the benefit may be greater for this select population.

No One-Size-Fits-All Model of Agent Selection Beyond any discussion of cetuximab, this analysis is also illustrative of the wider variation between tumors and their resultant susceptibility to various treatments, thus giving further argument against a one-size-fits-all model of agent selection. Of the nine currently approved systemic agents for the treatment of metastatic colorectal cancer in the United States, the two anti-EGFR monoclonal antibodies remain the only drugs that are selected for or excluded from use based upon further analysis of the individual tumor. All others are used in an appropriate sequence, based in part on the

RAS wild-type tumors, there is no guidance as to whether the biologic treatment should consist of an antiEGFR or an anti-VEGF (vascular endothelial growth factor) antibody; data presented at the plenary session of the 2014 ASCO meeting suggested neither biologic was superior.6 Nevertheless, as suggested by the further refinement of RAS status and anti-EGFR antibody effect from the analyses of the ­CRYSTAL and PRIME data, the most effective chemotherapy doublet and biotherapy selection could be personalized in the future, by using the unique features of the individual tumors rather than some uniformly applicable standard.

techniques are under development. At present, such tools must be used with caution, providing an additional piece of information to be considered rather than a definitive map to be followed.

However, in the future, they hold the promise of evolving into that map, guiding patients and their oncologists to optimal therapies for their unique cancer. As our understanding of the biomarkers and other unique drivers of individual cancers becomes more refined, it is hoped that we can extend the work done by Van Cutsem and colleagues to all cancer therapies, selecting what is truly the hand-chosen “right” drug for the unique tumor. n

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

More on Tumor Profiling To arrive at this point of personalization, we first need to know what these unique features are that we are looking for with each drug; in other words, using CRYSTAL as an example, one could ask what is the “RAS” for all of the other agents? Complicating this

Certainly, the RAS findings constitute only a single chapter of the anti-EGFR antibody selection story.

—Brandon G. Smaglo, MD

discretion and comfort of the treating search is the question as to what level physician, with a common credo ap- of the metabolome (genomic, proplied that all patients should, at some teomic, etc) will contain these treatpoint in their treatment course for met- ment-guiding tumor features. In all probability, the answer again will be astatic disease, receive every drug.

Barring any contraindication, this diverse, spanning the metabolome as usually means that for the first and opposed to residing within one layer second lines of therapy, patients are of it. Moreover, it is naive to think that treated with a fluoro­pyrimidine-based the answer will reside in a simple, sinchemotherapy doublet combined gle “yes-or-no” reference point within with a biologic agent. There is no this network. Rather, it will rely on guidance yet available as to whether the dynamic interplay throughout the that doublet should initially employ network. Certainly, the RAS findings irinotecan or oxaliplatin, and from constitute only a single chapter of the the efficacy point of view, the doublet anti-­EGFR antibody selection story. regimens FOLFOX (fluorouracil-­ Tumor profiling to guide treatment oxaliplatin) and FOLFIRI (fluoro- selection is one of the hottest topics uracil-irinotecan) have demonstrated in cancer research right now, and a equivalence.5 For those patients with number of different tumor-profiling

References 1. Van Cutsem E, Lenz HJ, Köhne CH, et al: Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 33:692-700, 2015.

2. Van Cutsem E, Köhne CH, Hitre E, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408-1417, 2009.

3. Douillard JY, Siena S, Cassidy J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol 28:4697-4705, 2010.

4. Douillard JY, Oliner KS, Siena S, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.

N Engl J Med 369:1023-1034, 2013.

5. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 23:4866-4875, 2005.

6. Venook AP, Niedzwiecki D, Lenz HJ, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wildtype untreated metastatic adenocarcinoma of the colon or rectum. 2014 ASCO Annual Meeting. Abstract LBA3.

Š 2015 Celgene Corporation

03/15

US-CELG140284c

IN MULTIPLE MYELOMA

RESIDUAL DISEASE AND IMMUNE DYSFUNCTION FORM A GROWING RISK OF RELAPSE An increased understanding of multiple myeloma has helped advance myeloma care over the past several decades.1,2 Despite a significant improvement in 5-year relative survival rates, patients still experience multiple periods of relapse and remission.2,3 Do residual disease and immune dysfunction form a cycle that complicates our strategies?

EVEN WITH THE ACHIEVEMENT OF A COMPLETE RESPONSE, 100 MILLION MYELOMA CELLS MAY REMAIN.4

~

The majority of patients with multiple myeloma have persistent levels of residual disease (minimal residual malignant cells) that are below the sensitivity of most protein and bone marrow diagnostic tests.5-7 Even in patients who achieve a complete response (by current International Myeloma Working Group criteria), residual disease may persist.4 In addition, dominant and minor clones continue to evolve, putting the patient at increased risk for relapse.8,9

IMMUNE DYSFUNCTION ALLOWS RESIDUAL DISEASE TO PROLIFERATE, FURTHER WEAKENING THE IMMUNE SYSTEM, AND MAY CAUSE A CYCLE OF DISEASE THAT RESULTS IN RELAPSE.5, 9-14 Myeloma tumor cells crowd out healthy cells in the bone marrow, leading to a compromised immune system and decreased immune surveillance—the immune system’s ability to identify and eliminate tumor cells.9-13 When immune surveillance is impaired, residual cells may proliferate and evolve, permitting a cycle that can lead to relapse.9,10,13

CONTINUOUS SUPPRESSION OF RESIDUAL DISEASE AND SUPPORT OF IMMUNE FUNCTION ARE IMPORTANT CONSIDERATIONS WHEN CREATING A LONG-TERM STRATEGY.13,15,16

References: 1. Kumar SK, et al. Leukemia. 2014;28:1122-1128. 2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER cancer statistics review 1975-2011. Available at http://www.seer.cancer.gov. Accessed October 22, 2014. 3. Hajek R. Multiple myeloma – a quick reflection on the fast progress. InTech; 2013. Available at http://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-onthe-fast-progress. Accessed December 12, 2014. 4. Poon ML, et al. Cancer Therapy. 2008;6:275-284. 5. Hart AJ, et al. Biol Blood Marrow Transplant. 2012;18:1790-1799. 6. Rajkumar SV, et al. Blood. 2011;117:4691-4695. 7. Martinez-Lopez J, et al. Blood. 2014;123:30733079. 8. Keats JJ, et al. Blood. 2012;120:1067-1076. 9. Morgan GJ, et al. Nat Rev Cancer. 2012;12:335-348. 10. Katodritou E, et al. Am J Hematol. 2011;86:967-973. 11. Braga WM, et al. Clin Dev Immunol. 2012;2012:Mar 27 EPub. 12. Kyle RA, et al. N Engl J Med. 2004;351:18601873. 13. Pratt G, et al. Br J Haematol. 2007;138:563-579. 14. Favaloro J, et al. Leuk Lymphoma. 2014. May 12:1-8. [Epub ahead of print].

15. Roschewski M, et al. Blood. 2013;122:486-490. 16. Pessoa de Magalhães RJ, et al. Haematologica. 2013;98:79-86.

The ASCO Post | APRIL 10, 2015

PAGE 82

Expert’s Corner Public Health

The Ongoing Struggle Against Tobacco: Past Accomplishments, Future Steps A Conversation With John Seffrin, PhD, CEO of the American Cancer Society

By Ronald Piana

John Seffrin, PhD

I

n 1913, 10 doctors and 5 laypersons in New York founded the American Cancer Society (ACS). At that time, a cancer diagnosis was almost always fatal and was rarely discussed in public. The Society’s original charter was to raise awareness about cancer, and although that mission has remained firm, over the past century, the ACS has also become the nation’s foremost advocate for research into the detection, treatment, and prevention of cancer. The ASCO Post recently spoke with John Seffrin, PhD, who has been the Chief Executive Officer of the ACS since 1992.

The Century’s Number 1 Health Problem You recently gave the keynote address at the annual meeting of the Society for Research on Nicotine and Tobacco. What was the gist of your address?

My main point was that tobacco will become the number 1 public health challenge and opportunity of this century. This is based on evidence. We know that tobacco killed 100 million people over the past century and is on track to kill more than 1 billion people this century. Most people are not aware of the devastating price we’ll pay in human suffering and economic loss unless we intervene. The tobacco problem is a scientific and public health issue, but it is also a moral issue.

Moreover, tobacco use is a shared risk factor, and arguably the most preventable, for the four leading noncommunicable diseases in the world: heart disease and stroke, cancer, diabetes, and chronic lung disease. It’s interesting to note that leading up to Y2K, the United Nations Millennium Development Goals discussed HIV/AIDS, tuberculosis, and malaria, but there was no mention of cancer.

Fast forward a decade or so and dur-

ing a high-level meeting with the United Nations on noncommunicable diseases, they passed a 13-page declaration in which cancer was the centerpiece of action, because of the global threat it presents for this century. The United Nations declaration states that cancer and other noncommunicable diseases will be the century’s number 1 health challenge.

We have proven interventions against this impending disaster that can be implemented for $3 to $5 per person, per year; failings to deploy these interventions will cost the world $47 trillion in lost economic output over the next 2 decades. Addressing tobacco alone in nations that desperately need it—low- and middle-income countries—would cost just 11 cents a day per capita, according to the most recent version of The Tobacco Atlas, released in March from my organization and the World Lung Foundation.

Efforts to Clear Secondhand Smoke We’ve just passed the 25th anniversary of the airline-smoking ban. Please shed light on what it took to get initiatives like this and others accepted and put into policy.

Remember, it has been a long, hard fought battle against Big Tobacco. It

smoke-free air laws in the other states so all our citizens get equal protection from the dangers of secondhand smoke.

We worked closely with Senator Dick Durbin from Illinois to get the airline-smoking ban legislation passed. We testified on behalf of the ACS, showing evidence that flight attendants regularly exposed to secondhand smoke were put at risk for heart and lung diseases. We also pointed out that this was an issue of human rights; in other words, you have a right to throw your fist out as long as it doesn’t hit my nose. The tobacco industry fights hard to keep selling its product, so it’s satisfying to celebrate the 25th anniversary of the airplane smoking ban legislation that the ACS helped make happen.

Using ‘All the Arrows in the Quiver’ What methods work in smoking ­cessation?

Raising the excise tax on tobacco is one of the only public health initiatives that has immediate measurable success in reducing smoking. We can predict with uncanny accuracy how many people will stop smoking according to the economic burden of increased cigarette taxes. Since 2002, 47 states, the District of Columbia, and several U.S. territories have increased their cigarette tax rates

One and a half million Americans who would have died of cancer did not, due to the work that’s been done in the fight against the disease.

—John Seffrin, PhD

has resulted in major policy and cultural changes, which reduced the incidence of tobacco use from more than 40% of the country down to about 18% today.

The next battle was putting policies in place that would protect people from the dangers of secondhand smoke, such as on commercial airlines. When I got involved in this issue, no state in this country had implemented a smoke-free workplace law; now about half of the nation’s population lives in an area that prohibits smoking in all workplaces, including bars and restaurants.

That said, about 42,000 Americans die of the effects of secondhand smoke each year. So we’re not there yet; we have to persuade legislators to pass

more than 110 times. Those changes are saving lives.

Using U.S. Food and Drug Administration–approved cessation medication along with counseling can also be effective in certain populations. And the new National Comprehensive Cancer Network smoking cessation guidelines make a substantial contribution. They provide oncologists with all the information they need to help their patients who smoke to stop. As we know, continuing to smoke, even when one has been diagnosed with cancer, can interfere with proper treatment and is associated with the development of second primary tumors.

But, certainly, we don’t have all the answers and we need more research. We

must use all the arrows in our quiver to put an end to tobacco-related deaths in our country.

Further, on the international level, we have developed the World Health Organization Framework Convention on Tobacco Control (FCTC), which is the first global public health treaty on record. So far, there are about 180 parties to the FCTC. Unfortunately, the United States is not one of them. A few years ago, I was at a World Health Organization conference in Geneva and said that if we knew where and when the next major tsunami was about to hit and we did not send out a warning, would that not be immoral?

We know that over the next couple of decades, the world will experience a tsunami of noncommunicable diseases, with cancer leading the way. For us not to send a clear warning would be immoral. Plus, we have the tools to at least avert a direct hit, which would save countless millions of lives. Our overall goal is “25 by 25”—reducing premature mortality from noncommunicable diseases such as cancer by 25% by 2025.

In short, we have to get even more serious-minded about smoking cessation advocacy and make more noise on this issue.

We can walk up the steps of Capitol Hill and work with state and local lawmakers to say if you help us pass tougher cigarette excise taxes and clean air acts and put more money into research, we’ll guarantee a hefty return on that investment.

For example, we’ve had 22 successive years in declining rates of cancer mortality. And for most of my career until 1991, the mortality rates were rising. This success is an admixture of prevention, early detection, and improved cancer therapies. Simply put, we’ve published data showing that 1.5 million Americans who would have died of cancer did not, due to the work that’s been done in the fight against the disease. Moreover, we have a greater responsibility than did our predecessors, because they didn’t have the scientific knowledge and tools we have today.

Not the Healthiest Nation in the World What do you think about the direction of American health care?

Well, it’s a work in progress. The passage of the Affordable Care Act, although far from perfect, was a step in the right direction toward building a better health-care system. And I’m not sure that the change

ASCOPost.com | APRIL 10, 2015

PAGE 83

Expert’s Corner

we’re seeing would have happened without the work of the ACS and our American Cancer Society Cancer Action Network, which we created about 14 years ago.

On the larger picture, I believe prevention and public health will have to become the preeminent health-care specialty of this century for the United States to become the healthiest nation in the world, which, sadly, we are not today.

Closing Thoughts The ACS has announced that you’ll soon be stepping down as the Society’s CEO. On behalf of The ASCO Post and

the oncology community at large, thank you for your selfless service and estimable contributions to our cancer patients. Please share some last thoughts with the readers.

Thank you. I was recently at the World Conference on Tobacco or Health in Abu Dhabi and presented the Luther Terry award for global tobacco control, which is the most prestigious tobacco-control award in the world. It was an honor and a fitting way to close out my tenure because, as you know, Dr. Terry’s Surgeon General’s report on smoking was a landmark in the ongoing struggle against ­tobacco.

I am so proud of having served the ACS, and largely due to the leadership of my organization, we are now saving nearly 500 lives each day that would have otherwise been lost to cancer.

We shouldn’t be satisfied, because that number of lives saved can reach a thousand each day if the right effort is levied. We realized several years ago at the Society that we needed a stem-to-stern transformation on how we operated, if we wanted to realize our full lifesaving potential as an organization and achieve that 1,000 lives per day goal. At the American Cancer Society, we are never

satisfied with the status quo. And today, we’ve probably had more positive change at the Society in the past 5 years than in the previous 95 years.

I’m very proud of the ACS, whose volunteers and staff members are second to none in terms of dedication to their mission. There are about 1,000 not-for-profit organizations across the country involved in some form of cancer advocacy, but the ACS stands alone in its comprehensive breadth and mission to prevent and treat cancer. n Disclosure: Dr. Seffrin reported no potential conflicts of interest.

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When faced with overactive signaling . . .

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi

Jakafi is a registered trademark of Incyte Corporation. Š 2015, Incyte Corporation. All rights reserved. RUX-1452a 03/15

Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis.

If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

Inhibit the JAK pathway* in polycythemia vera not controlled with hydroxyurea 1-3

Jakafi® (ruxolitinib) is the first and only FDA-approved treatment for patients who have had an inadequate response to or are intolerant of hydroxyurea3 Jakafi demonstrated superior results in a phase 3 trial vs best available therapy3,4†

Primary Response at Week 323,4 80

* Ruxolitinib, a kinase inhibitor, inhibits JAK1 and JAK2 (Janus-associated kinases 1 and 2), which mediate the signaling of cytokines and growth factors important for hematopoiesis and immune function.3 A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy (BAT) in 222 patients. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy, and exhibited splenomegaly. The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both hematocrit (Hct) control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a ≥35% reduction from baseline in spleen volume at week 32).

Phlebotomy eligibility was defined as Hct >45% that is ≥3 percentage points higher than baseline or Hct >48% (lower value).3,4

P < 0.0001

Jakafi (n = 110) BAT (n = 112)

(n = 66)

38%

40

21%

a

20 0

a

Individual Components of Primary End Point

60%

60

Patients (%)

†

Composite Primary End Point

(n = 23)

1%b

(n = 22)

(n = 1)

Hct Control + Spleen Volume Reduction

95% CI, 14%-30%

When discontinuing Jakafi, myeloproliferative neoplasmrelated symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non‐melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations The three most frequent non-hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy

20%

b

(n = 42)

1%

(n = 1)

Hct Control Without Phlebotomy

≥35% Spleen Volume Reduction

95% CI, 0%-5%

Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed

Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

References: 1. Rampal R et al. Blood. 2014;123(22):e123-e133. 2. Keohane C et al. Biologics.

2013;7:189-198. 3. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.

4. Vannucchi AM et al. N Engl J Med. 2015;372(5):426-435.

Review the clinical trial data at

www.jakafidata.com

Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakafi (N=110) BRIEF SUMMARY: For Full Prescribing Information, see package insert.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information].

Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1)]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly.

Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1)]. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations.

ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] • Risk of Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)] • Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]. 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. Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi (N=155) Adverse Reactions

Adverse Events

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Headache

16

<1

19

<1

Abdominal Painb

15

<1

15

<1

Diarrhea

15

0

7

<1

Dizzinessc

15

0

13

0

Fatigue

15

0

15

3

Pruritus

14

<1

23

4

Dyspnead

13

3

4

0

Muscle Spasms

12

<1

5

0

Nasopharyngitis

9

0

8

0

Constipation

8

0

3

0

Cough

8

0

5

0

Edemae

8

0

7

0

Arthralgia

7

0

6

<1

Asthenia

7

0

11

2

Epistaxis

6

0

3

0

Herpes Zosterf

6

<1

0

0

Nausea

6

0

4

0

a b c d e f

Laboratory Parameter

Grade 3 (%)

Grade 4 (%)

All Grades (%)

Anemia

72

<1

<1

58

0

0

Thrombocytopenia

27

5

<1

24

3

<1

Placebo (N=151)

Neutropenia

3

0

<1

10

<1

0

Hypercholesterolemia

35

0

0

8

0

0

Elevated ALT

25

<1

0

16

0

0

0

Elevated AST

23

0

0

23

<1

0

0

Hypertriglyceridemia

15

0

0

13

0

0

Grade 4 (%)

Bruisingb

23

<1

0

15

0

Dizzinessc

18

<1

0

7

0

Headache

15

0

0

5

0

0

a

Urinary Tract Infectionsd

9

0

0

5

<1

<1

b

Weight Gaine

7

<1

0

1

<1

0

Flatulence

5

0

0

<1

0

0

Herpes Zosterf

2

0

0

<1

0

0

f

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present includes weight increased, abnormal weight gain includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya Jakafi (N=155) Laboratory Parameter

All Gradesb (%)

Grade 3 (%)

Placebo (N=151) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Thrombocytopenia

70

9

4

31

1

0

Anemia

96

34

11

87

16

3

Neutropenia

19

5

2

4

<1

1

a b

Grade 4 (%)

Chemistry

Grade 3 (%)

e

Grade 3 (%)

Hematology

All Grades (%)

d

Best Available Therapy (N=111)

All Gradesb (%)

Grade 4 (%)

c

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes abdominal pain, abdominal pain lower, and abdominal pain upper includes dizziness and vertigo includes dyspnea and dyspnea exertional includes edema and peripheral edema includes herpes zoster and post-herpetic neuralgia

Jakafi (N=110)

Grade 3 (%)

b

Grade 3-4 (%)

Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were: Weight gain, hypertension, and urinary tract infections Clinically relevant laboratory abnormalities are shown in Table 4.

Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatmenta

All Gradesa (%)

a

Best Available Therapy (N=111)

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi.

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 52% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure.

Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information].

OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib.

Jakafi is a registered trademark of Incyte. All rights reserved.

U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013 © 2011-2014 Incyte Corporation. All rights reserved.

Issued: December 2014 RUX-1428a

ASCOPost.com | APRIL 10, 2015

PAGE 87

Book Review

Technology’s Double-Edged Sword: One Woman’s Story

By Ronald Piana

“I

f we wish to learn more about cancer, we must concentrate on the cellular genome,” wrote Nobel laureate Renato Dulbecco, MD, more than 20 years ago.

Dr. Dulbecco and his colleagues in the scientific community realized that sequencing the human genome was vital in fully understanding the biology of cancer. Less than 3 years after the monumental completion of the Human Genome Project, the National Institutes of Health launched the pilot stage of The Cancer Genome Atlas (TCGA) project, which will ultimately render a comprehensive catalogue of the genes involved in cancer. Although the scope of this genetic research project is mind-boggling, the endgame is simple: translating knowledge into better treatment for cancer patients.

However, knowledge of the inner workings of our cellular material prompts questions and medical decisions, some of which prove difficult. For instance, if you were a young woman, would you have your healthy breasts and ovaries surgically removed if you thought it might save your life many years down the line?

That is not a theoretical question for Lizzie Stark author of the affecting new book Pandora’s DNA: Tracing the Breast Cancer Genes Through History, Science, and One Family Tree. Ms. Stark uses her family’s experience of being genetically predisposed to breast cancer as a backdrop to tackle the larger ethical and medical questions that surround germline BRCA1 and BRCA2 mutations. This is an important subject that needs more elucidation, and Pandora’s DNA gives the readers of The ASCO Post a personal look into the quandary of genetic testing, something that has already made its footprint in oncology.

A Family’s Grim Legacy Ms. Stark’s prologue is mostly background information on breast cancer and basic genetics, which the lay public will find instructive before diving into the book. That said, the author ends the prologue with a pithy observation about our growing knowledge of human genetics and what that knowledge might portend: “Open up the box and the truth will escape. As with Pandora’s fable, you cannot gather up the knowledge or the plagues and stuff them back inside—the tenuousness and blissing of ignorance are gone forever. The only thing left is to cope with the present as best you can.”

As the book opens, we learn that Ms. Stark’s mother received her second diagnosis of cancer, which had spread from

her breast to her thyroid gland. By then, she was a 5-year survivor, but the road over those years had been bumpy, filled with emotion and pain. When Ms. Stark learned that every female relative on her mother’s side “had lost their breasts to cancer or the fear of cancer or both,” her life also took on a shadow companion of fear.

She writes chillingly, “By the time I reached my late teens, a graph has imprinted itself on the back of my mind, an image of what life is like, age-plotted on the y-axis. The graph described a rising curve that peaked around age 21 before dropping off sharply. At 30, or a little later, the chart ended.” This is the day-to-day reality of young women who are heavily predisposed to breast and ovarian cancers, and it’s a subject that needs more research and discussion.

Ms. Stark goes on to tell of her own struggle, for a while living an adventurous, risk-taking life, not wanting to miss out on one youthful desire or fling. At 23, she still felt invulnerable—or at least tricked herself into that self-serving delusion. But the self-breast exams and mammograms suddenly became routine.

Costs of Genetic Testing Then one day, her mother brought up the subject of genetic counseling, and that’s when her feeling of invulnerability fell off the cliff, and her internal battle started, beginning and ending with one question: Do I really want to know if I have the BRCA mutation?

Before the reader finds out the answer to that theme-driving question, Ms. Stark takes a necessary and highly informative detour in a chapter titled Myriad’s Monopoly. Readers of The ASCO Post will be well acquainted with the Myriad Genetics drama, centering on the ethical issue of patenting the human genome, but the author’s personal take on the issue is worth a revisit.

She writes, “In the United States, before 2013, if you wanted to know whether you carried your family’s grim legacy of breast and ovarian cancer, there was only one way to find out: Pay Myriad Genetics—or get your insurance company to pay—upward of $3,000 for DNA sequencing.”

Ms. Stark poses good ethical questions about the legality of one’s genes and the potential to exploit fear into revenue. She sums up the antigene patenting case: It limits scientific research and fails patients by creating cost barriers. Ms. Stark takes a fair look at all sides of the contentious issue, summing up the ethical case for gene

Bookmark Title: Pandora’s DNA: Tracing the Breast Cancer Genes Through History, Science, and One Family Tree Author: Lizzie Stark Publisher: Chicago Review Press Publication date: October 2014 Price: $26.95; hardcover, 336 pages

patenting: “It provides profit motives for companies to sink research money into discovering genes that effect heritable diseases, minimizes bureaucratic red tape that stalls progress.”

In the next chapter, the reader gets the answer: The author decides to get tested for BRCA mutations. The agony of waiting for the results is drawn with such breathholding care that everyone who has ever waited for a test result can empathize with her. Ms. Stark gets the call from her oncologist, who says, “I’ve got the results, but I’m afraid they’re not the ones you wanted.”

An Agonizing Journey From here, she takes us on the agonizing journey that ends, and in some ways

begins, with a bilateral prophylactic mastectomy. It is a journey of self-introspection and worries about sexual identity and mortality. Never once does she let the reader down, as she spools out her innermost feelings, rarely dipping into self-pity or misdirected anger. In short, we get to know Ms. Stark, and, despite the difficult scenario, we like her.

The postmastectomy chapters offer good insight into both breast cancer patients and their oncologists, as Ms. Stark meticulously details the symptoms and how she dealt with them. She ends with a message every woman in her situation can appreciate: “Although my BRCA mutation has deeply affected my body, my emotions, and my sense of self, it does not define me.” n

Spring

Photo credit: Nicholashan.

Send your high-resolution photo and caption to editor@ASCOPost.com. All photos will be considered for publication in a future issue of The ASCO Post.

The ASCO Post | APRIL 10, 2015

PAGE 88

2015

2015 Oncology Meetings April Melanoma and Cutaneous Malignancies Meeting April 10-11 • New York, New York For more information: www.healio.com/meeting/ hemonctodaymelanoma/ home?promocode689-8045 Hematologic Malignancies: New Therapies and the Evolving Role of Transplant April 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematology-andoncology-2015r919 2015 Business of Oncology Summit and 2015 Annual Meeting & Spring Session April 10-12 • Orlando, Florida For more information: www.flasco.org International Society of Geriatric Oncology (SIOG) USA Forum April 11 • Tampa, Florida For more information: www.siog.org HPV-Induced Head and Neck Cancer: Screening, Detection and Less Invasive Therapies April 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx OSMO Spring 2015 Oncology Conference April 11 • Portland, Oregon For more information: www.osmo.org/events/view/26

Multidisciplinary Spine Oncology Symposium April 17-18 • New York, New York For more information: www.mskcc.org/events/cme/ multidisciplinary-spine-oncologysymposium/form VAHO Spring 2015 Membership Conference April 17-18 • Hot Springs, Virginia For more information: www.accc-cancer.org/ossn_network/ VA/VAHO-meetings.asp American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org ONS 40th Annual Congress April 23-26 • Orlando, Florida For more information: www.ons.org/conferences/ congress-2015

Breast Cancer Conference May 7-9 • Brussels, Belgium For more information: www.esmo.org/Conferences/ IMPAKT-2015-Breast-Cancer 13th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) May 11-13 • Mainz, Germany For more information: www.meeting.cimt.eu 54th Annual Conference of the Particle Therapy Co-Operative Group May 18-23 • San Diego, California For more information: http://ptcog54.org

13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

Anticancer Drug Action and Resistance: From Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015 CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org/annual_meeting .php

3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum Fourth Annual Cancer Pain Conference April 24-26 • Scottsdale, Arizona For more information: www.cancerpainconference.org

May

ASCO/C-KIN Joint Session at Cancer & the Kidney International Network’s First Annual Conference (C-KIN 2015) April 14-15 • Brussels, Belgium For more information: www.c-kin.org/conference2015/

International Society of Geriatric Oncology (SIOG): Cancer Care of the Older Adult Across the Cancer Continuum May 1 • New York, New York For more information: www.siog.org

ASCO Multidisciplinary Cancer Management Course (MCMC) April 15 • Vina Del Mar, Chile For more information: www.asco.org/international-programs/ multidisciplinary-cancer-managementcourses

The 28th Annual Meeting of the American Society of Pediatric Hematology/Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/ annualmeeting.html

ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2015-Lung-Cancer

WCIO 2015 May 6-9 • New York, New York For more information: http://www.wcioevents.org

Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

continued on page 95

ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/ 2015 ASCO State Affiliates’ Reception May 31 • Chicago, Illinois For more information: www.asco.org/about-asco/ state-affiliate-leadership-conference

June International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/ 2015 Clinical Update: 21st Century Prevention of HPV-Associated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-CenturyPrevention-of-HPV-Associated-Cancer

Save the Date

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms.

For more information, visit www.lymphcon.ch/imcl/index.php

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ASCOPost.com | APRIL 10, 2015

PAGE 95

2015

2015 Oncology Meetings 25th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists September 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

continued from page 88

International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/ MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

August Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://boa.asco.org/

7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp

World Congress on Cancer and Prevention Methods August 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/ oncology-2015/

14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com

ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses

The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/ index.html

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

NRG Oncology Meeting July 16-19 • Denver, Colorado For more information: www.gog.org/ meetinginformation.html APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: www.apos-society.org 16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

ILCA 2015 —The International Liver Cancer Association’s 9th Annual Conference September 4-6 • Paris, France For more information: www.ilca2015.org 16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org American Society of Head and Neck Radiology (ASHNR) Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/ ISEH 44th Annual Scientific Meeting September 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting 4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015) September 25-26 • Seattle, Washington For more information: www.seattlechildrens.org/research/ childhood-cancer/CIPO-2015/

European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

September International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/internationalprograms/international-palliativecare-workshops

October 30th Annual Harvard “Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis and Immunology” October 5-8 • Boston, Massachusetts For more information: http://steele.mgh.harvard.edu/ tumorcourse Palliative Care in Oncology Symposium October 9-10 • Boston, Massachusetts For more information: http://pallonc.org National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies™ October 16-17 • San Francisco, California For more information: www.nccn.org/professionals/ meetings/hematological/default.aspx

November SITC 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.ncer.org/sitc-meetings/sitc2015 12th International Conference of the Society for Integrative Oncology November 15-16 • Boston, Massachusetts For more information: www.integrativeonc.org/index.php/ events

December

2015 Breast Cancer Symposium September 25-27 • San Francisco, California For more information: http://breastcasym.org European Cancer Congress (ECC 2015) September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/ European-Cancer-Congress-2015

57th Annual ASH Meeting & Exposition December 5-8 • Orlando, Florida For more information: www.hematology.org/ Annual-Meeting/ San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org

The ASCO Post | APRIL 10, 2015

PAGE 96

Book Review

A Surgeon Cuts to the Chase

By Ronald Piana

T

he woman seated on the exam table was lean and fit and seemed perfectly at ease. As the doctor—a general surgeon—scanned her medical history, the portrait of a person in good health came into view. Her lab work, blood pressure, weight: All were excellent. One question came into the doctor’s mind: Why was she in my office? Several weeks earlier, it turned out, the woman’s primary care doctor had ordered an abdominal computed tomography scan to investigate a nagging pain he hadn’t been able to diagnose. The radiologist noticed gallstones; hence, he referred her for a surgical consult.

As the surgeon finished the physical exam, he told the woman that her gallbladder was working fine and that the asymptomatic gallstones were simply incidental findings, not the cause of her ab-

technologies, such as magnetic resonance imaging, has produced a plethora of incidental findings that challenge the decision-making process of surgeons.

To that end, Dr. Ruggieri wades into some uncomfortable territory, taking some in the surgical community to task for abusing our fee-for-service payment system.

“Like every profession, surgery is not exempt from bad seeds. As difficult as it is to write this, some surgeons operate for solely economic reasons,” writes Dr. Ruggieri. He then elucidates his concern, using simpleto-grasp data sets and literature references.

To highlight abuse, Dr. Ruggieri cherrypicks some truly dastardly acts of profitover-patient greed that the vast majority of doctors will find incomprehensible. But never once do you feel that the author has an ax to grind; instead, he comes across as

The next time you find yourself on your back, staring at the operating room ceiling, about to be put to sleep for an operation, ask yourself how much a good surgeon is really worth. You might find the word priceless in your mind as you drift off. My hope is that you never have to think otherwise.

—Paul A. Ruggieri, MD

dominal discomfort. She replied, “Well, why not just take the thing out. I don’t need it anyway, right?”

The operation would have taken a stress-free 20 minutes, netting the surgeon $1,000. The only problem: There was no medical reason to do it.

The doctor describing this case history is Paul A. Ruggieri, MD, a board-certified general and laparoscopic surgeon and author of The Cost of Cutting: A Surgeon Reveals the Truth Behind a MultibillionDollar Industry, which is a follow-up to his previous book, Confessions of a Surgeon, in which he pushed open the doors of the operating room and revealed the inscrutable place where lives are improved, saved, and sometimes lost.

Shedding Light on Abuse In The Cost of Cutting, Dr. Ruggieri tackles a subject that is central to the oncology community’s ongoing self-evaluation process: choosing wisely. And, as the author points out in chapter 1, the dramatic increase in the use of imaging

a concerned member of the medical community who wants to shed light on abuses that tarnish his discipline, stressing that “they are also, I’m glad to say, rare.”

Readers of The ASCO Post will enjoy the sections on the business of practicing medicine in today’s cost-conscious environment, during which Dr. Ruggieri navigates the complex maze that doctors must trudge through to get reimbursed for services rendered. To contrast the before and after of our system, he writes, “When my senior partner started out in surgical practice more than 30 years ago, his billing system consisted of a pen, stationery, an envelope, and a stamp…. [H]e would instruct his secretary to write a letter to the insurance company … describing the operation and how much he was charging for it.… [S]everal weeks later a check would arrive in the requested amount.” Ah, the good old days.

At the end of this section, Dr. ­Ruggieri stresses another key point in today’s evolving world of oncology: “The reimbursement system has to be changed so

Bookmark Title: The Cost of Cutting: A Surgeon Reveals the Truth Behind a Multibillion-Dollar Industry Author: Paul A. Ruggieri, MD Publisher: Berkley Books Publication date: September 2014 Price: $16.00; paperback, 320 pages that doctors are financially rewarded for cost-efficient, quality outcomes, not just bulk of services.” Of course, this is easier said than done, and Dr. Ruggieri stumbles a bit in trying to find a clear path forward.

This is one of the most difficult challenges in medicine, and one can’t fault a surgeon for not offering a clearer solution.

Medical Drama Surgery, of course, is a compelling subject. There are few circumstances in human life that require more faith in another—under the glare of the operating room lights, the patient fades into the twilight of unconsciousness, left in the hands of a scalpel-wielding surgeon. And Dr. Ruggieri tells this life-and-death experience in finely honed prose: The blood was everywhere. I was sucking it out as fast as I could, but I was losing ground. The clock was ticking. If I did not cut open Mr. Bowmore’s belly within the next 60 seconds to get a clamp on the bleeding artery … I would have some explaining to do to his family. Damn it. The artery tore right off. The jet pulse of blood hitting my camera lens and obscuring my line of sight was coming from the inferior gastric artery that had somehow ripped from the abdominal wall muscle.

Operating theater aside, this tautly rendered book offers a lot to like for clinician readers. Structured in 10 concise chapters, the book explores the medical landscape in a way that overlaps all specialties.

In chapter 8 (“The Robot Will See You Now”)—perhaps the book’s best—Dr. Ruggieri takes on another issue that ASCO Post readers will enjoy: the ineluctable move toward robotic surgery. He gives a fair and balanced review of this technology,

with cautionary words about rushing into new technologies simply because they are new. While acknowledging the benefits of technologic advances, he also warns, “I worry that too much reliance on new surgical technology in the operating room has the potential to lull surgeons into a false sense of complacency and make them feel even more detached from their patients.”

Chapter 9 (“Obamacare, Medicare, and the Future of Your Healthcare”) does a splendid job in demystifying the philosophy behind the accountable care organization, a conceptual model based on improving cost-effective care and reforming our current payment system.

Still a work in progress, the accountable care organization movement sends shudders down the spines of some oncologists who fear more government oversight, less autonomy, and tighter bottom lines. Dr. Ruggieri’s levelheaded and well-written discussion on these organizations will assuage many of those concerns.

Sacred Trust In the end, Dr. Ruggieri is a doctor’s doctor, one who examines his field, his colleagues, and himself under a harsh light. He wants the reader to know that what doctors do is vitally important and emphasizes the sacred trust between doctors and their patients.

He concludes his fine book, one that is heartily recommended by this reviewer, thusly, “The next time you find yourself on your back, staring at the operating room ceiling, about to be put to sleep for an operation, ask yourself how much a good surgeon is really worth. You might find the word priceless in your mind as you drift off. My hope is that you never have to think otherwise.” n

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PAGE 97

Caregiver Perspective Rare Cancers

Shining a Spotlight on Epithelioid Hemangioendothelioma

By Jane Gutkovich

I

n the winter of 2013, my son, Dmitriy, now 26, had a cough that wouldn’t go away. After several rounds of antibiotics failed to halt the persistent problem, a pulmonologist we consulted ordered a chest x-ray, which showed a large tumor lodged between Dmitriy’s lungs. Although the doctor said the tumor was probably benign, he recommended having it surgically removed and ordered additional imaging tests, including a CT scan, which uncovered more tumors in Dmitriy’s liver.

The report suggested benign hemangiomas. But when we met with a surgeon, he took one look at the CT scan and ordered an MRI, which confirmed his and our worst fear. Dmitriy had cancer. A biopsy proved the cancer type was epithelioid hemangioendothelioma (EHE), an extremely rare vascular sarcoma that affects between 100 and 200 people, mostly young adults, each year in the United States.

The cancer is so rare that research funding is scarce and little is known about its natural history. Although localized epithelioid hemangioendothelioma can be surgically resected, there is no effective therapy for systemic disease, and mortality from the cancer ranges between 13% and 18% when confined to soft tissue, but life expectancy in metastatic cases is unpredictable and ranges from a couple of months to 15 to 20 years.

Visits to the top sarcoma specialists in the country only underscored just how little is understood about this cancer and heightened my fear for Dmitriy’s recovery. The surgeon successfully resected the large mediastinal tumor, but several small indolent nodules remain in his lungs. A year later, an experimental procedure called irreversible electroporation (a nonthermal focal ablation technique) was performed on Dmitriy’s liver, killing some tumors and decreasing the size of others.

Today, Dmitriy’s cancer is stable, and it is possible that he will remain that

Jane Gutkovich is the manager of a nuclear stress lab at CardioVascular Medical Associates in Garden City, New York. She lives in Forest Hills, New York.

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

generally reported in sarcomas, which might explain why doctors did not make the connection. I also learned that in many lymphoma cases, the appearance of the rash precedes cancer recurrence, and some authors consider these rashes to be a warning sign. I thought, “What if Clues to Pathogenesis this were true for EHE? What if the apThat said, I needed more certainty pearance or worsening of the rash could about his long-term prognosis than Two-Database Approach be used as a biomarker for EHE progresOne of my “EHE mates,” Dawn sion?” We will include questions about what the few known statistics could provide. More importantly, the fact Scott, decided to create a Facebook this rash and its timing in our question(www.facebook.com/groups/­ that epithelioid hemangioendothe- page naire, will get a statistical analysis, and lioma can remain indolent for a long EHEcancer/). Currently, we have near- will present the data to the doctors. time indicates that there are some ly 600 members, and that number grows Another example: Several female mechanisms that keep it from pro- every week. February 26 was the birth- patients from our group reported that gressing. This gave me hope that if day of the EHE Foundation. Our group their diagnosis was made during or those mechanisms are uncovered, epi- is pursuing several projects, including soon after pregnancy. Other patients thelioid hemangioendothelioma can the creation of a website and two data- responded with similar stories. Some be controlled. Over the past 2 years, I bases. One database is the continuation indicated that they had a recurrence, have been on a quest not to just raise of HEARD, containing self-reported progression, or worsening of symawareness and funding for research in patient stories. The other is a computer- toms during or right after pregnancy. epithelioid hemangioendothelioma, ized questionnaire, which does statisti- I searched HEARD and PubMed and but to gather data on the disease as cal analysis of the entered data. found other similar cases. I digged furWhy do we need both of these data- ther and learned that some types of well, and to hopefully uncover more adult hemangiomas are known to develop or progress during pregnancy.

I know it is possible to defeat this Epithelioid hemangioendothelioma disease.… My goal is to ensure that is a vascular cancer. Endothelial cells are known to be a target of estrogen. I my son and the thousands of other remembered that epithelioid hemanepithelioid hemangioendothelioma gioendothelioma happens predominantly in women and that many of our survivors won’t have to die from this female patients have either had breast cancer, maybe just with it. cancer themselves or have a family his—Jane Gutkovich tory of breast cancer. Maybe epithelioid hemangioendothelioma development/ clues about the pathogenesis of this bases? Epithelioid hemangioendothe- progression has a hormonal compolioma is so rare and understudied that, nent? After digging further on PubMed, weird, unpredictable cancer.

An online search for information led very often, relevant facts are overlooked I found a few “old” articles about epitheme to the epithelioid hemangioendo- or simply ignored by clinicians. The only lioid hemangioendothelioma suggestthelioma registry HEARD (Halt EHE way to recognize these facts is to look ing a hormonal influence on its developthrough Analysis, Research, and Dis- into stories to find patterns and then to ment. We are collecting more data, and covery; heardsupport.org), which was include them in a statistical analysis. once we get the statistics, we will bring For example, one epithelioid heman- the information to researchers. launched by Cynthia Pollak, an Australian, whose son was diagnosed with gioendothelioma patient complained on epithelioid hemangioendothelioma in our Facebook group’s page about a de- Hope on the Horizon Although I have a full-time job, I 2004 and has since died from the dis- bilitating rash that would not respond to ease. Mrs. Pollak was looking for epithe- creams. To my great surprise, many oth- spend at least 40 additional hours per lioid hemangioendothelioma patients ers commented that they had or have a week researching information about on Internet cancer chats and reaching similar problem. All patients mentioned epithelioid hemangioendothelioma out to them; she eventually collected that their doctors did not think the rash and everything that can be related to it. could be cancer-related. Looking at the I pass on what I learn to patients on our about 300 self-reported stories.

From this repository of patient cas- number of people with this rash and the Facebook page and to specialists studyes, I learned more about epithelioid similarity of presentation, I knew this ing this cancer. This communication between patients with rare cancer and hemangioendothelioma than I had could not be a coincidence.

I started looking on PubMed into the medical community is an incredgathered from all the sarcoma specialists I had seen. The experience was cancer-associated rashes and found that ible bridge, one that transforms data eye-opening. I extended my search they are typical for certain cancers, espe- into clinical and research decisions. continued on page 102 to PubMed, where I found informa- cially lymphomas. These rashes are not way for many years—possible but not assured. The behavior of epithelioid hemangioendothelioma is totally unpredictable; patients can remain stable for a long time (sometimes decades) or experience rapid disease progression and die.

tion on more than 700 patient cases. I knew that only by organizing a worldwide network of patients could we produce a foundation for epithelioid hemangioendothelioma research to move forward. I reached out to several patients, and we started discussing our plans.

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PAGE 102

Caregiver Perspective

Jane Gutkovich continued from page 97

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Several patients in our group have shown good long-term responses to mTOR inhibitors. I found several publications confirming that mTOR inhibitors have some efficacy in epithelioid hemangioendothelioma. I saw that this should be investigated further as a possible treatment for certain types of EHE patients. So I reached out to physicians who I knew had used mTOR inhibitors to treat epithelioid hemangioendothelioma and informed them about these additional successful cases. There is now ongoing communication between those doctors about publishing a retrospective analysis of mTOR inhibition in epithelioid hemangioendothelioma patients. It is extremely difficult to find funds for a clinical trial, but I hope that once the anecdotal stories lead to peer-reviewed publication, we will have a better chance.

Nothing gives me more satisfaction than to see my endless efforts bearing fruit. As a result of the information I collected and the resulting discussion we had online about mTOR inhibitors, one of our patients was put on sirolimus and has had disease stabilization, after the failure of several other regimens.

In addition, there is exciting research news on the horizon. The leading investigator in epithelioid hemangioendothelioma is Brian P. Rubin, MD, PhD, Professor and Vice-Chair of Pathology, Director of Soft Tissue Pathology, and Director of the Bone and Soft Tissue Pathology Fellowship Program at Robert J. Tomsich Pathology & Laboratory Medicine Institute and Department of Medicine Genetics at the Cleveland Clinic and Lerner Research Institute. Dr. Rubin and his colleagues discovered that a genetic translocation involving chromosomes 1 and 3 results in the fusion of the WWTR1 (or TAZ) gene to the CAMTA1 gene and is found in nearly all epithelioid hemangioendothelioma tumors. That discovery is leading to greater understanding of the molecular pathways in the cancer and potential therapies. (Editor’s note: See “Unraveling the Mysteries of Epithelioid Hemangioendothelioma: A Conversation With Brian P. Rubin, MD, PhD,” in the February 10, 2015, issue of The ASCO Post.)

Dr. Rubin is also investigating a MEK inhibitor, trametinib (Mekinist), which is showing efficacy in his laboratory studies. He

is currently working on the clinical trial that all epithelioid hemangioendothelioma patients have been waiting for. We are hopeful that it will show that trametinib can be an effective targeted therapy for epithelioid hemangioendothelioma.

Next Steps I am organizing an epithelioid hemangioendothelioma meeting to be held during the 2015 ASCO Annual Meeting. We will have 14 doctors from around the world discussing the latest developments in epithelioid hemangioendothelioma research and treatment strategies. I will present some data that I learned from our patients and from my research on PubMed. I am also almost done with structuring the PubMed data into a userfriendly EHE library, with open access to anybody who would like to find the most useful information on epithelioid hemangioendothelioma.

I organized files using axes such as location, pathologic correlations, radiologic correlations, successful treatment, most-informative studies, and so on. Once I am done, I will ask our patients to share the library access with their doctors, and I will send the library to major sarcoma clinics.

The patient registry is an ongoing project. We already have many stories collected. The next step is to translate these stories into a format that will be most useful to researchers and patients alike. We believe this will help aid progress in epithelioid hemangioendothelioma research. To that end, I need your help.

If you have epithelioid hemangioendothelioma patients, tell them about our Facebook group. If you have any resources on epithelioid hemangioendothelioma that you would like to share with us, and/or if I can provide you with the data that I have collected, please e-mail me at jgutkovich@ gmail.com or theehefoundation@ gmail.com.

I know it is possible to defeat this disease—maybe not to cure it but to make it a chronic condition like diabetes or coronary artery disease, well known and well controlled. My goal is to ensure that my son and the thousands of other epithelioid hemangioendothelioma survivors won’t have to die from this cancer, maybe just with it. n Disclosure: Ms. Gutkovich reported no potential financial conflicts of interest. Her research is uncompensated.

ASCOPost.com | APRIL 10, 2015

PAGE 103

In the News Gastrointestinal Oncology

Colorectal Cancer Is Significantly Increasing Among Younger Adults and Being Diagnosed at Later Stages

By Charlotte Bath

A

“growing body of literature” indicates that the incidence of colorectal cancer is rising among people under age 50, according to Jason A. Zell, DO, MPH. Dr. Zell is the corresponding author of one of the two recent studies finding significant increases in colorectal cancer among adults aged 20 to 49.1,2 Writing in the Journal of Adolescent and Young Adult Oncology, Dr. Zell and colleagues from the University of California (UC), Irvine, noted the study also found that colorectal cancer in young adults “was more likely to be diagnosed at an advanced stage and therefore less likely to be cured.” The investigators suggested, “greater focus on early detection among young, symptomatic individuals may be warranted.”1

Among the several possible explanations proposed “for the concerning increase in colorectal cancer incidence among adults younger than 50” is a “low index of suspicion from physicians.” Asked

by The ASCO Post if this study should serve to raise that index of suspicion, Dr. Zell replied, “I certainly hope so. But not just this study. There have been numerous reports showing that colon cancer is rising in those under 50. Our study shows a little more granularity, even looking at the very young, age 20 to 29, but overall I think there is enough literature out there to help inform the public and also primary care physicians that this is a problem.” Dr. Zell is Assistant Professor, Department of Medicine and Department of Epidemiol-

Colon cancer is rising in the young.

The risk is still low, but if a young patient presents with bleeding, pain, or some of these other symptoms you would associate with colon cancer, it should be considered in the differential diagnosis.

—Jason A. Zell, DO, MPH

ogy, and Program Director, Hematology/ Oncology Fellowship Program, Division of Hematology/Oncology at the UC Irvine Medical Center.

A recent article in JAMA Surgery2—

“which shows very similar findings— [and] our article essentially were published at the same time and are spawning a lot of interest right now,” Dr. Zell noted. Both continued on page 104

Don’t Disregard Questions About Possible Symptoms of Colorectal Cancer Just Because the Patient Is ‘Too Young’

By Charlotte Bath

W

hile colorectal cancer predominantly occurs in people over 50 years old, rates are increasing among younger patients. It is important for physicians not to ignore symptoms in patients who are young, “simply because they are young,” Jason A. Zell, DO, MPH, told The ASCO Post. Dr. Zell is the corresponding author of a recent study1 finding that colorectal cancer is significantly increasing among younger adults and Assistant Professor, Department of Medicine and Department of Epidemiology, and Program Director, Hematology/Oncology Fellowship Program, Division of Hematology/Oncology at the UC Irvine Medical Center, Orange.

‘Never Too Young’ “Individuals under 50 who have symptoms that may be consistent with colon cancer need to seek medical attention so the appropriate testing can be done and deserve a prompt and thorough examination,” according to the Never Too Young Coalition. “Physician-related delays (eg, missed symptoms, initial misdiagnosis) have been estimated to occur in 15% to 50% of young-onset colon cancer cases,” a coalition fact sheet noted.2 The Never Too Young Coalition member organizations include the Co-

lon Cancer Alliance, as well as other medical professionals, patient advocacy organizations, cancer survivors, and caregivers. Its aim is to educate the public about colon cancer among people younger than 50 and reduce the num-

all the procedures,” Dr. Zell said.

“But we are currently able to benefit from advantages in screening with tests such as the fecal immunochemical test [FIT] and the multitarget stool DNA test,” Dr. Zell said. The Cologuard test

Adherence to [the fecal immunochemical test and the multitarget stool DNA test] is much better, because you don’t have to undergo the colonoscopy procedure, and that may be more suitable to a younger population.

—Jason A. Zell, DO, MPH

ber of late-stage cases diagnosed among younger adults. The study coauthored

by Dr. Zell found that colorectal cancer in young adults “was more likely to be diagnosed at an advanced stage and therefore less likely to be cured.”

Tests More Suitable to a Younger Population “Because it is already a test that we don’t optimally deliver for screening,” Dr. Zell noted, colonoscopy does not seem a workable approach to detect colorectal cancer earlier in younger patients. Colonoscopies “are very expensive, and 50% to 60% of eligible patients are not being screened, either because they don’t like the test or because there are not enough gastroenterologists to do

uses an immunochemical test similar to FIT as well as DNA biomarkers that have been found in colorectal cancer and precancerous advanced adenoma.

These tests “have been shown in prior reports to have excellent results in determining who has colon cancer and who doesn’t when compared with colonoscopy,” Dr. Zell stated. “We don’t have the outcomes data that will inform us if they predict death from colorectal cancer, which is the ultimate goal of any screening test. But we have two very good tests. They pick up colon cancer at a very high rate. They are also more cost-effective.”

Having these two tests available to help detect colorectal cancer “does change the conversation a little bit,” Dr.

Zell said. “Adherence to these new tests is much better, because you don’t have to undergo the colonoscopy procedure, and that may be more suitable to a younger population.”

The largest biannual percentage increases of colorectal cancer among those aged 29 to 50 were observed for left-sided lesions, which the study report noted “are more likely to result in clinically identifiable rectal bleeding due to their distal location and also can be detected by all routine colorectal cancer screening modalities, including flexible sigmoidoscopy, which cannot be used to detect proximal (right-sided) colorectal cancer.”

“So we are not talking about lesions in the colon that are hiding out and developing with a more aggressive behavior. We are talking about a lesion on the left side, which is likely to bleed, which is easily detected by FIT, Cologuard, colonoscopy, or flexible sigmoidoscopy,” Dr. Zell stated. n References 1. Singh KE, Taylor TH, Pan CG, et al: Colorectal cancer incidence among young adults in California. J Adolesc Young Adult Oncol 3:176-184, 2014.

2. Never Too Young Coalition: Know the Facts. Available at http://ccalliance.org/ nevertooyoung/facts.html. Accessed March 14, 2015.

The ASCO Post | APRIL 10, 2015

PAGE 104

In the News Colorectal Cancer continued from page 103

studies found that the significant increase in colorectal cancer in young adults occurred amid a decline in colorectal cancer incidence among people older than 50.

This decline has been attributed to colorectal cancer screening and removal of polyps among the over-50 age group. While both studies recognize the importance of early detection and avoiding treatment delays, neither concludes that colorectal cancer screening should be generally extended to people under 50.

‘Considered on the Differential Diagnosis’ A Health Day article about the increasing incidence of colorectal cancer among younger adults quoted Dr. Zell as saying, “We need more awareness of the trend among patients and doctors. Because at this point, key symptoms among young adults, like blood in the stool, weight loss, or other complaints, are often ignored.”3 Dr. Zell expanded on this comment during an interview with The ASCO Post: “Patients come in with symptoms, and it is important for physicians not to ignore those symptoms in patients who are young, simply because they are young.

This is a message that we can promote without being very controversial at all: Colon cancer is rising in the young. The risk is still low, but if a young patient presents with bleeding, pain, or some of these other symptoms you would associate with colon cancer, it should be considered in the differential diagnosis.”

Identifying High-Risk Groups Data from the California Cancer Reg­ istry were used to examine colorectal cancer incidence with a focus on young adults in order to identify high-risk subgroups, the investigators explained. “We assessed age-specific incidence rates by race/ethnicity, gender, and colorectal tumor location and calculated the biannual percent change to monitor change in incidence over the 22-year study period.” The study population from the California Cancer Registry was 71% white, 12% Hispanic, 10% Asian/ Pacific Islander, and 7% African American.

The study found that the absolute incidence of colorectal cancer was far lower for young adults than for adults aged 50 and over. Among the 231,544 incident colorectal cancer cases, just 5,617 were among young adults. Rates ranged from 0.7 per 100,000 among Hispanic and African American females aged 20 to 29 up to 5.0 per 100,000 among Asian/Pacific Islander males aged 30 to 39. Those rates increased over time. Regional disease was the most common stage for all race/eth-

nicity and age groups, but young adults had a greater proportion of colorectal cancer diagnosed at a distant stage compared with any other age group.

Unexpected Findings The biannual percent change in colorectal cancer significantly decreased among people 50 years and older, but the biannual percent change significantly increased among pre–screening age adults aged 20 to 29, 30 to 39, and 40 to 49, the researchers reported. “Although we found Hispanics to have the lowest overall rates of [colorectal cancer], this group also had the largest increase in incidence over the 1988–2009 study period,” the researchers wrote. “Of note, the greatest observed biannual percentage changes were for distal colon cancer among Hispanic females aged 20 to 29 [biannual percent change = +15.9%, P = .042] and Hispanic males aged 30 to 39 [biannual percent change = +10.4%, P < .001].”

These “dramatic increases in the young Hispanics were unexpected findings,” Dr. Zell said. “We think it is important to analyze our data by race and ethnicity for a number of reasons. Historically, it is known that African Americans are at a higher risk of colon cancer, which is why several societies actually recommend lower screening ages for that population. But Hispanics have been essentially ignored by those types of recommendations.”

The American College of Gastro­ enterology and the Colon Cancer Alliance recommend screening for colorectal cancer start at age 45 for African Americans. The recommendations from the Colon Cancer Alliance, a national patient advocacy group that Dr. Zell works with, also state: “People with a personal or family history of colon cancer, inflammatory bowel disease, or who are experiencing symptoms are considered ‘high risk’ and should begin screening before age 50.”

The marked increases in colorectal cancer among young Hispanics need to be confirmed by additional studies, Dr. Zell added. “But the data are real. The state of California cancer registry database contains the highest quality reporting standards. So I do believe this is a true effect that is happening in California.”

The finding highlights the value of doing this kind of research, Dr. Zell noted.

“Occasionally you will find things that are new and unsuspected, which need to be confirmed. But it is also showing us that what we know in older adults is not necessarily the same for younger adults.”

Predisposing Risk Factors Another possible reason cited for the increase in colorectal cancer among adults

younger than 50 was a “a higher prevalence of predisposing risk factors that allow for accelerated tumorigenesis in younger patients.” These risk factors include a family history of hereditary colorectal cancer syndromes such as familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

“The greatest limitation of our study is that we cannot address how many of these people have either hereditary colon cancer syndrome, which we would expect to occur in up to 5% of patients, but also a simple family history of colon cancer in a first-degree relative, known as familial colon cancer,” the investigators noted. “We cannot determine from our data set who has familial colon cancer and who doesn’t.”

Even if family history was known, that wouldn’t be enough to adequately as­sess colorectal cancer risk among adults younger than 50. A previous study found that among 180 patients younger than 50 diagnosed with colorectal cancer, only 8% had a first-degree family member with colorectal cancer,4 “which clearly demonstrates that using family history alone is inadequate in prognosticating risk among the [young adult] and unscreened population,” Dr. Zell and his coauthors wrote.

Access to Care and Health Insurance “So 92% would go undetected if we solely relied on family history,” Dr. Zell told The ASCO Post. “We need to look at other things.” In addition to the patient’s symptoms, they include access to care and insurance coverage. Colon cancer patients under age 50 are more likely to be underinsured, an important factor that “relates to our study in two ways,” Dr. Zell noted.

“First, we found that young patients with colorectal cancer had higher-stage disease at diagnosis. That is the number 1 predictor of survival outcome—stage at diagnosis. It is expected in an unscreened population that you would find colon cancer at a more advanced stage, but it is also very concerning because colon cancer is a curable disease when detected early. So the lack of insurance could easily explain the higher stage at diagnosis,” he said.

“The other thing that it hints at is that patients without insurance are very unlikely to have early detection,” he continued. “If you don’t have access to care and you rely on an emergency room, for example, even if you do have signs of colon cancer, it is unlikely to be detected at an early stage.”

As more information about the rising incidence of colon cancer is published and reported in the news, raising aware-

ness among primary care physicians and their patients, Dr. Zell expected more cases of colorectal cancer among people under 50 would be detected early. In addition, “as access to care increases, it will be easier to effectively do early detection,” Dr. Zell said. The study looked at colorectal cancer incidence from 1988 through 2009, so the impact of the Affordable Care Act would not be reflected. “But certainly 5 years from now, we might start seeing the very beginning of those changes,” Dr. Zell noted.

Requires Further Investigation The role of diet among younger patients who develop colorectal cancer is “an important area of investigation that requires further study. Diet “also may inform some of the differences by race ethnicity, because we know diet is related to cultural background and race/ethnicity,” Dr. Zell stated. “We know that processed meats, red meats, are associated with colon cancer incidence, but interestingly, they are also associated with poor outcomes among survivors.”

The study concludes, “More research is needed to characterize individuals with young-onset [colorectal cancer] and to determine how these individuals differ from young people who do not develop [colorectal cancer].”

Now that large population-based studies have been completed, Dr. Zell suggested that it is time to focus on cohort studies, “not just looking at patients we already know have young onset colon cancer, particularly those without Lynch syndrome or [familial adenomatous polyposis], because there is already a lot of interest and research in that area—but broadening the focus to include both familial and sporadic colorectal cancer. I think that would be really important.” n

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

References 1. Singh KE, Taylor TH, Pan CG, et al: Colorectal cancer incidence among young adults in California. J Adolesc Young Adult Oncol 3:176-184, 2014.

2. Bailey CE, Hu C-Y, You YN, et al: Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975-2010. JAMA Surgery 150:17-22, 2015.

3. Mozes A: Colon cancer rates rising among Americans under 50. Health Day, January 30, 2015.

4. Myers EA, Feingold DL, Forde KA, et al: Colorectal cancer in patients under 50 years of age: A retrospective analysis of two institutions’ experience. World J Gastroenterol 19:5651-5657, 2013.

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PAGE 107

Patient’s Corner Special Reprint

I Refuse to Capitulate to Cancer

By Paul Kalanithi, MD, as was told to Jo Cavallo

Editor’s note: We regret to announce that Paul Kalanithi, MD, passed away on March 9, 2015. Dr. Kalanithi was Chief Resident in Neurological Surgery at Stanford University when he shared his story, reprinted here, with The ASCO Post just over 1 year ago, in March 2014.

See page 114 in this issue for a memorial tribute to Dr. Kalanithi. We extend our deepest sympathies to Dr. Kalanithi’s family.

E

arly last year, just as I returned to my residency in neurologic surgery at Stanford University after completing 2 years of my postdoctoral fellowship in a laboratory developing optogenetic techniques, I started losing weight— dropping from 180 lb to 160 lb in just 6 months—and I was having fairly significant back pain. The symptoms didn’t sound any alarm bells at first. After all, I had gone from a sedentary job in the laboratory where I was eating three or four meals a day—and had put on a fair amount of weight—to working 90 hours a week at the hospital and grabbing food in between seeing patients and performing surgeries, which also put a lot of stress on my back.

Nevertheless, when the symptoms persisted, I saw my primary care physician. She ordered some x-rays to rule out isthmic spondylolisthesis as a cause of the back pain, and when they came back negative, she suggested that I have physical therapy to strengthen my back muscles and take ibuprofen for the pain, which helped. Still, I had a nagging suspicion that things were not quite right.

By May, my symptoms had exploded into spontaneous fevers, night sweats, and chest and back pain so severe, they kept me awake at night and frightened me. My weight, which had stabilized, started dropping again and I developed

a slight cough. I knew something was seriously wrong, and I started considering cancers that commonly occur in young people, including testicular cancer, but I didn’t feel any masses, so that seemed unlikely. Next, I saw my dermatologist to check for melanoma, but I had no suspicious skin lesions.

Finally, I went back to my primary care physician for a chest x-ray, which showed indistinct lesions on my lungs. I went to the hospital, was admitted, and had a CT scan performed. As I watched the images come on the screen, I could clearly see masses of lesions matting my lungs and deforming my spine. Although I’m not a thoracic oncologist, having re-

oncologist, I asked her what my KaplanMeier survival estimate was. She flatly refused to tell me. Instead, she appropriately laid out my treatment options.

What was interesting to me is that when she talked about my options, she suggested that I could go back to work someday. Even though my oncologist wouldn’t give me statistics on my prognosis, I knew from my own research that large general studies showed that between 70% and 80% of patients with lung cancer died within 2 years of their diagnosis. Of course, most of those patients were older and heavy smokers.

What was the study result in nonsmoking, 36-year-old neurosurgeons?

I’ve been fortunate to overcome the immediate challenge of having advanced lung cancer and wondering how much time I have left. Now the question is, how do I proceed toward realizing my hopes and ambitions in a responsible and productive way?

—Paul Kalanithi, MD

viewed dozens of patients’ scans for colleagues to determine if surgery offered any hope, I knew immediately what I was seeing: metastatic cancer. When I put the results of the scans together with my lab values, which showed anemia and other system abnormalities, I knew things looked grim. I thought to myself, I have a matter of months to live.

Seeking Survival Statistics After being in medical training for 11 years—and poised to launch an excellent career in neurosurgery and neuroscience—the news that I had stage IV non–small cell EGFR-positive lung cancer was devastating. When I saw my

Having No Regrets I was prescribed erlotinib (Tarceva) and, fortunately, I’m having a really good response to the drug. The majority of the spots on my lungs have disappeared, and the primary lung nodule has shrunk. I’ve put back all the weight I lost, and last November I returned to work full-time.

Some days I feel that maybe I should be in a less demanding, less stressful job, but doing that would be a capitulation to cancer. Yes, life is harder now. I’m a little more tired than I used to be, and everything takes a bit more effort, but I can still operate every day, sometimes for more than 12 hours a day.

As I continue to get stronger, I’m be-

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

ginning to feel that it’s possible I will have a very long career, although I still realize I may not. At least I know what’s important to me. You have to ask yourself, which do you want more: to have a career and life that you love, knowing that they can come crashing down if you get sick again, or not to do those things and feel regret? I choose the former.

Appreciating the Stresses of Living At the moment, my life is at the maximum point of uncertainty. I need to get my career trajectory fully back on course, and my wife is pregnant with our first child. So life is really exciting— and stressful. But these are the stresses of living, not of dying. The fact that I get to deal with all of the worries of having a highly demanding career and a new family is a blessing.

Being both a doctor and a patient has been an interesting experience. I’ve gotten occasional advice from well-meaning colleagues who say that coming back to neurosurgery is crazy. Some of their advice is quite useful because their feedback helps me assess whether I’m making the right decisions or in complete denial of the seriousness of my medical situation.

But the flip side of their advice is that it can persuade you to limit your goals, and I’d rather not let cancer do that.

I’ve been fortunate to overcome the immediate challenge of having advanced lung cancer and wondering how much time I have left. Now the question is, how do I proceed toward realizing my hopes and ambitions in a responsible and productive way? The answer may mean building backup plans into the equation in case the cancer becomes uncontrollable and aggressive.

In the meantime, I’m pursuing the things that drive me. The fact of death is unsettling. Yet there is no other way to live. n

The ASCO Post Wants to Hear From You

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

Write to The ASCO Post at editor@ASCOPost.com

The ASCO Post | APRIL 10, 2015

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In the Literature

Emerging Clinical Data on Cancer Management SKIN CANCER Health and Economic Burden of Skin Cancer Substantial and Increasing, Highlighting the Value of Prevention Efforts The average annual number of adults treated for skin cancer, both melanoma and nonmelanoma, in the United States increased from 3.4 million in 2002 to 2006 to 4.9 million in 2007 to 2011 (P < .001), according to a study published in the American Journal of Preventive Medicine.

“During this period, the average annual total cost for skin cancer increased from $3.6 billion to $8.1 billion (P = .001), representing an increase of 126.2%, while the average annual total cost for all other cancers increased by 25.1%,” reported Gery P. Guy Jr, PhD, MPH, and colleagues from the Centers for Disease Control and Prevention, the National Cancer Institute, and the Agency for Healthcare Research and Quality.

The study used data on adults from the 2002 to 2011 Medical Expenditure Panel Survey to estimate the treated prevalence and treatment cost of nonmelanoma skin cancer, melanoma, and other cancer sites. “Individuals were classified as being treated for nonmelanoma skin cancer, melanoma, or other cancers if they had any ambulatory visits (office-based and hospital outpatient), inpatient stays, home health visits, or prescribed medication purchases associated with the corresponding” clinical classification software code, the authors explained. “Costs were defined as expenditures from all sources for health-care services reported in the survey, including out-of-pocket, private insurance, Medicare, Medicaid, and other miscellaneous sources.”

Prevention Efforts Noting that skin cancer is the most commonly diagnosed cancer in the United States, the authors stated: “These findings demonstrate that the health and economic burden of skin cancer treatment is substantial and increasing. Such findings highlight the importance of skin cancer prevention efforts, which may result in future savings to the health-care system.”

One primary prevention program the authors cited was the U.S. Environmental Protection Agency’s Sunwise Program, which teaches children and their caregivers how to protect themselves from the sun. The program “could avert nearly 11,000 skin cancer cases while saving $2 to $4 in medical care costs and

lost productivity for each dollar invested in the program,” the authors asserted.

“Reducing indoor tanning, which is associated with an increased risk of nonmelanoma skin cancer and melanoma, is also an important strategy for decreasing the burden of skin cancer,” the authors added.

Guy GP Jr, et al: Am J Prev Med. November 9, 2014 (early release online).

COLORECTAL CANCER Adding Aflibercept to FOLFIRI Resulted in Persistent Improvement in Overall Survival Over Time in Patients With Metastatic Disease Patients with metastatic colorectal cancer showed a continued and persistent improvement in overall survival over time when they received the VEGF inhibitor aflibercept in addition to FOLFIRI (leucovorin, fluorouracil, irinotecan), according to a study reporting on the overall survival benefit and safety of aflibercept over the course of the VELOUR trial. Survival was improved by 50% at 24 months and almost doubled at 30 months.

A large, international, randomized trial, VELOUR found a statistically significant and meaningful benefit in median overall and progression-free survival and response rates among patients with metastatic colorectal cancer previously treated with oxaliplatin who then received FOLFIRI plus aflibercept vs FOLFIRI alone.

The median overall survival, the primary endpoint of the VELOUR trial, was 13.5 months for patients randomized to receive aflibercept vs 12 months for those receiving placebo, representing an 18.3% reduction in the risk of death for those receiving aflibercept (also called ziv-aflibercept [Zaltrap] in the United States).

“However, the increase in median overall survival underestimates the clinical benefit gained for the overall patient population as the Kaplan-Meier survival curves continue to separate past the median time point, indicating that the magnitude of the aflibercept treatment effect is increasing over time,” Paul Ruff, MD, Director of Medical Oncology, University of Witwatersrand, Johannesburg, and colleagues noted in the European Journal of Cancer.

The analysis of the time course of the efficacy and safety results was based on data from the VELOUR intent-to-treat patient population of 1,226 patients, 612

randomized to receive aflibercept and 614, placebo. “The estimated probabilities of survival were 38.5% vs 30.9% at 18 months, 28.0% vs 18.7% at 24 months, and 22.3% vs 12.0% at 30 months for the aflibercept- and placebo-treated arms, respectively,” the investigators stated.

“The absolute percent increase in the probability of survival in the aflibercept arm over the placebo arm at 12, 18, 24, and 30 months is 5.8%, 7.6%, 9.3%, and 10.3%, respectively. Correspondingly, the proportional increase in the probability of survival at 12, 18, 24, and 30 months is 11.5%, 24.6%, 49.3%, and 85.8% in the aflibercept arm over the placebo arm,” the authors added.

Severe adverse events (grade 3 to 4) occurred among 83.5% of patients receiving aflibercept vs 62.5% of patients receiving placebo, but the adverse event “profile did not affect patients’ abilities to continue to receive treatment,” the researchers reported. The most common adverse events, including diarrhea, stomatitis, infection, and hypertension, occurred only once. Adverse events “were generally reversible, and the vast majority of patients recovered from grade 3/4 events, with the exception of those patients who developed proteinuria,” the investigators noted. Most of the grade 3/4 adverse events associated with aflibercept occurred in early treatment cycles and then decreased sharply.

Time Course Analysis “The time course analysis of adverse events in VELOUR provides healthcare practitioners with the ability to anticipate expected treatment toxicities and manage them accordingly. The anticipation and appropriate management of adverse events are all the more important in light of an on-treatment progression-free survival analysis of VELOUR, which supports the continuation of aflibercept treatment as close to tumor progression as is reasonably possible. This on-treatment progression-free survival analysis, within 28 days of the end of treatment, demonstrated a significantly improved treatment effect for the addition of aflibercept to FOLFIRI in metastatic colorectal cancer (hazard ratio [HR] = 0.55 [95% confidence interval (CI): 0.46–0.66], P < .00001) over the primary VELOUR analysis (HR = 0.76 [95% CI: 0.66–0.87], P = .00007),” the researchers wrote.

“This integrated analysis of the time course of both the efficacy and safety of the aflibercept plus FOLFIRI regimen

complements and expands the original results of the VELOUR study, making this regimen an effective and manageable therapeutic option for patients with metastatic colorectal cancer previously treated with an oxaliplatin regimen and demonstrates a meaningful clinical benefit, which is sustained over a significant time period,” the authors concluded.

Ruff P, et al: Eur J Cancer 51:18-26, 2015.

Use of Minimally Invasive Colorectal Cancer Surgery Increases at NCCN Centers, but Wide Variation Exists “Laparoscopic colectomy has been shown to have equivalent oncologic outcomes to open colectomy for the management of colon cancer, but its adoption nationally has been slow,” Heather Yeo, MD, of Memorial Sloan-Kettering Cancer Center in New York, and colleagues noted in reporting on a study investigating the prevalence and factors associated with minimally invasive surgery for colorectal cancer at National Comprehensive Cancer Network (NCCN) centers.

An analysis of data obtained from chart review of medical records for 4,032 patients undergoing surgery for colon and rectal cancer at NCCN centers showed that the use of minimally invasive surgery increased. “However, there was statistically significant variation in adoption of minimally invasive surgery technique among centers,” the investigators stated in the Journal of the National Cancer Institute.

“The study cohort consisted of patients with stage I to IV colon or rectal cancer, diagnosed between September 1, 2005, and December 31, 2010, who received primary surgical care at one of eight institutions participating in the NCCN Colorectal Cancer Outcomes Project,” the researchers explained. These institutions “are geographically diverse and represent the composition of patients seen at all 21 NCCN institutions,” the authors added. Among the 2,493 patients who had colon surgery, 51% were female, and the median age was 62.6 years.

Among the 1,539 patients who had rectal surgery, 56% were male, and the median age was 55.9 years.

Looking at trends from 2006 to 2010 (when complete years of data were available), investigators found that the rate of patients with stage I to III colon cancer undergoing minimally invasive surgery increased from 35% to 51%. For patients with stage I to III

ASCOPost.com | APRIL 10, 2015

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In the Literature

rectal cancer, use of minimally invasive surgery increased from 14% in 2006 to 37% in 2010. “Minimally invasive surgery for stage IV colon and rectal cancer has been relatively stable over time,” the researchers reported.

Although stage IV patients are less likely to be managed with minimally invasive surgery, “these are the patients who may benefit from it most,” the investigators noted. “Minimally invasive surgery is strongly associated with less short-term morbidity and the potential to begin adjuvant therapy sooner. As techniques improve, combined procedures may become more feasible, increasing the number of stage IV patients who are minimally invasive surgery candidates. As surgeons gain technical proficiency, use of minimally invasive surgery is likely to increase—even in this higher-risk population,” the researchers wrote.

geons. The lag may be related, as many surgeons require retraining in laparoscopic techniques,” the authors noted.

An additional reason for the delay may be the investment in laparoscopic equipment required to support a minimally invasive surgery program.

Yeo H, et al: J Natl Cancer Inst 107:362, 2014 (print January 2015).

BREAST CANCER Are Physicians Choosing Wisely When Imaging for Distant Metastases in Early-Stage Breast Cancer?

Patients with early-stage breast cancer still undergo imaging for distant

TUMOR BOARD SERIES

metastases despite evidence-based local, national, and international guidelines—and a recommendation from ASCO—to avoid such imaging, according to a retrospective review of staging imaging for distant metastases in patients with primary early-stage breast cancer treated at a large Cana-

continued on page 110

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Multivariable Analysis “On multivariable analysis, factors associated with minimally invasive surgery for colon cancer patients who had surgery at an NCCN institution were older age (P = .02), being male (P = .006), fewer comorbidities (P ≤ .001), lower final T stage (P < .001), median household income greater than or equal to $80 000 (P < .001), Eastern Cooperative Oncology Group performance status = 0 (P = .02), and NCCN institution (P ≤ .001),” the investigators stated. “Even after controlling for other parameters, NCCN institution was a statistically significant predictor of minimally invasive surgery,” the authors noted.

“Given the much smaller proportion of rectal cancer patients undergoing minimally invasive surgery and the complex controversy in the use of minimally invasive surgery for rectal cancer, which is not yet recommended in NCCN Guidelines, we did not do a multivariable analysis on this group,” the investigators stated. Although the benefits of minimally invasive surgery are not as clear in rectal cancer, “recent retrospective studies have shown that total mesenteric excision can be safely performed using minimally invasive surgery, with no statistically significant differences in survival compared with an open approach,” the authors pointed out.

Rates of minimally invasive surgery at individual NCCN centers ranged from 15% to 86% of patients across the entire period and from 23% to 79% in the past 2 years. “Variation in use of minimally invasive surgery among NCCN institutions is intriguing. All employ highly trained, specialized sur-

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The ASCO Post | APRIL 10, 2015

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In the Literature Emerging Clinical Data continued from page 109

dian academic cancer center.

Demetrios Simos, MD, of Ottawa Hospital Cancer Center, and colleagues reviewed 200 patient medical records, 100 from patients treated before and 100 from patients treated after publication of ASCO’s Top Five Recommendations for Choosing Wisely in Oncology in 2012. One of the recommendations was to avoid routine use of staging imaging in patients with earlystage breast cancer and no clinical findings to suggest metastatic disease.

“ASCO recommended against the routine use of staging imaging in asymptomatic patients with early-stage disease, arguing that this practice has never been shown to extend survival, is costly, and in some cases may lead to harm, because false-positive results from such tests may necessitate invasive procedures and overtreatment, all of which can impair quality of life,” the authors wrote in the Journal of Oncology Practice. They also noted that the ASCO recommendation “is in keeping with the spirit of the published guidelines.”

The mean age of patients was 60 years; 57% of tumors were self-detected; 89% were pathologic stage I or II disease, and 11% were stage III. Overall, 169 patients (84.5%) had at least one imaging test (mean, 3.6 tests per imaged patient). Of the 608 total imaging tests, 500 (82.2%) “were initial imaging tests assessing the most common metastatic sites for breast cancer (ie, skeleton, thorax, and abdomen), whereas the remaining 108 tests (17.8%) were confirmatory imaging tests,” the investigators stated.

Confirmatory imaging to clarify indeterminate initial imaging was performed in 51 (30.2%) of the 169 women undergoing imaging. None of the patients with stage I or II disease had metastatic disease detected by imaging. Metastatic disease was ultimately detected by imaging in two women, both with pathologic N3 (stage IIIC) disease detected by postoperative computed tomography (one with lung metastases and the other with liver metastases).

“Overall, 77% (154 of 200) and 75% (150 of 200) of the patients reviewed in our study underwent imaging for distant metastases, [which was] not in keeping with the spirit of the provincial guidelines and ASCO recommendations, respectively,” the researchers reported. The frequency of imaging did not change after the ASCO recommendations were published.

“Generally, the majority of patients with stage I or II disease underwent excessive imaging relative to these recommendations, and almost all patients with stage III disease underwent imaging of the skeleton, abdomen, and thorax, as recommended,” the investigators observed. Factors associated with undergoing more staging imaging than recommended included ductal histology, lower-stage disease, and a community vs academic hospital.

The lack of demonstrated benefit and the potential for harm from imaging for metastatic disease in asymptomatic patients mean that such imaging “should be avoided,” the authors concluded. “If guideline recommendations are to be implemented in

©Peter Steiner/The New Yorker Collection/www.cartoonbank.com

practice, clearly additional knowledge translation strategies are needed beyond the simple publication of guideline documents.”

Simos D, et al: J Oncol Pract. November 12, 2014 (early release online).

PROSTATE CANCER Targeted MR/Ultrasound Fusion–Guided Biopsy Increased Detection of High-Risk Prostate Cancer Among men undergoing biopsy for suspected prostate cancer, targeted magnetic resonance (MR)/ultrasound fusion–guided biopsy was associated with an increased rate of detection of high-risk prostate cancer and a decreased rate of detection of low-risk prostate cancer than was standard extended-sextant ultrasoundguided biopsy. The results from a prospective cohort study of 1,003 men undergoing both targeted and standard biopsy concurrently from 2007 through 2014 at the National Cancer Institute were published in JAMA. “Patients were referred for an elevated level of prostate-specific antigen (PSA) or abnormal digital rectal examination results, often with prior negative biopsy results. Risk categorization was compared among targeted and standard biopsy and, when available, whole-gland pathology after prostatectomy as the ‘gold standard,’” Peter A. Pinto, MD, and M. Minhaj Siddiqui, MD, of the National Cancer Institute and colleagues reported.

Multiparametric prostate MR imaging “allows for imaging-based identification of prostate cancer, which may improve diagnostic accuracy for high-risk tumors,” the authors explained. These images are electronically superimposed in real time on transrectal ultrasound images by targeted (MR)/ultrasound fusion– guided biopsy platforms. “Numerous targeted biopsy platforms exist and are capable of performing biopsies of suspicious prostate regions on multiparametric prostate MR imaging,” the authors noted.

“Targeted MR/ultrasound fusion–guided biopsy diagnosed 461 prostate cancer cases, and standard biopsy diagnosed 469 cases. There was exact agreement between targeted and standard biopsy in 690 men (69%) undergoing biopsy,” the researchers reported. Targeted biopsy, however, diagnosed 30% more high-risk cancers than standard biopsy (173 vs 122 cas-

es, P < .001) and 17% fewer low-risk cancers (213 vs 258 cases, P < .001).

Combining standard biopsy cores with the targeted approach led to an additional 103 cases (22%), but mostly low-risk prostate cancer was diagnosed (83% low risk, 12% intermediate risk, and 5% high risk). “This equated to a number needed to biopsy with standard biopsy in addition to targeted biopsy of 200 men to diagnose 1 additional high-risk cancer,” the researchers stated.

“Furthermore, for every additional case of high-risk cancer diagnosed, 17 additional cases of low-risk cancer would be diagnosed.”

Targeted biopsy was also better at predicting whole-gland pathology at prostatectomy than standard biopsy or the two approaches combined. The sensitivity of targeted biopsy was 77% vs 53% for standard biopsy, and the specificities were similar, 68% vs 66%.

Study Implications “This study demonstrated that targeted biopsy could significantly change the distribution of risk in men newly diagnosed with prostate cancer toward diagnosis of more high-risk disease,” the authors concluded. “Although these improvements in risk stratification could translate into substantial clinical benefits, it is important to recognize that this study is preliminary with regard to clinical endpoints such as recurrence of disease and prostate cancer–specific mortality. These findings provide a strong rationale for the conduct of randomized clinical trials to determine the effect of targeted biopsy on clinical outcomes.”

In an accompanying editorial, Lawrence H. Schwartz, MD, of Columbia University College of Physicians and Surgeons, New York, and JAMA Associate Editor Ethan Basch, MD, of the University of North Carolina, Chapel Hill, noted that “any new technology that improves the ability of biopsy to distinguish between men with lower- and higher-risk cancers has the potential to influence clinical decisions and improve patient outcomes.” The editorialists cautioned, however, that “a new test should not be widely adopted in the absence of direct evidence showing benefits on quality of life, life expectancy, or ideally both.” n Siddiqui MM, et al: JAMA 313:390397, 2015.

Schwartz LH, Basch E: JAMA 313:367-368, 2015.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Letters to the Editor

Radiotherapy in Good-Prognosis DLBCL

I

was disturbed by the article on “Radiotherapy in Good-Prognosis DLBCL” published recently in The ­ ASCO Post.1 As a practicing radiation oncologist for 30 years, I have seen the evolution of radiation techniques (and philosophy) for non-Hodgkin lymphoma progress from regional—or even systemic— dosing to just localized. Radiotherapy is now utilized for either primary or consolidation regimens for a patient with localized, good-prognosis diffuse large B-cell lymphoma (DLBCL).

Modern localized radiotherapy for non-Hodgkin lymphoma consists of a very modest and almost asymptomatic dose administered to the original presentation site(s) after chemotherapy produces either a complete or partial response, or even as primary treatment alone. The combination technique (RCHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone] plus radiotherapy), as used in the study by the Lysa/Goelams Group reported in The ASCO Post, also produced excellent localized control.2 Similarly, excellent localized control is reported in study after study in American, European, and Asian reports.3

such a small number of systemic failures is to actually compare the raw numbers.

Systemic failure occurred in 8 patients with radiotherapy vs 12 patients without radiotherapy. This equals a 35% absolute reduction in systemic failures with radiotherapy—with 100% local control—

which is statistically significant.

Finally, seven patients achieved a partial response without radiotherapy and only one with radiotherapy. This is an absolute 85% difference at the “end of treatment.”

Achieving complete response (with

or without radiotherapy) matured into a 90% overall 5-year survival rate.

Therefore the goal is to achieve a “complete” response. Inducing maximum local control with consolidation radiotherapy is an additional tool to facilitate continued on page 112

Misleading Report?

It is well recognized that the localregional radiation treatment intent is not to increase systemic control or overall survival but to diminish local failures. The report published in The ASCO Post seems to misrepresent these accepted findings by indicating consolidative radiotherapy is (completely?) unnecessary for DLBCL patients achieving complete response after chemotherapy.

In contrast, the reported local relapse rate in this study differs significantly in the two arms when “local control” is analyzed (100% with radiotherapy vs 42% without) rather than systemic relapses (5% with radiotherapy vs 8% without).

The latter actually reflects the failure of systemic chemotherapy and not localized consolidation radiotherapy (or salvage radiotherapy for patients achieving a partial response). This is not clearly reported and can mislead the casual reader.

‘Survival Bias’ Furthermore, failures occurred in only 20 (7%) of 301 enrolled patients. This confirms an excellent prognosis overall in the analyzed population but can distract from any radiotherapy advantage by “survival bias.” A better analysis for

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The ASCO Post | APRIL 10, 2015

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Perspective Lee M. Krug, MD continued from page 1

puted tomography (CT) scan showed that the chemotherapy has stopped working, and we need to come up with a plan for your next course of therapy.

There are other chemotherapy options, or we could consider a clinical trial with a new drug.

Ms. Smith: I can’t say I’m too enthusiastic about getting more chemotherapy. Tell me more about the clinical trial.

MD: We have seen excellent results with this drug in other cancers, and we

Ms. Smith: Ugh, okay. It’s just that I live an hour away. Can I start after that?

MD: Well, you also need a biopsy of the tumor in your lung.

Ms. Smith: Don’t we already know this is cancer?

MD: Yes, but this biopsy is being done for research purposes.

Ms. Smith: When will I get the results of this biopsy?

MD: You won’t. The samples are sent to the pharmaceutical company for analysis.

Ms. Smith: How is the biopsy done?

As physicians, we need to be cognizant of the tremendous impact that participation in a clinical trial has on the quality of life of our patients.

—Lee M. Krug, MD

think it has a good chance of working in your cancer also. You are in good shape, so I think you would make an excellent candidate for the study.

Ms. Smith: That sounds encouraging. Can I start that treatment today?

MD: No. First you need to have some testing done to make sure you are eligible to participate. You will need to come back later this week to get some blood work and three electrocardiograms (ECGs).

Ms. Smith: Can I get the blood work done today while I am here?

MD: No. It needs to be collected in the morning after fasting.

MD: You will have a consultation with the doctor from interventional radiology, who will explain the procedure. Then you will return a few days later to have the biopsy. You will be sedated for the procedure, so you will need to have someone come with you to take you home.

Ms. Smith: Okay. I guess my husband will need to take another day off of work.

MD: You also need a CT scan with contrast of the chest, abdomen, and pelvis.

Ms. Smith: But I just had a CT scan 2 weeks ago.

MD: I know, but by the time all of

Radiotherapy for DLBCL

University of North Carolina at Chapel Hill Distinguished Alumnus of Drexel University, Philadelphia Medical Director, McCreary Cancer Center Lenoir, North Carolina

continued from page 111

that worthwhile outcome, as the study confirms. n —Theodore E. Yaeger, MD, FACR, FACRO, FRSM Professor of Radiation Oncology

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

this testing is completed, the CT scan will be outdated.

Ms. Smith: Okay. So I will need to come back in for the blood work and ECGs, then the biopsy, and then the new CT scan. How soon can I start? I’m worried the cancer in my body is growing!

MD: This will all take about 2 weeks.

The day you start, you will need to get to the office first thing in the morning.

You will get more blood work. Then you will receive the treatment, which takes about 30 minutes.

Ms. Smith: That doesn’t sound too bad. I should be home by noon then.

MD: Well, not really. You will remain in the office for 8 hours after the treatment, so we can draw multiple blood samples to measure the drug levels in your body. You will then go home that night, but you need to come back the next day for additional blood work.

Ms. Smith: Wow. And then when is my next treatment?

MD: Three weeks later. But you need to come back each week for a checkup and more blood work.

Ms. Smith: Can I do any of the blood work near my home?

MD: No. It all needs to be done here.

Ms. Smith: Doctor, is this all worth it?

Increasing Complexity

side lab. ECGs must be performed and transmitted from machines provided by the outsourced company, which reviews them. CT scans must be digitized and sent to the vendor, who is independently reading them. Pathology specimens must be prepared and shipped to yet another site for the correlative studies. And all of the testing must be conducted and reported in strictly defined windows of time; otherwise, paperwork regarding violations to the protocol must be filed.

As oncologists and cancer care specialists we obviously want to maintain safety in drug development, but we need to do a better job asking whether each added test improves on that.

Each box that is checked on the table of clinical trial assessments has real implications for the patient who has to go through that test and adds another layer of complexity for the investigator and the research staff. Perhaps it is time to open the dialogue with pharmaceutical companies and the U.S. Food and Drug Administration and push back on the intense testing and monitoring that have insidiously become the standard in clinical research.

When our patient asks, “Doctor, is this all worth it?”, we should be able to say “Yes, but we recognize the process is burdensome and we are working to minimize the inconveniences and maximize the potential for beneficial outcomes. Clinical trials are our best means to advancing research and improving patient care. I believe you are a good candidate for this trial.” n

This anecdotal description of the requirements for participation in a clinical trial does not even touch on the behind-the-scenes work involved with this patient’s accrual into the study. Her blood work must be properly collected in special kits and shipped to the out-

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

References 1. Helwick C: Radiotherapy in good-prognosis DLBCL. The ASCO Post 6(3):17, 2015.

2. Lamy T, Damaj G, Gyan E, et al: RCHOP with or without radiotherapy in non-bulky limited-stage diffuse large B-cell lymphoma (DLBCL): Preliminary results

of the prospective randomized phase III 02-03 trial from the Lysa/Goelams Group.

2014 ASH Annual Meeting. Abstract 393.

Presented December 8, 2014.

3. Brady LW, Yaeger TE (eds): Encyclopedia of Radiation Oncology. New York, Springer, 2012.

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PAGE 113

Announcements

Association of Community Cancer Centers Names Steven L. D’Amato, BSPharm, BCOP, President

S

teven L. D’Amato, BSPharm, BCOP, became President of the Association of Community Cancer Centers (ACCC) at its 41st Annual Meeting on March 18, 2015, in Arlington, Virginia. He is Executive Director of New Eng-

looking forward to a focus on the oncology medical home—an issue which resonates with the themes of quality and value, and the multidisciplinary nature of cancer care delivery.”

Mr. D’Amato has lectured extensively on pain management, end-of-life care, and oncology practice. He is a board member of the Community Cancer Center in South Portland, Maine, a

non-profit organization providing education and support to cancer patients.

He earned his undergraduate degree from the Massachusetts College of Pharmacy. n

Register now at

NCCN.org/events 2015

CONGRESS SERIES

TM

National Comprehensive Cancer Network

I’m looking forward to a focus on the oncology medical home—an issue which resonates with the themes of quality and value, and the multidisciplinary nature of cancer care delivery.

—Steven L. D’Amato, BSPharm, BCOP

land Cancer Specialists and a Clinical Associate Professor at the University of Tufts College of Medicine. Mr. D’Amato serves as a member of the Maine Medical Center Institutional Review Board, and he has had 30 years of experience in clinical oncology in both the hospital and private practice settings.

Mr. D’Amato has been active in ACCC for many years, serving on the Program Committee, and as an Advisory Board Member for ACCC’s Oncology Pharmacy Education Network. Most recently, he served on ACCC’s Board of Trustees as Secretary for 2 years.

The Oncology Medical Home “I want to thank the ACCC membership for giving me this opportunity to serve,” said Mr. D’Amato. “Each ACCC President selects a theme issue. I’m

The ASCO Post Wants to Hear From You

Write to The ASCO Post at editor@ASCOPost.com

LIVE WEBINARS BREAST CANCER with Updates from the 2014 San Antonio Breast Cancer Symposium Learn how to implement the NCCN Guidelines® recommendations into your practice and gain a clear understanding of the most current treatment recommendations for breast cancer.

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The ASCO Post | APRIL 10, 2015

PAGE 114

In Memoriam

Remembering Neurosurgeon and Writer Paul Kalanithi, MD

By Jo Cavallo

W

hat initially drew me to read the eloquent essay by Paul Kalanithi, MD, in The New York Times—“How Long Have I Got Left?”—was its provocative title.1 What kept me there was the moving description of his quick transition from healthy physician with a brilliant career in neurosurgery to terminally ill cancer patient. A lifelong nonsmoker, Dr. Kalanithi was diagnosed with stage IV non–small cell EGFR-positive lung cancer in spring 2013 at age 35. He died from the disease on March 9, 2015.

In his essay, Dr. Kalanithi said that even more difficult than facing the certainty of death was facing an uncertain life. “The path forward would seem obvious, if only I knew how many months or years I had left,” he wrote. “Tell me 3 months, I’d just spend time with my family. Tell me 1 year, I’d have a plan….

Give me 10 years, I’d get back to treating diseases. The pedestrian truth that you live one day at a time didn’t help: What was I supposed to do with that day? My oncologist would only say, ‘I can’t tell you a time. You’ve got to find what matters to you most.’”

Living With an Uncertain Future When Dr. Kalanithi wrote that essay, he was 8 months from his diagnosis and was having a positive response to erlotinib. The majority of the malignant spots on his lungs had disappeared, and the primary lung nodule had shrunk. In fact, his strength had recovered so substantially, he had returned to work as Chief Resident in Neurological Surgery at Stanford University School of Medicine in California.

Just 2 months later, when I inter-

viewed Dr. Kalanithi for his Patient’s Corner column, “I Refuse to Capitulate to Cancer” (reprinted on page 107), he was feeling so much stronger, he said he was beginning to overcome the immediate challenge of having advanced lung cancer and wondering how much time he had left. He was also excited about starting a family with his wife, Lucy Goddard Kalanithi, MD, FACP, a Clinical Instructor in Medicine at the Stanford School of Medicine.

“At the moment, my life is at the maximum point of uncertainty,” said Dr. Kalanithi. “I need to get my career trajectory fully back on course, and my wife is pregnant with our first child. So life is really exciting—and stressful. But these are the stresses of the living, not of dying. The fact that I get to deal with all of the worries of having a highly demanding career and a new family is a blessing.”

Confronting Death While Celebrating Life Unfortunately, soon after our interview, Dr. Kalanithi relapsed and underwent 3 months of chemotherapy and endured a prolonged hospitalization. On July 4, 2014, just days after Dr. Kalanithi was released from the hospital, Lucy Kalanithi gave birth to their daughter, Elizabeth Acadia.

Nicknamed “Cady,” Dr. Kalanithi wrote about the joy his infant daughter brought to his life in an essay penned in Stanford Medicine,2 which he ended with this message to her: “When you come to one of the many moments in life when you must give an account of yourself, provide a ledger of what you have been, and done, and meant to the world, do not, I pray, discount that you

filled a dying man’s days with a sated joy, a joy unknown to me in all my prior years, a joy that does not hunger for more and more, but rests, satisfied.

In this time, right now, that is an enormous thing.”

A Life Well Lived Dr. Kalanithi was born in New York in April 1977, and moved with his family to Kingman, Arizona, when he was 10. He graduated from Stanford University in 2000 with bachelor’s and master’s degrees in English literature and a bachelor’s degree in human biology. He earned a master’s degree in the history and philosophy of science and medicine at the University of Cambridge and then attended Yale School of Medicine, graduating cum laude in 2007. While at Yale, Dr. Kalanithi was awarded the Lewis H. Nahum Prize for his research on Tourette’s syndrome and became a member of the Alpha Omega Alpha Honor Medical Society.

In 2007, Dr. Kalanithi returned to Stanford for a residency in neurological surgery and a postdoctoral fellowship in neuroscience, developing optogenetic techniques. It was during his sixth year of residency that Dr. Kalanithi began experiencing a constellation of troubling symptoms, including weight loss, fevers, night sweats, severe chest and back pain, and a cough. When he reviewed the images from his CT scans and saw masses of lesions spreading across his lungs and deforming his spine, he knew immediately that what he was seeing was metastatic cancer.

The experience of being a patient, said Dr. Kalanithi, gave him a much deeper appreciation of how difficult it is for patients to navigate their way

 In Memoriam

Paul Kalanithi, MD 1977 – 2015 

Lucy, Paul, and Cady Kalanithi.

through a serious illness. “[That experience] is something I will never forget, and I wish in some ways that every doctor can experience a really hard diagnosis and the impact it has [on patients],” said Dr. Kalanithi.

Aware of the precariousness of his illness, Dr. Kalanithi was determined to proceed with his life, knowing that at any moment his cancer could become uncontrollable. Until that happens, he said, “I’m pursuing the things that drive me. The fact of death is unsettling. Yet there is no other way to live.”

Dr. Kalanithi is survived by his wife, Lucy; his daughter, Cady; his parents, Sujatha and A. Paul Kalanithi, MD; his brothers, Suman Kalanithi, MD, and Jeevan Kalanithi; his sister-in-law, Emily Kalanithi, JD; and his niece and nephew, Eve and James Kalanithi. n References 1. Kalanithi P: How long have I got left?

The New York Times, January 24, 2014.

2. Kalanithi P: Before I go. Stanford Medicine, Spring 2015.

May 29-June 2, 2015

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In melanoma…

A T CELL IS ONLY AS EFFECTIVE AS THE ANTIGEN THAT ACTIVATES IT1 T cell

Dendritic cell

Tumor-derived antigens (TDAs) set the immune system in motion by priming and activating T cells. Once released, TDAs are processed by dendritic cells and subsequently presented to T cells, initiating an adaptive immune response.1-3 Learn more at

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References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079. © 2014 Amgen Inc. All rights reserved. 8/14 USA-678-100568