TAP Vol 5 Issue 9 by Harborside Press LLC

ASCO Plenary Reports 1, 3, 4, 13 | Young Adults and Cancer

| Debate: Randomized Trial vs Meta-Analysis

VOLUME 5, ISSUE 9

JUNE 10, 2014

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

ASCO Annual Meeting Plenary Session

‘Unprecedented’ Survival Benefit in Prostate Cancer With Addition of Docetaxel to Hormone Therapy

‘Small Practices Like Mine’

By Alice Goodman

By Carolyn B. Hendricks, MD

dding docetaxel to standard androgen ablation ter of Genitourinary Oncoltherapy (ie, testosterone suppression) extended ogy at the Dana-Farber Cansurvival by more than 1 year in men with newly diag- cer Institute in Boston. “This nosed metastatic hormone-sensitive prostate cancer is the first study to identify a in the phase III E3805 trial, funded by the National In- strategy that prolongs survivstitutes of Health. As reported at the ASCO al in newly diag1 Annual Meeting in Chicago, the survival nosed metastatic benefit was observed mainly in men with prostate cancer. more extensive metastatic disease. The benefit is subASCO Immediate Past President stantial and war- Christopher J. Sweeney, MBBS Clifford A. Hudis, MD, FACP, called rants this being these results achieved with an older drug adopted as a new standard treatment for men See page 53 “unprecedented” and “transformative.” who have high-extent disease and are able to tolerate chemotherapy,” he stated. New Standard of Care The E3805 study utilized two older therapies. Andro“We asked the question of whether you treat hormone- gen-deprivation therapy has been used to treat prostate sensitive cancers more aggressively in the beginning or cancer for more than 50 years. Docetaxel transformed the wait to add docetaxel,” said lead author Christopher landscape of treatment for prostate cancer when it was apcontinued on page 4 J. Sweeney, MBBS, medical oncologist at the Lank CenHealth-Care Policy

Medicare Advisory Panel Cast Doubts on Lung Cancer Screening, Leaving Advocates Dismayed but Undaunted

continued on page 46

Dr. Hendricks is a medical oncologist specializing in breast cancer. She is in private practice in Bethesda, Maryland. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE

By Ronald Piana n April 30, 2014, the Centers for Medicare & Medicaid Services (CMS) convened the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) to assess the value of lowdose computed tomography (CT) lung cancer screening in the Medicare population. After a decades-long battle, lung cancer advocates were confident that the evidence proved that screening was a cost-effective

ecently, I participated in ASCO’s Congressional news briefing in Washington, DC, following the release of its report, The State of Cancer Care in America: 2014. During my presentation I talked about the workforce shortage of approximately 1,500 medical oncologists that is predicted by 2025. A number of factors are converging to make this shortage a reality, including increasing demand for cancer care services over the next decade as the number of new cancer cases rise—largely the result of an aging population—and the growing population of cancer survivors, just as many oncologists start to retire. (According to ASCO’s report, in 2008,

way to save thousands of lives each year. Surprisingly, the MEDCAC panel gave very low confidence scores for lung cancer screening, which further confounds the ongoing debate over Medicare reimbursement.

Focus on the Negatives

In December 2013, the U.S. Preventive Services Task Force (USPSTF) issued a grade B recommendation, endorsing annual lowdose CT screening in highrisk, asymptomatic adults. The Task Force—considNot endorsing a modality that saves ered the “gold standard” for clinical preventive lives is a missed opportunity. services—based its recom—Benjamin P. Levy, MD mendation largely on results of the National Lung Screening Trial (NLST).

Oncology Meetings Coverage ASCO 50th Annual Meeting �� 3–6, 12 NCCN Annual Conference ��33, 38, 39 American Society of Breast Surgeons ��15, 16 Society of Surgical Oncology ��29 John C. Byrd, MD, on CLL ��39 ASCO Guideline Update on Sentinel Lymph Node Biopsy �� 44 With Perspective by Armando E. Giuliano, MD ��45 Postmastectomy Radiotherapy �� 48 With Perspective by Bruce G. Haffty, MD ��52 Direct From ASCO �� 58–61 Ceritinib in ALK-Positive NSCLC �� 64 Pancreatic Cancer Clinical Trials ��77

continued on page 70

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The ASCO Post | JUNE 10, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Paul F. Engstrom, MD Fox Chase Cancer Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Samuel Silver, MD, PhD University of Michigan Health System

Associate Editors

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Jame Abraham, MD Cleveland Clinic Manmeet Ahluwalia, MD, FACP Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute

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ASCO Annual Meeting Plenary Session

ALTTO Trial Finds Dual Anti-HER2 Therapy No Better Than Trastuzumab Alone

he highly anticipated results from the phase III ALTTO trial show no additional benefit for adding lapatinib (Tykerb) to trastuzumab (Herceptin) in the adjuvant treatment of HER2positive breast cancer.1

Dr. Piccart-Gebhart and Dr. Perez are co–principal investigators of ALTTO. “The study failed to show that lapatinib adds to the benefit of trastuzumab in terms of disease-free survival,” Dr. P erez reported prior to the plenary presenta-

The doubling in pathologic complete response observed with lapatinib plus trastuzumab in NeoALTTO did not translate into improved survival outcomes in ALTTO. —Martine J. Piccart-Gebhart, MD, PhD

The results were presented at the 2014 ASCO Annual Meeting’s Plenary Session by Martine J. Piccart-Gebhart, MD, PhD, Chair of the Breast International Group in Brussels, and at a media briefing by Edith A. Perez, MD, Deputy Director at Large at the Mayo Clinic Cancer Center, Jacksonville, Florida.

tion. “At this time of follow-up, there is also no statistically significant difference in overall survival with dual [concomitant] blockade, or sequential anti-HER2 treatment, vs single-agent trastuzumab.” As the discussant of this paper at the Plenary Session, George W. Sledge, Jr, MD, Professor of Medicine

and Director of the Division of Oncology at Stanford University, and a Past President of ASCO, delivered some somber remarks. “This is a negative trial.… This is a serious disappointment,” he said (see Expert Point of View below). But Dr. Perez did find something positive in the results, as she noted to the media that the 555 disease-free events that occurred at 4.5 years fell far short of the 850 that were anticipated in the statistical plan. “Another way of looking at this study is that the patients overall did pretty well—better than anticipated,” she said. “In addition, we were very impressed by the very low rate (< 1%) of observed significant cardiac toxicity in all of the treatment arms, in the context of approximately 97% having received anthracyclines,” she told The ASCO Post.

Unexpected Results Dr. Perez emphasized that failure to meet the primary endpoint—improved outcomes with dual HER2 blockade— was unexpected. “We were surprised

©ASCO/Silas Crews 2014

By Caroline Helwick

Edith A. Perez, MD

that adding lapatinib did not provide further benefit, since the combination of these drugs was promising in a smaller study,” she said. Dr. Perez was referring to the NeoALTTO trial, which evaluated the combination vs each single agent as neoadjuvant treatment in 455 patients. In NeoALTTO, dual HER2 blockade resulted in a near doubling of the pathologic complete response rate (51.3%), vs single-agent trastuzumab (29.5%) or lapatinib (24.7%); the reaching of pathologic complete response corresponded to a 62% recontinued on page 13

EXPERT POINT OF VIEW

n his commentary on the ALTTO results, George W. Sledge, Jr, MD, Professor of Medicine and Director of the Division of Oncology at Stanford University, reminded attendees that the announcement of the first results for adjuvant trastuzumab, which occurred at the 2005 ASCO Annual Meeting, was “a defining moment in our field.” The 50% reduction in the annual odds of recurrence “remains one of the great success stories,” he said.

“HER2 has reverted to the incrementalism we see so commonly in the adjuvant field,” Dr. Sledge offered. “This is not, alas, 2005. This is not a great leap forward. This is a serious disappointment, not just for the investigators but for the entire field.”

‘A Serious Disappointment’ “But a 50% improvement still meant that far too many women were relapsing and dying, and there was still real work to be done,” he continued. That work, he noted, was the exploration of a number of biology-based approaches, of which the combining of trastuzumab with kinase inhibition “at the time appeared to be the best bet.” This proposal was subsequently supported by preclinical and clinical evidence, leading to the development of the ALTTO trial. “What mattered was whether dual HER2 blockade would move us further up the disease-free survival ladder, bringing us closer to a cure for HER2positive breast cancer,” Dr. Sledge said.

George W. Sledge, Jr, MD

The negative findings “tell us at a simple level that we won’t be using lapatinib in the adjuvant setting,” he continued, predicting that further follow-up will not produce a statistically significant result. Furthermore, he added, “It’s difficult to mount any enthusiasm for dual blockade in the adjuvant setting, at least for the combination shown here.” But he added that the findings have importance beyond the obvious. “You might be wondering why a negative adjuvant trial occupies a Plenary Ses-

sion spot, a place usually reserved for practice-changing data. I suggest that the answer requires us to rethink our approach to the development of new drugs for early breast cancer,” he said. “ALTTO represented a reasonable test of the hypothesis that improvements in pathologic complete response rates were associated with improved disease-free survival. These hopes have now been dashed. The null hypothesis won,” Dr. Sledge observed. The results of the adjuvant A PHINITY trial in which pertuzumab plus trastuzumab are being tested will be of great interest, he added.

The Larger Question Furthermore, Dr. Sledge suggested that ALTTO “invites a larger question,” specifically, whether drugs that prove themselves in the metastatic or neoadjuvant setting are similarly effective as adjuvant therapies. He noted that the ALTTO “failure” joins several others, including drugs targeting the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) in colorectal cancer, and anti-VEGF drugs in breast cancer. These approaches may have failed

because they are the wrong drugs, are given for an inadequate duration, or are given to inappropriately selected patients, or perhaps because the biology of early vs metastatic cancer is poorly understood. “Why have these approaches failed in the adjuvant setting, despite a plethora of preclinical evidence and numerous positive trials in the metastatic setting that show an overall survival advantage?” he asked. “These setbacks should prompt us to ask, are we facing a systemic crisis in the adjuvant failure of targeted therapies, or just having a string of bad luck?” These failures must be elucidated in order to move forward and create new successes, he suggested. “But, move forward we shall, in HER2-positive breast cancer,” he said. Many novel approaches are active areas of research. “I hope and I believe that at least one of these will prove fruitful,” he said, “and move us closer to the day when HER2-positive breast cancer will no longer be a public health problem.” n Disclosure: Dr. Sledge has received honoraria from Genentech for lecture and is a member of the science advisory board for Syndax.

The ASCO Post | JUNE 10, 2014

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ASCO Annual Meeting Docetaxel/Hormone Therapy continued from page 1

proved 10 years ago for the treatment of disease that has progressed on androgendeprivation therapy (ie, castration-resistant prostate cancer). This study evaluated whether docetaxel can make a difference if given earlier in the course of disease, when the cancer is still hormone-sensitive. From 2006 to 2012, E3805 enrolled

At the Annual Meeting, Dr. Sweeney presented updated overall survival results. Median overall survival was significantly improved with the addition of docetaxel to androgen-deprivation therapy: 57.6 months vs 44 months for androgen-deprivation therapy alone (P = .0003), representing a 39% reduction in risk of death at every time point assessed. Deaths totaled 136 in the androgen-deprivation therapy–

This is the first study to identify a strategy that prolongs survival in newly diagnosed metastatic prostate cancer. The benefit is substantial and warrants this being adopted as a new standard treatment for men who have highextent disease and are able to tolerate chemotherapy. —Christopher J. Sweeney, MBBS

790 men with newly diagnosed metastatic prostate cancer and randomized them to androgen-deprivation therapy alone vs androgen-deprivation therapy plus six cycles of docetaxel. A preplanned interim analysis performed in October 2013 showed a significant improvement in survival with the addition of docetaxel.

alone arm vs 101 in the androgen-deprivation therapy/docetaxel arm.

Greatest Benefit Looking at the data in greater depth, most of the survival benefit was observed in men with extensive disease— either a high burden of bone metastases

New Role for Docetaxel in Prostate Cancer ■■ A large federally funded study shows that adding docetaxel chemotherapy upfront to androgen-deprivation therapy improves survival by a median of 13 months in newly diagnosed metastatic hormone-sensitive prostate cancer. ■■ Results were driven mainly by an effect in high-volume disease, confirming the role of docetaxel given earlier in the course of disease. ■■ This represents a new standard of care for “chemo-fit” patients with highvolume disease. Use of docetaxel in low-volume disease needs to be confirmed. ■■ This is a cost-effective option compared with waiting to use docetaxel until castration resistance develops.

or liver or lung metastases. In that group (60% of study participants), median overall survival was 49.2 months for the combination vs 32.2 months for androgen-deprivation therapy alone (P = .0006), representing a 40% reduction in risk of death. In patients with lowvolume disease, median overall survival has not yet been reached in either arm. Dr. Sweeney said that longer follow-up is needed to get more certainty on the benefit of docetaxel added to androgendeprivation therapy in patients with low-volume metastatic disease. Docetaxel delayed disease progression as assessed by prostate-specific antigen

EXPERT POINT OF VIEW

ormal discussant of the E3805 study, Michael J. Morris, MD, Associate Member at Memorial Sloan Kettering Cancer Center in New York, said that these results confirm the role of upfront chemotherapy along with

Michael J. Morris, MD

androgen-deprivation therapy in men with newly diagnosed metastatic hormone-sensitive prostate cancer who have high-volume disease. “The investigators have adequately shown that upfront docetaxel confers a survival advantage for patients with high-volume newly diagnosed metastatic disease. However, there are insufficient data at this time to recommend that low-volume patients with metastatic hormone-sensitive prostate cancer undergo chemotherapy,” Dr. Morris told listeners.

Study Implications The original survival benefits reported with docetaxel in metastatic castration-resistant prostate cancer were modest—about 2 to 3 months absolute improvement with a 20% to 25% reduction in death. “Today, we are moving docetaxel forward from the castrationresistant state to the castration-sensitive state. The survival benefits of docetaxel are amplified in this setting, with a 40% reduction in risk of death and prolonged time to radiographic progression and the castration-resistant state,” he said. “The study results bear on the ongoing dialog about cost vs value in cancer care. Docetaxel is going to cost less than our newer therapies. I estimate that using docetaxel in castration-resistant prostate cancer gains 81 days of life for $15,000 of drug costs at wholesale prices. If docetaxel is applied in castrationsensitive disease, it gains 476 days of life at a cost of $9,000 for six cycles,” Dr. Morris said. How do the results apply to clinical practice? Dr. Morris said that oncologists need to avoid misapprehension of true risk, which leads to a misapplication of therapy. “We need to be able to identify the appropriate high-volume patients who need che-

motherapy and low-volume patients who should not get chemotherapy at this juncture,” he continued. The definition used in the study for high-volume disease was four or more bone metastases and one or more lesions in any bony structure beyond the spine/ pelvis or visceral disease. Dr. Morris said a more precise definition of extensive disease is needed to identify which patients can benefit from early chemotherapy. A more refined definition should be based on disease distribution and volume. Four lesions could reflect low or high disease burden depending on where they are and how much area they affect.

Federal Funding Dr. Morris emphasized that the study was sponsored by National Institutes of Health. “This difficult and long study has changed the standard of care for some patients in the face of ever-diminishing resources,” he noted. In fact, all four of ASCO’s Plenary Session studies were federally funded. In 2009, approximately 500 abstracts submitted to ASCO were federally funded, compared to 169 in 2014—indeed, shrinking resources. n

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

(PSA) or emergence of new metastases or symptom worsening. At 1 year, the percentage of patients with PSA < 2 ng/mL was 11.7% in the androgen-deprivation therapy group vs 22.7% in the androgendeprivation therapy/docetaxel group (P < .0001). Median time to clinical progression was 19.8 months vs 32.7 months, respectively (P < .0001). Docetaxel also significantly improved median time to developing castration-resistant prostate cancer: 20.7 months vs 14.7 months for androgen-deprivation therapy alone (P < .0001).

Safety Profile “It is feasible to administer docetaxel in this patient population,” Dr. Sweeney said. Nonhematologic toxicity and hematologic toxicity were consistent with what is described for docetaxel. Overall, 28% of patients had grade 3 or 4 events related to treatment. The main toxicities associated with docetaxel were neutropenic fever (6%); sensory neuropathy (1%) and motor neuropathy (1%); and 1 of the 397 patients who received early docetaxel died due to treatment. Quality-of-life data will be analyzed and presented at a later time. At the press briefing where these findings were featured, Dr. Hudis praised the study. “This is an old drug and it reduces cost. I am not aware of another study that showed this magnitude of benefit in survival in sold tumors. This is an almost unprecedented improvement in survival.” n

Disclosure: Dr. Sweeney reported a consulting or advisory role with Astellas Pharma, BIND Biosciences, Bionomics, Exelixis, Genentech, Janssen Pharmaceuticals, Roche, and Sanofi. For full disclosures of the study authors, visit abstracts.asco.org.

Reference 1. Sweeney C, Chen Y-H, Carducci MA, et al: Impact on overall survival with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer: An ECOGled phase III randomized trial. ASCO Annual Meeting. Abstract LBA2. Presented June 1, 2014.

ASCOPost.com | JUNE 10, 2014

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ASCO Annual Meeting Thoracic Oncology

Phase I Study of Novel Third-Generation EGFR Inhibitor Holds Promise Against Resistance Mutation in Patients With Non–Small Cell Lung Cancer By Alice Goodman

reliminary evidence suggests that AZD9291, a novel mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, may become a treatment option for patients with advanced, EGFRmutant, non–small cell lung cancer

There is currently no approved therapy for treatment of T790M-positive NSCLC. The combination of two EGFR inhibitors—afatinib and cetuximab (Erbitux)—is somewhat effective in patients with the T790M mutation, but it is very toxic. AZD9291

This is a promising treatment with no dose-limiting toxicities identified and no maximal tolerated dose identified in phase I. [AZD9291] warrants further study, which is now ongoing. —Pasi A. Jänne, MD, PhD

(NSCLC) that has progressed on standard EGFR inhibitors. Promising results of a phase I study, presented at the 2014 ASCO Annual Meeting,1 pave the way for further investigation of this new agent.

Targeted Therapies EGFR mutations were the first biomarkers for lung cancer, leading to the development of targeted therapies. Currently, three different tyrosine kinase inhibitors are approved for treatment of patients with EGFR-mutant NSCLC (erlotinib [Tarceva], gefitinib [Iressa], and afatinib [Gilotrif ]). Although patients will respond to these drugs, most will acquire resistance to EGFR tyrosine kinase inhibitors within 10 to 14 months. About 60% of patients who become resistant have a secondary EGFR mutation known as T790M.

appears able to overcome the T790M mutation, and it is a “kinder, gentler” drug than the approved tyrosine kinase inhibitors, explained lead author Pasi A. Jänne, MD, PhD, Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston. “This is a promising effective treatment with no dose-limiting toxicities identified and no maximal tolerated dose identified in phase I. This drug warrants further study, which is now ongoing,” Dr. Jänne said. AZD9291 has been granted breakthrough status by the U.S. Food and Drug Administration for metastatic T790M-positive NSCLC that has progressed on treatment with an EGFR tyrosine kinase inhibitor.

Study Details In the open-label, multicenter, phase I AURA study, patients were assigned to one of five dosing cohorts at doses ranging from 20 mg/d to 240

AZD9291 in Resistant Lung Cancer ■■ A mutant-selective tyrosine kinase inhibitor appears safe and effective in phase I study of non–small cell lung cancer patients with acquired resistance to other EGFR tyrosine kinase inhibitors. ■■ Thus far, no dose-limiting toxicity and no maximal tolerated dose have been identified. ■■ The new agent has less toxicity than currently approved EGFR tyrosine kinase inhibitors. ■■ Development is ongoing, and AZD9291 has been granted breakthrough status by FDA for metastatic T790M-positive NSCLC that has progressed on treatment with an EGFR tyrosine kinase inhibitor.

mg/d. These cohorts were not preselected according to T790M status. Five expansion cohorts were preselected according to T790M status (T790Mpositive or -negative). As of January 2014, 199 patients were enrolled. No dose-limiting toxicity was identified at 20 to 240 mg/d, and maximal tolerated dose was not defined. Adverse events were mainly grade 1 diarrhea (30%), rash (24%), and nausea (17%). Grade 3 or 4 adverse events occurred in 16%; six patients (3%) required dose reductions and seven discontinued treatment due to adverse events. There were five reports of interstitial lung disease that responded to treatment, and investigators are exploring this side effect further. The overall response rate in all evaluable patients was 51%. The over-

all response rate was higher in cancers with the T790M mutation: 64% in mutation-positive patients, and 23% in mutation-negative patients. The overall disease control rate (response plus stable disease) was 96% in mutation-positive patients (85 of 89). The longest duration of response was 8 months, and responses were seen across all dose levels. n

Disclosure: For full disclosures of the study authors, visit abstracts.asco.org.

Reference 1. Janne PA, Ramalingam SS, Yang JC, et al: Clinical activity of the mutant selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC). ASCO Annual Meeting. Abstract 8009. Presented May 31, 2014.

EXPERT POINT OF VIEW

ommenting on the study by Jänne et al, ASCO President Peter P. Yu, MD, said that the issue of drug resistance is important to understand for all cancers, but it is difficult to overcome resistance. “This clinical trial has important implications not only for NSCLC patients but for all patients treated with targeted therapy who subsequently develop drug resistance. In this phase I study, the investigators were able to demonstrate that precise knowledge about the mechanism of acquired drug resistance directly led to the design of a third-generation EGFR-targeted

This clinical trial has important implications not only for NSCLC patients but for all patients treated with targeted therapy who subsequently develop drug resistance. —Peter P. Yu, MD

therapy to overcome this resistance. In addition, the greater precision appears to have reduced the toxicity rendered to normal tissues that presumably do not express this mutation,” Dr. Yu told The ASCO Post. “Like any good study,” he continued, “this study raises interesting questions that will be addressed in phase II and III trials to follow. Since about 25% of patients who did not harbor the targeted mutation responded to therapy, it raises the question of whether this drug may have a role in first-line therapy of EGFR-mutated lung cancer, either because of reduced toxicity or more durable responses. Alternatively, it may be best to reserve this drug to treat acquired resistance if the initial tumor at presentation did not have the targeted T790M mutation.” n Disclosure: Dr. Yu reported no potential conflicts of interest.

The ASCO Post | JUNE 10, 2014

PAGE 6

ASCO Annual Meeting Genitourinary Oncology

Delaying Androgen Deprivation Therapy May Not Compromise Survival in Men With Prostate Cancer and PSA-Only Relapse By Alice Goodman

n men with prostate cancer and a prostate-specific antigen (PSA)only recurrence after curative surgery or radiation, delaying androgen deprivation therapy for at least 2 years or until clinical progression (ie, new symptoms, metastasis by imaging

noted lead author Xabier Garcia- Albeniz, MD, a research associate at the Harvard University School of Public Health in Boston. “These findings suggest that there may be no need to rush to [androgen deprivation therapy]. Obviously, this is an observational

Obviously, this is an observational study with several limitations, and the issue of when to start [androgen deprivation therapy] is being studied in an ongoing randomized phase III trial. —Xabier Garcia-Albeniz, MD

techniques or short PSA doubling time) did not appear to impact survival or prostate cancer–specific survival compared with immediate initiation of androgen deprivation therapy within 3 months of PSA-only recurrence. These results of a large, populationbased study, developed jointly by the Harvard School of Public Health and University of California, San Francisco, are suggestive and can be included in discussions with patients, but they are by no means definitive, say experts. The study was presented at the 2014 ASCO Annual Meeting.1

Grey Area “Immediate vs deferred androgen deprivation therapy for men with a PSA-only recurrence is a grey area. The [National Comprehensive Cancer Network] guidelines say that the role of [androgen deprivation therapy] in this setting is a ‘therapeutic dilemma,’”

study with several limitations, and the issue of when to start [androgen deprivation therapy] is being studied in an ongoing randomized phase III trial. The results of that trial will answer the question and serve as the gold standard.” The study analyzed data on more than 14,000 patients included in a prospective registry called CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor, based at the University of California, San Francisco). Among these patients, 2,012 men experienced a PSA-only relapse following curative surgery or radiation. PSA relapse was defined as ≥ 0.02 ng/mL if treated with radical prostatectomy or three rising PSA levels 1 month apart if primary treatment was radiation-based. Patients had to be asymptomatic and without evidence of metastasis. These patients were treated in usual practice

Immediate vs Deferred Androgen Deprivation ■■ Delaying androgen deprivation therapy for up to 2 years after a PSA-only relapse following treatment of prostate cancer with curative intent did not appear to worsen survival compared with immediate initiation of androgen deprivation therapy. ■■ These results are from a large observational study and can be included in discussions with patients. ■■ Results from an ongoing randomized trial should provide definitive evidence about when to initiate androgen deprivation therapy in men with a PSA-only relapse.

EXPERT POINT OF VIEW

iscussing the study on immediate vs deferred androgen deprivation therapy in the setting of prostate cancer with prostate-specific antigen (PSA)-only relapse, ASCO President Peter P. Yu, MD, noted that more than 60,000 men each year will face the dilemma of when to start androgen deprivation therapy for a PSA relapse after treatment with surgery or radiation with curative intent. “These men get the devastating news that their PSA is rising, but they are asymptomatic. They may have an emotional need to start therapy, but androgen deprivation therapy has side effects such as fatigue, anemia, cardiovascular deterioration, osteoporosis and risk of bone fracture, weight gain and loss of muscle mass, hot flashes, and other problems. Up until now, there is little evidence to support delaying treatment until clinical signs of disease appear. The results of this study can start the conversation,” he said. ASCO Immediate Past President Clifford A. Hudis, MD, FACP, said, “This study may provide reassurance about deferring androgen deprivation therapy for quality-of-life reasons. We can tell patients that they don’t have to rush to treatment, and the results provide reassurance for us about withholding androgen deprivation therapy.” n Disclosure: Drs. Yu and Hudis reported no potential conflicts of interest.

settings. The evaluated strategies were (1) immediate androgen deprivation therapy (within 3 months of rising PSA) and (2) deferred androgen deprivation therapy (at least 2 years after PSA-only relapse, or when they had metastasis, symptoms, or short PSA doubling time).

Key Findings Median time from primary treatment to PSA relapse was 27 months. Median follow-up after PSA relapse was 41 months. Median age was 69 years (range, 63 to 74 years); 33.8% had a Gleason score > 7; and 31.8% received radiation as primary treatment. There were 176 deaths recorded during follow-up; 37 were due to prostate cancer. Five-year survival rates were 87.2% (95% confidence interval [CI] = 84.5%–90.0%) for the deferred androgen deprivation therapy group and 85.1% (95% CI = 77.6%–92.7%) for those treated with immediate androgen deprivation therapy. Ten-year survival was identical in both groups: 71.6%.

Study Limitations As with every observational study, this investigation has limitations, Dr. Garcia-Albeniz acknowledged. Al-

though the best statistical resources were used to adjust for prognostic differences between strategies, we still rely on the assumption of absence of unmeasured confounding factors. He looks forward to results of the large randomized trial studying this issue.2 “Ideally we base treatment decisions on randomized trials. In real practice, we don’t have the answers to the question yet. We can use this information from an observational study in our discussions with patients. This study won’t change clinical practice, but it might help men make decisions. We need to wait for the gold standard,” Dr. Garcia-Albeniz stated. n

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

References 1. Garcia-Albeniz X, Chan JM, Paciorek AT, et al: Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. ASCO Annual Meeting. Abstract 5003. Presented June 1, 2014. 2. Androgen deprivation therapy in treating patients with prostate cancer. Available at clinicaltrials.gov, identifier NCT00110162, last updated August 6, 2013.

VOTRIENT is indicated for the treatment of advanced renal cell carcinoma (RCC)1

EFFICACY AGAINST PROGRESSION

VOTRIENT demonstrated an overall median progression-free survival (PFS) of

9.2 months vs 4.2 months with placebo (HR 0.46; 95% CI 0.34-0.62; P<0.001)1*

*Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efﬁcacy and safety of VOTRIENT in ﬁrst-line or cytokine-pretreated patients (N=435) with advanced RCC of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. Please see additional Important Safety Information for VOTRIENT on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

EFFICACY LIGHTS THE WAY

VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2 12 10

VOTRIENT Placebo

11.1

MONTHS

9.2

MONTHS

7.4

Months

8 6 4

MONTHS

4.2

2.8

MONTHS

4.2

MONTHS

2 0

HR 0.46; 95% CI 0.34-0.62 (P<0.001) All patients

HR 0.40; 95% CI 0.27-0.60 (P<0.001) First-line patients

HR 0.54; 95% CI 0.35-0.84 (P<0.001) Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included first-line patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).1

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary

emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence

of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced • No dose adjustment is required in patients with mild hepatic impairment • In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

VOTRIENT (pazopanib) has a Category 1 recommendation as a ﬁrst-line therapy in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for relapsed or Stage IV unresectable RCC of predominant clear cell histology.3 NCCN Guidelines® also include therapies other than VOTRIENT (pazopanib) as ﬁrst-line treatment options.

• Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. • Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax.

• Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT.

• Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2014. ©National Comprehensive Cancer Network, Inc. 2013. All rights reserved. Accessed December 9, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

www.GSKSource.com

VOTRIENT.com/HCP/aRCC

EFFICACY LIGHTS THE WAY

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/ intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and

hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Gradesa Grade 3 Grade 4 % % % % Adverse Reactions Diarrhea 52 3 <1 9 Hypertension 40 4 0 10 Hair color changes 38 <1 0 3 Nausea 26 <1 0 9 Anorexia 22 2 0 10 Vomiting 21 2 <1 8 Fatigue 19 2 0 8 Asthenia 14 3 0 8 Abdominal pain 11 2 0 1 Headache 10 0 0 5 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Grade 3 % <1 <1 0 0 <1 2 1 0 0 0

Grade 4 % 0 0 0 0 0 0 1 0 0 0

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms. Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290) All Gradesa %

Grade 3 %

Placebo (N=145) Grade 4 %

All Gradesa %

Parameters Hematologic Leukopenia 37 0 0 6 Neutropenia 34 1 <1 6 Thrombocytopenia 32 <1 <1 5 Lymphocytopenia 31 4 <1 24 Chemistry ALT increased 53 10 2 22 AST increased 53 7 <1 19 Glucose increased 41 <1 0 33 Total bilirubin increased 36 3 <1 10 Phosphorus decreased 34 4 0 11 Sodium decreased 31 4 1 24 Magnesium decreased 26 <1 1 14 Glucose decreased 17 0 <1 3 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Grade 3 %

Grade 4 %

0 0 0 1

0 0 <1 0

1 <1 1 1 0 4 0 0

0 0 0 <1 0 0 0 0

T:14”

B:14.25”

S:13”

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of

dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a registered trademark of GlaxoSmithKline.

The ASCO Post | JUNE 10, 2014

PAGE 12

ASCO Annual Meeting Breast Cancer

Obesity Increases Breast Cancer Mortality in Premenopausal Women With Estrogen Receptor–Positive Disease By Alice Goodman

ccording to results of a large study of women with early breast cancer, the presence of obesity increased the risk of breast cancer–related mortality by 34% in premenopausal women with estrogen receptor– positive breast cancer. Obesity had little effect on breast cancer–related mortality in postmenopausal estrogen receptor–positive disease and no effect in estrogen receptor–negative disease.

Surprising Findings “These results were the opposite of what we expected. Obesity substantially increases blood estrogen levels in postmenopausal women only, so we expected to find increased risk in postmenopausal [estrogen receptor–positive] women as well as premenopausal [estrogen receptor–positive] women. This shows that our understanding of the mechanisms associated with obesity and prognosis is incomplete,” said lead author Hongchao Pan, PhD, a researcher at the University of Oxford in the United Kingdom. Dr. Pan presented these findings at the 2014 ASCO Annual Meeting.1

These results were the opposite of what we expected…. This shows that our understanding of the mechanisms associated with obesity and prognosis is incomplete. —Hongchao Pan, PhD

Nevertheless, these results provide yet another reason to maintain normal weight. “It has been shown that obesity increases the risk of developing cancer, and this study says it increases the risk of poor outcome once you have cancer, if you are premenopausal and have [estrogen receptor–positive] breast cancer,” Dr. Pan said. Investigators from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) compared records of 80,000 women enrolled in 70 clinical trials who received the same treatment in the same clinical trial. Obesity was defined as body mass index ≥ 30 kg/ m2, overweight as body mass index of 25 to 30 kg/m2, and normal weight as

Guides for Oncology Providers and Patients Now Available

s the prevalence of obesity increases in the U.S. population and potentially complicates all aspects of cancer treatment and survival, many cancer care providers struggle with addressing the topics of weight loss and weight management with their patients. Obesity and Cancer: A Guide for Oncology Providers is a tool for oncology professionals developed by a multidisciplinary group of cancer, nutrition, and exercise science experts. This guide will help oncology providers integrate strategies for weight loss into their practices by offering practical tips and implementation strategies for weight assessment and weight loss, as well as information about how to be reimbursed for these services. The obesity and cancer provider guide is funded through the Conquer Cancer Foundation with the generous support of Roche and Ethicon Endo-Surgery. To complement the provider guide, this bundle also includes Managing Your Weight After a Diagnosis of Cancer: A Guide for Patient and Families. This booklet provides clear, practical information especially for patients and their caregivers about different weight loss methods, common challenges to losing and maintaining one’s weight, a discussion of the emotional challenges that accompany making lifestyle changes, and tips for talking with the health-care team about weight. Both the provider and the patient guides are now available on ASCO’s website, at www.ASCO.org/obesity. n

body mass index of 20 to 25 kg/m2. The researchers collected data on estrogen receptor status, menopausal status, cancer recurrence, and death. Data were adjusted for tumor characteristics, in-

cluding size and nodal status, and for any differences in treatment.

Independent Risk Factor A Cox regression analysis was undertaken to compare the effects of obesity on breast cancer mortality in obese vs normalweight women. Obesity was a significant and independent factor associated with breast cancer–related death in 20,000 premenopausal estrogen receptor–positive women (relative risk [RR] = 1.34 (95% confidence interval [CI] = 1.22–1.47, 2-sided P < .00001). Little effect of obesity was observed in 40,000 postmenopausal estrogen receptor–positive women (RR = continued on page 13

EXPERT POINT OF VIEW

“T

o our surprise, obesity had a negative prognostic effect on premenopausal patients with breast cancer but not on those who were postmenopausal. We need to consider these findings in the context of results from other data sources that suggest that obesity remains a negative prognostic feature in women with breast cancer,” said ASCO Immediate Past President Clifford A. Hudis, MD, FACP, discussing the results of the study by Pan et al. “We know that obesity and overweight are associated with increased risk of developing estrogen receptor–positive postmenopausal breast cancer. Obesity is often associated with low-grade chronic inflammation of adipose

With some two-thirds of adults in the United States now obese or overweight, there is no avoiding it is a complicating factor in cancer care. —Clifford A. Hudis, MD, FACP

tissue in the breast, and this is now known to activate aromatase activity and thereby tissue production of estrogen even after the ovarian function has decreased. It is therefore somewhat surprising to see that the effect of obesity is less clear in postmenopausal women than in premenopausal women,” Dr. Hudis continued. “Obesity is a major challenge, and if current trends continue it will replace tobacco as the leading modifiable risk factor for cancer. It is also a general public health problem. With some two-thirds of adults in the United States now obese or overweight, there is no avoiding it is a complicating factor in cancer care. ASCO is working to support physicians and patients who need to manage cancer in the setting of increased body mass index, and we are seeking new strategies to address this challenge,” Dr. Hudis said. n Disclosure: Dr. Hudis reported no potential conflicts of interest.

ASCOPost.com | JUNE 10, 2014

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ASCO Annual Meeting ALTTO Trial continued from page 3

year. The current efficacy results were based on 6,281 patients randomized.

duction in events as compared with no pathologic complete response, Dr. Pic- ALTTO Schema In the design, described as “pragcart-Gebhart reported at the 2013 San 2 matic” by Dr. Piccart-Gebhart, paAntonio Breast Cancer Symposium. In her presentation at ASCO, Dr. tients were randomly assigned after Piccart-Gebhart noted that surgery to the concurrent NeoALTTO was not alone: use of trastuzumab and lapafour out of six previous tinib, to the sequential use studies of dual blockade of trastuzumab followed by in the neoadjuvant setlapatinib, or to trastuzumab ting—using mostly trastualone for 1 year. The followzumab and lapatinib, but ing dosing schemes were See page 53 also, in the NeoSphere trial, used: trastuzumab and pertuzumb (Per- • Design 1, after completion of chejeta)—demonstrated benefit, as did motherapy: (1) trastuzumab at two studies in the advanced-disease an 8 mg/kg intravenous loading setting. dose, followed by 6 mg/kg intraveThe ALTTO (Adjuvant Lapatinib nously every 3 weeks for 52 weeks; and/or Trastuzumab Treatment Optior (2) lapatinib at 1,500 mg/d for misation) investigators hypothesized 52 weeks; or (3) trastuzumab at a that in the adjuvant setting, two HER24 mg/kg intravenous loading dose targeted agents would be superior to followed by 2 mg/kg intravenously trastuzumab alone in preventing breast weekly for a total of 12 weeks, folcancer recurrences. It was the largestlowed by a 6-week treatment-free ever adjuvant clinical trial in HER2interval, followed by lapatinib at positive breast cancer, involving 8,381 1,500 mg/d for 34 weeks total; or women from 946 centers in 44 coun(4) trastuzumab at an 8 mg/kg intratries, Dr. Piccart-Gebhart noted in her venous loading dose followed by 6 presentation. mg/kg intravenously every 3 weeks A P value of ≤.025 was required for concomitant with lapatinib at 1,000 statistical significance in order to test mg/d for 52 weeks (later reduced to

Dual HER2 Targeting in Breast Cancer ■■ No statistically significant benefit was shown for dual HER2 targeting with trastuzumab plus lapatinib in the phase III adjuvant ALTTO trial. ■■ After 4.5 years of follow-up, median disease-free survival was approximately 88% in each arm, and median overall survival was approximately 95%. ■■ The results are surprising in light of the previous NeoALTTO study, in which dual HER2 blockade significantly increased pathologic complete response rates and this significantly correlated with clinical outcomes.

both the concurrent and the sequential treatments, vs trastuzumab. The single-agent lapatinib arm was closed early due to futility, and the results of that arm will be presented later this

750 mg/d when given concomitantly with chemotherapy). • Design 2, concomitantly with a taxane following anthracycline: 80 mg/m2 weekly paclitaxel or 75 mg/m2 docetax-

Obesity and Breast Cancer Mortality

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

continued from page 12

1.06; 95% CI = 0.99–1.14), and no effect was found in 20,000 estrogen receptor– negative women (RR = 1.00, 95% CI = 0.93–1.08). At 10 years, breast cancer–related mortality was reported in 21.5% of obese women and 16.6% of normal-weight women, a difference of about 5%. n

Reference 1. Pan H, Gray RG, on behalf of the Early Breast Cancer Trialists’ Collaborative Group: Effect of obesity in premenopausal ER+ early breast cancer: EBCTCG data on 80,000 patients in 70 trials. ASCO Annual Meeting. Abstract 503. Presented May 31, 2014.

el every 3 weeks, concomitantly with the anti-HER2 agent. • Design 2B: docetaxel at 75 mg/m2 for six cycles with carboplatin (AUC 6) concomitantly with the anti-HER2 agent; trastuzumab was given weekly, and lapatinib doses were reduced when combined with chemotherapy. The majority (n = 4,613) received the anti-HER2 agents after completing chemotherapy. Patients with hormone receptor–positive cancers also received appropriate hormonal therapy.

Negative Findings At a median follow-up of 4.5 years, dual targeting—either concurrently or sequentially—was associated with slight numerical reductions in disease recurrences, but the differences were not statistically significant, vs trastuzumab alone. “The ALTTO trial did not meet its endpoints,” Dr. Piccart-Gebhart announced. Disease-free survival rates at 4 years were 86% with trastuzumab, 88% with concurrent HER2-directed treatment, and 87% in the sequential arm. Median overall survival rates were 94%, 95%, and 95%, respectively. Hazard ratios ranged from 0.80 to 1.00, with none statistically significant. The analysis by hormone receptor status was similar. For the disease-free survival noninferiority analysis, the hazard ratio was 0.93 (P = .044 [P ≤ .025 required for statistical significance]). “The doubling in pathologic complete response observed with lapatinib plus trastuzumab in NeoALTTO did not translate into improved survival outcomes in ALTTO,” Dr. Piccart-Gebhart said.

Lapatinib More Toxic “Lapatinib was also associated with significant increases in adverse events of special interesting—diarrhea, skin rash or erythema, and hepatobiliary prob-

lems,” Dr. Piccart-Gebhart said. The toxicity may account for the fact that only 60% to 78% of patients in the lapatinib-containing arms received at least 85% of the protocol-specified dose, she added. Importantly, in ALTTO the rates of serious cardiotoxicity were very low—less than 1%—in spite of the fact that 97% of women received anthracyclines. Correlative analyses of tissue samples is underway, and this may help to identify whether subsets of patients did benefit from the adjuvant combination. A protocol-specified updated efficacy analysis is planned in 2 years. n

Disclosure: Dr. Piccart-Gebhart reported employment or leadership position with PharmaMar; a consulting or advisory role with Amgen, Astellas Pharma, AstraZeneca, Bayer, Invivis, Lilly, MSD, Novartis, Pfizer, Roche/ Genentech, Sanofi, Symphogen, Synthon, and Verastem; and honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer, Invivis, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, Symphogen, Synthon, and Verastem. Dr. Perez reported no potential conflicts of interest. For full disclosures of all the study authors, visit abstracts.asco.org.

References 1. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al: First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adjuvant treatment of HER2-positive early breast cancer. ASCO Annual Meeting. Abstract LBA4. Presented June 1, 2014. 2. Piccart-Gebhart M, Holmes AP, de Azambuja E, et al: The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab, or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study. 2013 San Antonio Breast Cancer Symposium. Abstract S1-01. Presented December 11, 2013.

Obesity and Breast Cancer ■■ A large study found that obesity increased the 10-year rate of breast cancer death by 34% in premenopausal estrogen receptor–positive women. ■■ Little independent effect of obesity was seen on death rates in postmenopausal women with estrogen receptor–positive disease, and no effect was seen in women with estrogen receptor–negative disease. ■■ Obesity remains a public health threat and increases the risk of developing breast cancer and having a worse prognosis in premenopausal women.

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References: 1. Leone P, Shin EC, Perosa F, Vacca A, Dammacco F, Racanelli V. J Natl Cancer Inst. 2013;105:1172-1187. 2. Warrington R, Watson W, Kim HL, Antonetti FR. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S1. 3. Rabinovich GA, Gabrilovich D, Sotomayer EM. Annu Rev Immunol. 2007;25:267-296. 4. Baeuerle PA, Reinhardt C. Cancer Res. 2009;69:4941-4944.

ASCOPost.com | JUNE 10, 2014

PAGE 15

American Society of Breast Surgeons Annual Meeting Breast Cancer

Cryoablation of Breast Tumors Shows Promise in Patients With Early-Stage Disease By Caroline Helwick

ryoablation of breast tumors, which destroys lesions by exposing them to extremely low temperatures, shows promise as an alternative to surgery in carefully selected women with early-stage disease, according to a study presented at the American Society of Breast Surgeons Annual Meeting in Las Vegas. In the multicenter phase II ACOSOG (Alliance) Z1072 trial of 99 patients with early-stage invasive ductal carcinoma, cryoablation resulted in complete ablation of tumor in 69% of patients overall, but in 94% of patients with tumors < 1 cm, according to Rache Simmons, MD, Professor and Chief of Breast Surgery at Weill Cornell Breast Center, New York. “A handful of studies have looked at cryoablation of breast tumors, but this is the first multicenter [National Institutes of Health]-sponsored national trial,” Dr. Simmons said in a press briefing. Cryoablation is an established technique for the treatment of fibroadenomas. The modality involves the percutaneous insertion under ultrasound guidance of a cryoprobe, which destroys the lesion by

resected so that the surgical specimen could be examined for residual disease. Patients also underwent postablation magnetic resonance imaging (MRI) to evaluate its negative predictive value in predicting residual disease. A total of 99 patients from 19 centers were enrolled in the trial; of these, 86

patients (87 tumors) were evaluable for data analysis. Eligible patients included those with unifocal invasive ductal breast cancer ≤ 2 cm, with < 25% intraductal component and with tumor enhancement on MRI. Successful tumor ablation was defined two ways: no remaining invasive cancer present on the pathologic examination of the targeted lesion, and no

■■ In the phase II ACOSOG Z1072 trial of 99 patients, 69% of women achieved complete ablation of tumor via cryoablation, rising to 94% for those with tumors < 1 cm.

In the Z1072 study, patients underwent cryoablation, then had their tumor

“When we broke this down by tumor size, we showed something quite important,” Dr. Simmons added. “Tu-

—Rache Simmons, MD

■■ For patients with early-stage invasive ductal carcinoma, cryoablation could be a reasonable alternative to lumpectomy.

Study Details

Smaller Tumors, Greater Success Rate

When we broke this down by tumor size, we showed something quite important: [small] tumor size was a strong predictor of success [of cryoablation].

Role of Cryoablation in Breast Cancer

means of a freeze-thaw-freeze cycle lasting about 20 minutes. Pilot studies have suggested it could also be an effective treatment for breast cancer.

tal carcinoma in situ), 69% of patients achieved complete ablation.

residual invasive ductal breast cancer or ductal carcinoma in situ present on the specimen. Dr. Simmons reported that by the first definition (no residual invasive disease), the success rate was 80.5%, and by the second definition (no residual invasive ductal carcinoma or duc-

mor size was a strong predictor of success.” For tumors ≥ 1 cm, the success rate was 63%, but in those < 1 cm, it rose to 94%, “which we consider quite a success,” she said. Only one patient had some residual disease, but this was successfully revealed by MRI. “Therefore, 100% of all 16 tumors less than 1 cm had either complete ablation or residual invasive ductal breast cancer/ ductal carcinoma in situ predicted by MRI,” she said. For the whole group, MRI following the procedure predicted the disease status of 75% of patients with negative reports for both invasive ductal carcinoma or ductal carcinoma in situ and 85.9% of patients with negative pathology reports for invasive residual disease. The findings indicated that MRI has an important role in evaluation of the results after cryoablation, and could potentially be used in future trials as a surrogate for pathologic examination of the tissue, Dr. Simmons suggested. In fibroadenoma patients (from

other studies), pre- and post-treatment mammography has indicated a lack of distortion, calcification, and fat necrosis, and a complete disappearance of the lesion. Anecdotally, this mirrors what has been seen in some cancer patients off-study who refused resection after cryoablation, she added. “We may see the same with breast cancer, but we don’t have data yet,” she said.

Looking Ahead Dr. Simmons indicated this treatment might be applicable to a growing population of patients—in particular, those with small tumors. “We have lots of patients with tumors less than 1 cm. They probably constitute 25% to 30% of our patients at Cornell. This number will be increasing as our imaging becomes more sophisticated,” she said. Future studies are needed, but the next step will not be a randomized phase III trial, she said. “The numbers would have to be enormous to compare patients with cancers smaller than 1 cm and follow them for recurrence. Equally important, it would be very difficult to get patients to agree to be randomized,” she noted. Along with the type of trial—or perhaps, registry—it is also unclear whether these patients should undergo radiotherapy, and if so, what type. Issues of thirdparty reimbursement are also unsettled. These and other factors are under discussion, she said. n

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

Reference 1. Simmons R, Ballman K, Cox C, et al: A phase II trial exploring the success of cryoablation therapy in the treatment of invasive breast carcinoma: Results from ACOSOG (Alliance) Z1072. American Society of Breast Surgeons Annual Meeting. Presented April 30, 2014.

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | JUNE 10, 2014

PAGE 16

American Society of Breast Surgeons Annual Meeting Breast Cancer

Axillary Radiotherapy Associated With Fewer Side Effects Than Lymph Node Dissection in AMAROS Analysis By Caroline Helwick

adiation therapy is associated with significantly fewer postoperative complications than axillary lymph node dissection, according to a detailed analysis of morbidity from the AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial presented at a press briefing prior to the American Society of Breast Surgeons

lymph node dissection [vs axillary radiotherapy] and the rate of lymphedema at 5 years was also twice as high,” Dr. Donker reported.

The AMAROS trial of 4,806 earlystage breast cancer patients randomly assigned those with positive sentinel nodes (n = 1,425) to treatment with axillary

lymph node dissection (n = 744) or axillary radiotherapy (n = 681), including the medial part of the supraclavicular fossa. At the ASBS meeting, investigators present-

FOR 1ST-LINE TREATMENT

Prescribe GILOTRIF for mNSCLC with common EGFR mutations Identify common EGFR mutations (Del19 and L858R). Treat with GILOTRIF and support patients through the Solutions PlusTM program.

Our morbidity data strongly supports radiotherapy as the preferred treatment. —Mila Donker, MD

25 75 M+Y 25

WARNINGS AND PRECAUTIONS

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■■ Patients in the radiation therapy arm had significantly less lymphedema at 1 and 5 years, and fewer postoperative surgical complications. 75

Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations.

SELECTED IMPORTANT SAFETY INFORMATION

■■ An analysis of morbidity from the AMAROS trial found equivalent disease control after axillary radiation therapy and axillary lymph node dissection in breast cancer patients with positive nodes, but radiation therapy was associated with fewer side effects. 0.5

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INDICATION AND LIMITATION OF USE Indication: GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

Axillary Radiotherapy vs Lymph Node Dissection

99.5

EGFR=epidermal growth factor receptor; FDA=US Food and Drug Administration; mNSCLC=metastatic non-small cell lung cancer.

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(ASBS) Annual Meeting in Las Vegas. Previous reports from this trial have shown no difference in survival among women receiving either treatment, but results from this international prospective multicenter trial suggest that radiation therapy has the advantage of producing fewer side effects, said Mila Donker, MD, of the Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital in Amsterdam. “Surgical complications [in patients receiving radiotherapy] were more than twice as high for patients having

Diarrhea • Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3. • For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours. Bullous and Exfoliative Skin Disorders • Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials. In the pivotal study, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction.

ASCOPost.com | JUNE 10, 2014

PAGE 17

American Society of Breast Surgeons Annual Meeting ed the analysis of morbidity, including the predictive value of treatment factors.

tive infections, and other conditions. Lymphedema at 1 year post-treatment was observed in 25% and 15%, respectively (P < .001), and in 59% of the 27 patients who received both axillary lymph node dissection plus axillary radiotherapy (P < .001 vs axillary radiotherapy). After 5 years, the rates of lymphedema were 21%, 10%, and 58%, respectively

Surgical Complications Patients receiving axillary dissection had an overall surgical complication rate of 22.6% vs 9.0% for the axillary radiotherapy group (P < .001). This included higher rates of hemorrhage, postopera-

ASCO POST

(P < .001 vs axillary radiotherapy). The independent risk factors for the development of lymphedema within the first year were treatment with axillary lymph node dissection, which carried more than twice the risk vs axillary radiotherapy, or treatment with the combination, where the risk was more than sevenfold; a body mass index > 25 kg/m2, premenopausal

IN THE INDICATED POPULATION OF PATIENTS WITH COMMON MUTATIONS*

GILOTRIF: Nearly double the PFS vs pemetrexed/cisplatin1 Progression-free survival (PFS) by independent review (common mutations*)1

Estimated PFS probability

1.0

• 30.3 months OS with GILOTRIF vs 26.2 months with pemetrexed/ cisplatin in patients with common EGFR mutations (HR: 0.82; 95% CI, 0.59-1.14)2,3

GILOTRIF (40 mg orally once daily; n=204) Pemetrexed/cisplatin (500 mg/m2 / 75 mg/m2 every 3 weeks, up to 6 cycles; n=104)

13.6 13.6 months

0.8

Overall survival (OS)

Common mutations population1,a,b

Median PFS in LUX-Lung 3

months

HR: 0.47 (95% CI, 0.34-0.65)

0.6

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reduction in risk of death or progression

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months

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In a prespecified subgroup analysis of patients with exon 19 deletions or exon 21 L858R point mutations. Measured by an independent central radiology review.

– More than 70% of patients in LUX-Lung 3 received subsequent treatment at progression4 LUX-Lung 3: A randomized, multicenter, openlabel trial that assessed the efficacy and safety of GILOTRIF 40 mg orally once daily (n=230) vs up to 6 cycles of pemetrexed/cisplatin (n=115) as 1st-line therapy in patients with EGFR mutation-positive mNSCLC. Randomization was stratified according to EGFR mutation status (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The primary endpoint was PFS (assessed by independent review).2 CI=confi dence interval; HR=hazard ratio. *Common mutations=Del19 and L858R.

• Common EGFR mutations (n=308)2-4 – Del19 (n=170) • 13.7 months median PFS for GILOTRIF vs 5.6 months for pemetrexed/cisplatin (HR: 0.28; 95% CI, 0.18-0.44) • 31.6 months median OS for GILOTRIF vs 21.1 months for pemetrexed/cisplatin (HR: 0.55; 95% CI, 0.36-0.85) – L858R (n=138) • 10.8 months median PFS for GILOTRIF vs 8.1 months for pemetrexed/cisplatin (HR: 0.73; 95% CI, 0.46-1.17) • 27.2 months median OS for GILOTRIF; pemetrexed/cisplatin not estimable (HR: 1.30; 95% CI, 0.76-2.23) • Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations – Uncommon mutations (n=37)2,3,5 • There were 26 GILOTRIF-treated patients in the “other” (uncommon) EGFR mutations subgroup, which consisted of 9 unique mutation patterns • Median PFS: 2.8 months with GILOTRIF vs 9.9 months with pemetrexed/cisplatin (HR: 1.89; 95% CI, 0.84-4.28) • Median OS: 15.9 months with GILOTRIF; pemetrexed/cisplatin not estimable (HR: 3.08; 95% CI, 1.04-9.15)

SELECTED IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD) • ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In the pivotal study, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients. • Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD. Please see full Important Safety Information and brief summary of full Prescribing Information on adjacent pages. Learn more at www.GILOTRIF.com. References: 1. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. doi:10.1200/JCO.2012.44.2806. 2. Gilotrif ® (afatinib) tablets Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; November 2013. 3. Data on file. Boehringer Ingelheim. OS tables. 4. Data on file. Boehringer Ingelheim. CTR. 5. Data on file. Boehringer Ingelheim. Other mutations PFS table.

TEST. IDENTIFY. TREAT.

status, and treatment on the dominant side also raised the risk for lymphedema. Paresthesia of the arm was observed in 10% after axillary lymph node dissection and 9% after axillary radiotherapy. Shoulder mobility decreased temporarily, particularly during the first year in both treatment arms. Risk factors for continued on page 18

The ASCO Post | JUNE 10, 2014

PAGE 18

American Society of Breast Surgeons Annual Meeting Axillary Radiotherapy vs Lymph Node Dissection

sive axillary lymph node dissection. “Our morbidity data strongly support radiotherapy as the preferred treatment,” Dr. Donker concluded. Deanna J. Attai, MD, of the Center for Breast Care in Burbank, California, who moderated the press briefing, commented, “We have been performing fewer axillary dissections as there is a growing

continued from page 17

shoulder problems at 1 year included treatment with axillary lymph node dissection (as compared to axillary radiotherapy), the addition of isolated supraclavicular radiotherapy after axillary lymph node dissection, and more exten-

body of literature demonstrating no local recurrence or survival benefit as well as an increased rate of complications. However, there are still patients for whom an axillary dissection may be indicated. This study demonstrates that we do have alternatives for reducing local recurrence rates and can safely avoid surgery and the associated complications in some patients.” n

Disclosure: Drs. Donker and Attai reported no potential conflicts of interest.

Reference 1. Donker M, Rutgers E, van de Velde C, et al: Axillary lymph node dissection vs axillary radiotherapy: A detailed analysis of morbidity. ASBS Annual Meeting. Presented April 30, 2014.

ASCO POST

Indication and Important Safety Information INDICATION AND LIMITATION OF USE Indication: GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

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0.5

Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations. WARNINGS AND PRECAUTIONS Diarrhea • Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3. • For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for selfadministration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours. Bullous and Exfoliative Skin Disorders • Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials. In the pivotal study, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Interstitial Lung Disease (ILD) • ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to nonAsians (1.2%). In the pivotal study, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients. • Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD. Hepatic Toxicity • In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In the pivotal study, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF. • Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued. Keratitis • Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in the pivotal study, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with

GILOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration. Embryofetal Toxicity • GILOTRIF is Pregnancy Category D. Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. • Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF. ADVERSE REACTIONS • In GILOTRIF-treated patients (n=229) the most common adverse reactions in the pivotal study (≥20% all grades and vs pemetrexed/cisplatin-treated patients (n=111)) were diarrhea (96% vs 23%), rash/dermatitis acneiform (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%), decreased appetite (29% vs 55%), pruritus (21% vs 1%). • Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIFtreated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%). • More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1). DRUG INTERACTIONS Effect of P-glycoprotein (P-gp) Inhibitors and Inducers • Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib. • Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib. USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether afatinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, 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. Renal Impairment • GILOTRIF has not been studied in patients with severely impaired renal function. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated. Hepatic Impairment • GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

TEST. IDENTIFY. TREAT.

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PAGE 19

Announcements Smoking

IASLC Issues Statement on E-Cigarettes

here are currently no evidencebased guidelines to support the recommendation of e-cigarettes as a cessation tool to help patients stop smoking. In a recent article in the Journal of Thoracic Oncology,1 members of the International Association for the Study of

GILOTRIF™ (afatinib) tablets, for oral use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. INDICATIONS AND USAGE: GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations. DOSAGE AND ADMINISTRATION: Patient Selection: Select patients for the first-line treatment of metastatic NSCLC with GILOTRIF based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens [see Indications and Usage]. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose: The recommended dose of GILOTRIF is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Take GILOTRIF at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose. Dose Modification: Withhold GILOTRIF for any drug-related adverse reactions of: NCI CTCAE* Grade 3 or higher; Diarrhea of Grade 2 or higher persisting for 2 or more consecutive days while taking anti-diarrheal medication [see Warnings and Precautions]; Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [see Warnings and Precautions]; Renal dysfunction of Grade 2 or higher. Resume treatment when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute GILOTRIF at a reduced dose, i.e., 10 mg per day less than the dose at which the adverse reaction occurred. Permanently discontinue GILOTRIF for: Life-threatening bullous, blistering, or exfoliative skin lesions [see Warnings and Precautions]; Confirmed interstitial lung disease (ILD) [see Warnings and Precautions]; Severe drug-induced hepatic impairment [see Warnings and Precautions]; Persistent ulcerative keratitis [see Warnings and Precautions]; Symptomatic left ventricular dysfunction; Severe or intolerable adverse reaction occurring at a dose of 20 mg per day. P-gp Inhibitors: For patients who require therapy with a P-glycoprotein (P-gp) inhibitor, reduce GILOTRIF daily dose by 10 mg if not tolerated. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated [see Drug Interactions]. P-gp Inducers: For patients who require chronic therapy with a P-gp inducer, increase GILOTRIF daily dose by 10 mg as tolerated. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer [see Drug Interactions]. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS: Diarrhea: Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In Study 1, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks [see Adverse Reactions]. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3. For patients who develop prolonged Grade 2 diarrhea lasting more than *National Cancer Institute Common Terminology Criteria for Adverse Events, v 3.0

Lung Cancer (IASLC) Tobacco Control and Smoking Cessation Committee advised against recommending their use at this time. They urged clinicians to use evidence-based cessation strategies wherever possible, and recommended that clinicians consider the strong need

48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours. Bullous and Exfoliative Skin Disorders: Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials [see Adverse Reactions]. In Study 1, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions [see Dosage and Administration]. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration]. Interstitial Lung Disease (ILD): ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In Study 1, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients. Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD [see Dosage and Administration]. Hepatic Toxicity: In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF. Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function [see Dosage and Administration]. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued. Keratitis: Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in Study 1, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued [see Dosage and Administration]. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye [see Adverse Reactions]. Contact lens use is also a risk factor for keratitis and ulceration. Embryofetal Toxicity: Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the human exposure at the recommended dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

for cancer patients to stop smoking as soon as possible. This will help promote the most effective outcomes of their patients’ cancer therapy. The increasing popularity and availability of electronic cigarettes (e-cigarettes) in many countries has created

ASCO POST

Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF [see Use in Specific Populations]. ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling: Diarrhea [see Warnings and Precautions]; Bullous and Exfoliative Skin Disorders [see Warnings and Precautions]; Interstitial Lung Disease [see Warnings and Precautions]; Hepatic Toxicity [see Warnings and Precautions]; Keratitis [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 practice. The safety evaluation of GILOTRIF is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving GILOTRIF monotherapy at or above the recommended dose. Controlled Study: The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naïve GILOTRIF-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses. The median exposure was 11.0 months for patients treated with GILOTRIF and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the GILOTRIF arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on GILOTRIF and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (GILOTRIF 70%; pemetrexed/cisplatin 72%). Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients in Study 1 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%). Dose reductions due to adverse reactions were required in 57% of GILOTRIF-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%). Discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%). Clinical trials of GILOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In Study 1, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GILOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).

interest among health professionals and patients about the applicability of e-cigarettes in tobacco cessation activities. IASLC does recommend that research be done to evaluate the safety and efficacy of e-cigarettes as a cessacontinued on page 20

The ASCO Post | JUNE 10, 2014

PAGE 20

News E-Cigarettes continued from page 19

tion treatment in cancer patients and to help guide clinical practice.

Ongoing Initiatives Through the IASLC Tobacco Control and Smoking Cessation Committee, the association is committed to making

policymakers, association members, and the public aware of the benefits of initiatives to reduce the further use of tobacco and the associated health problems including lung cancer. IASLC is connecting experts worldwide to share the growing evidence base with policymakers and works with the IASLC membership to share this information globally.

Table 1 Adverse Reactions Reported in ≥10% (including but not limited to ritonavir, cyclosporine A, of Gilotrif™ (afatinib) tablets-Treated ketoconazole, itraconazole, erythromycin, verapamil, Patients in Study 1 quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase expoPemetrexed/ sure to afatinib [see Dosage and Administration]. GILOTRIF Cisplatin Co-administration with oral dose of a P-gp n=229 n=111 inducer (rifampicin at 600 mg once daily for All Grade All Grade 7 days) decreased exposure to afatinib by 34%. Adverse Grades 3* Grades 3* Concomitant taking of P-gp inducers (including but Reaction (%) (%) (%) (%) not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF Gastrointestinal disorders can decrease exposure to afatinib [see Dosage and Diarrhea 96 15 23 2 Administration]. 1 Stomatitis 71 9 15 1 USE IN SPECIFIC POPULATIONS: Pregnancy: Cheilitis 12 0 1 0 Pregnancy Category D. Risk Summary: Based on Skin and subcutaneous tissue disorders its mechanism of action, GILOTRIF can cause fetal Rash/Dermatitis 90 16 11 0 harm when administered to a pregnant woman. acneiform2 Afatinib was embryotoxic and, in animals with Pruritus 21 0 1 0 maternal toxicity, led to abortions at late gestational Dry skin 31 0 2 0 stages in rabbits at doses of 5 mg/kg (approximately Infections and infestations 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater. If this drug Paronychia3 58 11 0 0 is used during pregnancy, or if the patient becomes Cystitis 13 1 5 0 pregnant while taking this drug, the patient should Metabolism and nutrition disorders be apprised of the potential hazard to the fetus [see Decreased Warnings and Precautions]. Animal Data: Admin29 4 55 4 appetite istration of afatinib to pregnant rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by Respiratory, thoracic and mediastinal AUC at the recommended human dose of 40 mg disorders daily) or greater during the period of organogeneEpistaxis 17 0 2 1 sis caused increased post implantation loss and, in Rhinorrhea 11 0 6 0 animals showing maternal toxicity, abortion at late Investigations gestational stages. In the same study, at the high dose level of 10 mg/kg (approximately 0.7 times Weight 17 1 14 1 the exposure by AUC at the recommended human decreased dose of 40 mg daily) there were reduced fetal General disorders and administration site weights, and increases in the incidence of runts, conditions as well as visceral and dermal variations. In an Pyrexia 12 0 6 0 embryofetal development study in rats, there were Eye disorders skeletal alterations consisting of incomplete or Conjunctivitis 11 0 3 0 delayed ossifications and reduced fetal weight at a *None of the adverse reactions in this table except stomatitis (one dose of 16 mg/kg (approximately twice the exposure patient on GILOTRIF [0.4%]) were Grade 4 in severity. at the recommended human dose of 40 mg daily). 1 Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal Nursing Mothers: It is not known whether afatinib is present in human milk. Afatinib was present ulceration 2 Includes group of rash preferred terms, acne, acne pustular, in the milk of lactating rats at concentrations 80dermatitis acneiform 150 times higher than those found in plasma from 1 to 3 Includes paronychia, nail infection, nail bed infection 6 hours after administration. Because many drugs Table 2 Adverse Reactions of Laboratory Abnor- are present in human milk and because of the malities from the Investigations SOC potential for serious adverse reactions in nursing Reported in ≥5% of GILOTRIF-Treated infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue Patients in Study 1 the drug, taking into account the importance of GILOTRIF Pemetrexed/ the drug to the mother. Pediatric Use: Safety n=229 Cisplatin and effectiveness of GILOTRIF in pediatric patients n=111 have not been established. Geriatric Use: Of the Adverse All Grades All Grades 3865 patients in the clinical studies of GILOTRIF, Reaction Grades 3-4 Grades 3-4 32% of patients were 65 years and older, while 7% (%) (%) (%) (%) were 75 years and older. No overall differences in safety were observed between patients 65 years and Alanine 11 2 4 0 over and younger patients. In Study 1, 39% of the amino345 patients were 65 years of age or older and transferase 4% were 75 years or older. No overall differences increased in effectiveness were observed between patients Hypokalemia1 11 4 5 4 65 years and older and younger patients. Females Aspartate 8 2 2 1 and Males of Reproductive Potential: Contraaminoception: Females: Counsel patients on pregnancy transferase planning and prevention. Advise female patients of increased reproductive potential to use highly effective contra1 Includes hypokalemia, blood potassium decreased ception during treatment with GILOTRIF, and for at SOC=system organ class least 2 weeks after the last dose of GILOTRIF. Advise DRUG INTERACTIONS: Effect of P-glycoprotein patients to contact their healthcare provider if they (P-gp) Inhibitors and Inducers: Oral administration become pregnant, or if pregnancy is suspected, of a P-gp inhibitor (ritonavir at 200 mg twice daily) while taking GILOTRIF [see Use in Specific Popu1 hour before administration of GILOTRIF increased lations]. Renal Impairment: GILOTRIF has not systemic exposure to afatinib by 48%. There was been studied in patients with severely impaired no change in afatinib exposure when ritonavir was renal function (creatinine clearance [CLcr] administered simultaneously with or 6 hours after <30 mL/min). Adjustments to the starting dose of GILOTRIF. Concomitant taking of P-gp inhibitors GILOTRIF are not considered necessary in patients

For more information on this statement and other Tobacco Cessation information, visit: www.iaslc.org /patient-resources/tobacco-cessation-0 n Reference 1. Cummings KM1, Dresler CM, Field JK, et al: E-cigarettes and cancer patients. J Thorac Oncol 9:438-441, 2014.

ASCO POST

with mild (CLcr 60-89 mL/min) renal impairment. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated. Hepatic Impairment: GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Adjustments to the starting dose of GILOTRIF are not considered necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated. OVERDOSAGE Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of GILOTRIF (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase (<1.5 times upper limit of normal [ULN]). Both subjects recovered. PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Patient Information). Diarrhea: Advise patients that diarrhea occurs in nearly all patients who receive GILOTRIF. Inform patients that diarrhea may result in dehydration and renal impairment if not treated. Advise patients to notify their physician if diarrhea develops and to seek medical attention promptly for severe or persistent diarrhea [see Warnings and Precautions (5.1) and Adverse Reactions]. Bullous and Exfoliative Skin Disorders: Advise patients to minimize sun exposure with protective clothing and use of sunscreen while taking GILOTRIF [see Warnings and Precautions]. Interstitial Lung Disease: Advise patients to immediately report any new or worsening lung symptoms, or any combination of the following symptoms: trouble breathing or shortness of breath, cough, fever [see Warnings and Precautions]. Hepatic Toxicity: Advise patients that they will need to undergo liver function monitoring periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy) [see Warnings and Precautions]. Keratitis: Advise patients to immediately report eye problems (e.g., eye pain, swelling, redness, blurred vision, or other vision changes) [see Warnings and Precautions]. Left Ventricular Dysfunction: Advise patients to contact a healthcare professional immediately for any of the following: new onset or worsening shortness of breath or exercise intolerance, cough, fatigue, swelling of the ankles/legs, palpitations, or sudden weight gain [see Dosage and Administration and Adverse Reactions]. Instructions for Taking GILOTRIF: Advise patients to take GILOTRIF on an empty stomach at least 1 hour before or 2 hours after eating [see Dosage and Administration]. Advise patients not to take a missed dose within 12 hours of the next dose. Embryofetal Toxicity: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after taking the last dose of GILOTRIF [see Warnings and Precautions and Use in Specific Populations]. Nursing Mothers: Advise patients to discontinue nursing while taking GILOTRIF [see Use in Specific Populations)]. Copyright 2013 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Revised: November 2013 GF-BS (11-13) GF592915PROF

About the IASLC The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated to the study of lung cancer. Founded in 1974, the association’s membership includes more than 3,500 lung cancer specialists in 80 countries. To learn more about IASLC, visit www.iaslc.org.

Hookah Tobacco Smoking Among Students

ducational campaigns meant to dissuade college students from initiating hookah tobacco smoking may be more successful if they combat positive perceptions of hookah use as attractive and romantic, rather than focusing solely on the harmful components of hookah tobacco smoke, a new University of Pittsburgh School of Medicine study found.1 Researchers analyzed a sample of 569 first- and second-year University of Florida college students who were surveyed twice over a 7-month period about their attitudes, knowledge, and behaviors regarding hookah smoking. During that time, 13% of the students initiated hookah tobacco use. The students were more likely to initiate hookah use if they had positive attitudes toward hookah smoking. “Hookah tobacco smoking does not seem to be hampered by many of the negative social stigmas of cigarette smoking,” said lead author Jaime Sidani, PhD, MPH, Senior Research Specialist in the Program for Research on Media and Health (PROMH) at University of Pittsburgh School of Medicine. Senior author Brian Primack, MD, PhD, Director of PROMH, added that regulation of hookah tobacco smoking and marketing in the United States is confusing and less rigorous than laws meant to prevent cigarette smoking, which may contribute to misperceptions about hookah smoking. n Disclosure: This research was supported by National Cancer Institute grant no. R01CA140150 and the Steven Manners Memorial Fund at Pitt’s University Center for Social & Urban Research.

Reference 1. Sidani JE, Shensa A, Barnett TE, et al: Knowledge, attitudes, and normative beliefs as predictors of hookah smoking initiation: A longitudinal study of university students. Nicotine Tob Res 16(6):647-654, 2014.

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In the Clinic Hematology

Mercaptopurine Oral Suspension for Acute Lymphoblastic Leukemia 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.

n April 28, 2014, an oral suspension of mercaptopurine (Purixan) was approved for use in patients with acute lymphoblastic leukemia (ALL) as part of a combination regimen.1,2 Mercaptopurine has been available only as a 50 mg tablet since its initial approval in 1953. Treatment of children with a 50-mg tablet is complicated by the ranges of age and weight that make body surface area dosing and dose adjustments difficult. Tablets also are not an ideal dosage form for children aged < 6 years. The current formulation is a 20-mg/ mL oral suspension, which offers the advantage of more accurate delivery of desired doses to children with a wide range of weights using a consistent administration schedule and more flexibility in dose adjustment. The commercially produced suspension is more likely to provide a more consistent dose of mercaptopurine than compounded formulations.

Pivotal Study Approval was based on assessment of the bioequivalence of mercaptopurine from 50 mg Purinethol tablets and mercaptopurine from the oral suspension in a single-dose crossover clinical pharmacology study conducted in 62 healthy adult subjects under fasting conditions. Bioequivalence was demonstrated based on the primary pharmacokinetic parameters of area under the concentration-time curve (AUC) (0-t) and AUC(0-∞). Maximum con-

OF NOTE Mercaptopurine activation occurs via HGPRTase and several enzymes to form 6-thioguanine nucleotides, incorporation of which into nucleic acids (instead of purine bases) results in cell-cycle arrest and cell death.

centration (Cmax) was not bioequivalent, with mean Cmax being 34% higher with the oral suspension. Other clinical studies have shown that the absorption of an oral dose of mercaptopurine is incomplete and variable, averaging approximately 50% of the administered dose, and the factors affecting absorption are unknown. Following a single 50-mg dose of mercaptopurine oral suspension under fasting conditions, median AUC was 136 h*ng/mL (range = 74.2–264.8 h*ng/mL) and Cmax was 95 ng/mL (range = 39.5–204 ng/mL).

How It Works Mercaptopurine activation occurs via hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) and several enzymes to form 6-thioguanine nucleotides, incorporation of which into nucleic acids, instead of purine bases, results in cell-cycle arrest and cell death. Mercaptopurine competes with hypoxanthine and gua-

priate dosing requires periodic monitoring of absolute neutrophil count and platelet count to assure sufficient drug exposure to maintain absolute neutrophil count at a desirable level and to adjust for excessive hematologic toxicity. Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for

OF NOTE Mercaptopurine carries warnings/ precautions for myelosuppression, hepatotoxicity, immunosuppression, and embryo-fetal toxicity.

severe toxicity from conventional doses of mercaptopurine and generally require dose reduction. Testing for TPMT gene polymorphism should be considered in patients who experience severe bone marrow toxicities. Homozygous deficient patients may require a dose reduction of up to 90%. Most patients with

Mercaptopurine Oral Suspension for ALL ■■ An oral suspension of mercaptopurine (Purixan) was approved for use in patients with acute lymphoblastic leukemia as part of a combination regimen. ■■ The starting dose of mercaptopurine in multiagent combination chemotherapy maintenance regimens in ALL is 1.5 to 2.5 mg/kg (50 to 75 mg/m2) as a single daily dose; continued appropriate dosing requires monitoring of absolute neutrophil count and platelet count.

nine for HGPRTase and is converted to thioinosinic acid. This intracellular nucleotide inhibits several reactions involving inosinic acid, including the conversion of inosinic acid to xanthylic acid and adenylic acid. Methylation of thioinosinic acid produces 6-methylthioinosinate. Both have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis.

How It Is Given The starting dose of mercaptopurine in multiagent combination chemotherapy maintenance regimens in ALL is 1.5 to 2.5 mg/kg (50 to 75 mg/m2) as a single daily dose. Continuation of appro-

heterozygous TPMT deficiency have tolerated recommended mercaptopurine doses, with some requiring dose reduction based on toxicities.

Safety Profile Based on multicenter cooperative group ALL trials, the most common adverse events in > 20% of patients are anemia, neutropenia, lymphopenia, and thrombocytopenia. Adverse events occurring in 5% to 20% of patients include anorexia, nausea, vomiting, diarrhea, malaise, and rash. Rare adverse events occurring in < 5% include urticaria, hyperuricemia, oral lesions, elevated transaminases, hyperbilirubinemia, hyperpigmentation, and pancreatitis. Oral lesions resemble thrush rather than antifolic ulcerations.

Delayed or late toxicities include hepatic fibrosis, hyperbilirubinemia, alopecia, pulmonary fibrosis, oligospermia, and secondary malignancies. Drug fever has been rarely reported with mercaptopurine; every attempt should be made to exclude more common causes of pyrexia, such as sepsis, in patients with acute leukemia. Mercaptopurine carries warnings/ precautions for myelosuppression, hepatotoxicity, immunosuppression, and embryo-fetal toxicity. Complete blood count should be monitored and the mercaptopurine dose adjusted for severe neutropenia and thrombocytopenia. Patients with repeated severe myelosuppression should be evaluated for TPMT deficiency. Serum transaminase levels, alkaline phosphatase, and bilirubin levels should be monitored weekly at the start of therapy and monthly thereafter. Due to immunosuppression associated with maintenance chemotherapy for ALL, response to all vaccines may be diminished and there is a risk of infection with live virus vaccines. Immunization guidelines for immunocompromised children should be consulted. n References 1. U.S. Food and Drug Administration: Mercaptopurine. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm395156.htm. 2. PURIXAN™ (mercaptopurine) oral suspension prescribing information, NOVA Laboratories Limited, April 2014. Available at www.accessdata.fda.gov/drugsatfda_ docs/label/2014/205919s000lbl.pdf.

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).

Caris Life Sciences: The World’s Most Comprehensive Molecular Profiling Service. There is a reason why more physicians choose Caris Life Sciences.® We provide drug associations that are Evidenced Based and Clinically Actionable. No other company can provide you with more potential treatment options for your patients:

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3 600+ NGS genes analyzed

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To learn more, please visit www.CarisLifeSciences.com. ©2014 Caris Life Sciences and affiliates. All rights reserved. Other trademarks are the property of their respective owners. **CLIA & ISO launch Q3 2014. TN0204

Technologies Used:

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Actionable Drug/Target Associations

• PyroSequencing - DNA Next-Generation Sequencing (NGS) - DNA Fluorescence in situ Hybridization (FISH) - DNA • Fragment Analysis - DNA & RNA Chromogenic in situ Hybridization (CISH) - DNA • Quantitative Polymerase Chain Reaction (qPCR - cobas®) - DNA Immunohistochemistry (IHC) - Protein Sanger Sequencing - DNA

††

abarelix

carboplatin†

degarelix

everolimus†

gemcitabine

leuprolide

panitumumab†

temozolomide†

triptorelin

abiraterone

cetuximab†

docetaxel

exemestane

goserelin

liposomal-doxorubicin†

pemetrexed

temsirolimus†

vandetanib

afatinib

cisplatin†

doxorubicin†

fluorouracil

imatinib

megestrol acetate

pertuzumab†

topotecan

vemurafenib

anastrozole

crizotinib

enzalutamide

flutamide

irinotecan

nab-paclitaxel

sunitinib

toremifene

bicalutamide

dabrafenib

epirubicin†

fulvestrant

lapatinib†

oxaliplatin

tamoxifen

trametinib

capecitabine

dacarbazine†

erlotinib†

gefitinib†

letrozole

paclitaxel

T-DM1†

trastuzumab†

† Associations driven by profiling multiple analytes.

96%

of Caris Molecular Intelligence actionable drug/target associations are based on Level 1or Level 2 evidence

Evidence Level:

• Level 1: Randomized, controlled trials; meta-analyses • Level 2: Non-randomized controlled trials, single arm, cohort/case-control studies • Level 3: Expert committee opinion, case reports or series Level 1

Caris Molecular Intelligence incorporates

multiple technologies to profile actionable targets.

More than 25 therapies associated with companion markers and NCCN-Guidelines®

trastuzumab lapatinib pertuzumab T-DM1 everolimus

Level 2

46%

Level 3

CISH crizotinib everolimus lapatinib pertuzumab T-DM1 trastuzumab

50% 4%

afatinib cetuximab erlotinib gefitinib imatinib panitumumab

Sequencing (NGS, Sanger)

FISH IHC

dabrafenib trametinib vemurafenib

PCR everolimus hormone therapy lapatinib pertuzumab T-DM1 trastuzumab

FoundationOne™ from Foundation Medicine* Technologies Used: Next-Generation Sequencing (NGS) - DNA

Actionable Drug/Target Associations

††

afatinib

everolimus

temsirolimus

carboplatin

gefitinib

trametinib

cetuximab

imatinib

trastuzumab

cisplatin

oxaliplatin

vandetanib

dabrafenib

panitumumab

vemurafenib

dacarbazine

sunitinib

erlotinib

temozolomide

The same 19 drug/target associations are included in the 51 drug/target associations for Caris Molecular Intelligence. * Based on information found at www.foundationone.com. † † Drug/target associations supported by Levels 1, 2 or 3 evidence.

600+ NGS Genes

FoundationOne™

236

NGS Genes

** CLIA & ISO launch Q3 2014. The same 236 NGS genes are included in the 600+ NGS profile for Caris Molecular Intelligence.

The ASCO Post | JUNE 10, 2014

PAGE 24

Expert’s Corner Neuro-oncology

Glioblastoma: Can We Make This Intractable Disease Tractable? By Ronald Piana

n the clinical array of brain tumors, glioblastoma is the most difficult to treat, and despite decades of research and the advent of new therapies, patients with glioblastoma continue to have a very poor prognosis. Leading brain tumor experts at the recent 25th Annual Cancer Progress Conference in New York discussed this difficult clinical scenario. The ASCO Post spoke with the chair of the brain tumor session, Minesh P. Mehta, MD, FASTRO, Medical Director of the Maryland Proton Treatment Center at the University of Maryland, Baltimore.

A Lethal Tumor Please give us a brief natural history of glioblastoma. Glioblastoma is one of the most malignant neoplasms that affect mankind. It is a relatively uncommon tumor within the wider scope of cancer, but it is one of the most common brain tumors, accounting for almost 20% of all new primary brain tumors. Its clinical significance rests largely on its lethality, and most patients with glioblastoma will die within the first year of diagnosis. The historic median survival has ranged from 6 to 14 months. It usually presents in the elderly and progresses rapidly. In fact, on computed tomography (CT) scan, we can see a doubling of tumor size within several days. What are the clinical challenges of such a fast-growing tumor? Because of such rapid growth within the confines of the skull, it produces considerable edema of the brain. Therefore, we have to manage both the tumor and the consequential mass effect and swelling. The tumor is also highly infiltrative without a well-defined margin that can easily be resected by a neurosurgeon. The tumor we see on a magnetic resonance imaging (MRI) scan is the tip of the iceberg because, even if resected, microscopic infiltrative disease is almost universally present; for most patients with glioblastoma, a total resection is not achievable.

Standard of Care What are the current management strategies in glioblastoma? The standard of care is maximal surgical resection followed by combination adjuvant therapy, which is typically 6 weeks of radiation to a total of about

a 60-Gy dose in conjunction with the oral alkylating agent temozolomide given every day during the course of radiation therapy. After the 6 weeks of radiation, patients usually stay on maintenance temozolomide for several months, up to a maximum of 12 or so months, depending on how they tolerate the therapy and whether the disease is stable on treatment. What kind of survival are we seeing after such aggressive management? Depending on certain patient characteristics, median survival with this standard-of-care approach can range anywhere from 12 to 16 months. We have recognized that a subset of patients appear to do better, especially with this regimen, when we test for the activity of a specific enzyme—O6-alkylguanine-DNA alkyltransferase, known as MGMT.

groups, the median survival is still very poor, and long-term cures are quite uncommon in glioblastoma.

Role of Antiangiogenic Agents Given the poor prognosis for survival, where do we go from here? Fortunately, there’s much interest in new therapies. In the past few years, antiangiogenic agents have received a lot of attention, which is not surprising since the tumor induces a substantial degree of neovascularization and secretes a host of proangiogenic factors. In fact, glioblastoma might be the most angiogenic known neoplasm. Antiangiogenic agents were first used in recurrent glioblastoma with a modest level of activity. On MRI scan, we clearly see a dramatic response. There also appears to be clinical benefit with the reduction of swelling on the

The nihilism once associated with glioblastoma is slowly diminishing because we are beginning to establish strategies that are not necessarily home runs, but singles. Each single is a step closer in identifying subsets of patients who will derive long-term benefits from therapy. —Minesh P. Mehta, MD, FASTRO

The test specifically looks at the silencing of MGMT at the epigenetic level. If the enzyme is silenced, the tumor is therefore MGMT-methylated, and the patient will have superior outcome compared with a patient whose tumor does not halt the activity of the MGMT enzyme. So methylation testing has become common practice for many patients with glioblastoma. Even patients with unmethylated tumors appear to have a modest degree of benefit with the addition of temozolomide. That said, this is a fairly controversial issue, and some in the community contend that the small benefit we see in unmethylated tumors might actually be the result of our failure to detect all patients with methylated tumors. There is no question that glioblastoma patients with methylated MGMT derive the maximum benefit from combination therapy with temozolomide. However, even in the best of these

brain, and the breakdown of the bloodbrain barrier along with the consequential edema all seem to resolve rather quickly. In short, we have highly symptomatic patients who become functional in a matter of days to weeks after receiving these agents. So there is definitely a place for them in the setting of recurrent symptomatic glioblastoma. Are we optimistic about seeing durable survival with these agents? It is still unclear whether antiangiogenic agents produce a genuine, robust response and survival advantage in the recurrent setting. Therefore, the agents were moved upfront to assess survival benefit. The most widely studied antiangiogenic agent is bevacizumab (Avastin), and earlier this year, two major trials of the drug in glioblastoma were reported in The New England Journal of Medi-

cine—an industry-funded European trial called AVAglio and a National Cancer Institute–funded intergroup trial.1,2 In both trials, the patients were randomly assigned to a backbone of temozolomide and radiation therapy to compare how well they work when given together with or without bevacizumab. In terms of overall survival, there was no categorical benefit seen in either trial. Some argue that the trials’ crossover design might have taken away from any survival advantage. But if the agent were truly producing a substantial survival benefit, we would have seen that. So even though angiogenic agents clearly have activity in this setting, our ability to convert that activity into meaningful survival prolongation is still not there. These trials also assessed whether there might be other benefits, such as progression-free survival, which was demonstrated in one of the trials but not the other. The statistical methodology and definitional differences could have influenced why this endpoint was positive in one trial, but not another. But in terms of overall survival, the use of antiangiogenic agents is clearly not a home run. That said, exploratory work is being conducted to see if there are subsets of patients in whom new agents can be used on other targetable pathways to produce durable responses in glioblastoma. This is a highly heterogeneous tumor, so we need to look at multiple subsets of patients and match those patients with the correct agent.

Other Approaches What other novel strategies are being looked at? Traditionally, we have viewed brain tumors as existing in a relatively immune-privileged site, where the penetrability of immune modulators was assumed to be very limited. This concept is now being challenged, and it appears that a number of immune approaches, such as vaccines, could be developed for this tumor. About 20% to 40% of glioblastomas express a variant form of epidermal growth factor receptor (EGFR). We can use this to develop an anti-EGFR vaccine strategy, and some early phase II trials in this area have already shown promise. We are also looking at immune checkpoint inhibitors that target CTLA-4 activity or PD-1, which could have a role in this disease. continued on page 25

ASCOPost.com | JUNE 10, 2014

PAGE 25

News Health-Care Policy

AACR Calls on Congress to Support Cancer Research Funding to Meet the Challenges of Our Aging Population

reat progress is being made in the battle against cancer, but a renewed commitment of federal support for medical research is needed to speed its eradication, according to leaders of the American Association for Cancer Research (AACR), commenting in connection with a recent Senate

younger than 65. However, while the majority of cancers occur in people 55 and older, the fact remains that hundreds of thousands of people under the age of 55 will also develop cancer each year.

Special Committee Harold Varmus, MD, Director of the National Cancer Institute (NCI), and Thomas A. Sellers, PhD, MPH, Executive Vice President and Director of the

Moffitt Research Institute at the Moffitt Cancer Center in Tampa, Florida, and a former member of the AACR Board of Directors, will participate in a panel of continued on page 26

Trim: 7.625 X 10.5

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

Harold Varmus, MD

hearing on “The Fight Against Cancer: Challenges, Progress, and Promise.” Aging is the single biggest risk factor for developing cancer, with 75% of new cancer cases occurring in individuals over age 55, according to demographic experts. By the year 2030, the number of cancer cases in Americans over age 65 is expected to increase by 67%, compared with only an 11% increase in incidence for Americans

Go with FASLODEX.

Glioblastoma continued from page 24

Closing Thoughts

Any last thoughts on this perplexing clinical issue? It is fair to say that the nihilism once associated with glioblastoma is slowly diminishing because we are beginning to establish strategies that are not necessarily home runs, but singles. Each single is a step closer in identifying subsets of patients who will derive longterm benefits from therapy. We will learn from our failures and enhance our knowledge, which will eventually turn the tide in this disease. n

Disclosure: Dr. Mehta is a consultant for AbbiVe, BMS, Celldex, Elekta, Merck, Novocure, Novellos, Philips, and Roche; he has received research funding from Novocure; and is on the board of directors, with stock options, for Pharmacyclics.

References 1. Chinot OL, Wick W, Mason W, et al: Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709-722, 2014. 2. Gilbert MR1, Dignam JJ, Armstrong TS, et al: A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699-708, 2014.

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

Secondary Endpoint: Overall Survival (OS)1

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

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

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

• Not statistically signifcant as no adjustments were made for multiplicity2

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

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

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

Go with Confdence Learn more at www.faslodex.com/hcp

The ASCO Post | JUNE 10, 2014

PAGE 26

News Cancer Research Funding continued from page 25

distinguished scientists, advocates, and cancer survivors at a Senate Special Committee on Aging congressional hearing. “On behalf of the more than 34,000 members of the AACR, we wish to thank Senators Bill Nelson (D-FL) and Susan Collins (R-ME) for convening this impor-

Thomas A. Sellers, PhD, MPH

Margaret Foti, PhD, MD (hc)

tant cancer research hearing to discuss the relationship of aging to cancer,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. “The congressional hearing will highlight how cancer research is advancing at an amazing pace and is bringing new hope and significantly

Trim: 7.625 X 10.5

improved survival time to cancer patients everywhere,” she commented. “However, in order to continue the progress that has been made and to speed the eradication of this disease that affects so many around the world, Congress must step up and provide a major increase in funding for cancer research now,” Dr. Foti said.

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

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,†

FASLODEX 500 mg Showed a Comparable Safety Profle to FASLODEX 250 mg in CONFIRM1

• Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2

Additional Important Safety Information About FASLODEX (continued)

• Objective response rates (ORRs)‡ were not signifcantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2

• Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX

— Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

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

• The most common, clinically signifcant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot fash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent

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

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

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

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

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

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

2873001

10/13

ASCOPost.com | JUNE 10, 2014

PAGE 27

News Bulge in Cancer Cases “Because cancer is more likely to occur in older people, the aging of the baby boom generation is expected to create a bulge in cancer cases,” said Carlos L. Arteaga, MD, AACR President, Professor of Medicine and Cancer Biology, and Associate Director for Clinical Research at the Vanderbilt-Ingram

L. Arteaga, MD Trim:Carlos 7.625 X 10.5

FASLODEX® (fulvestrant) Injection

Cancer Center of Vanderbilt University in Nashville, Tennessee. “With the aging of our population, demographic experts predict there will be a dramatic increase in the number of cancer diagnoses and mortalities,” he said. “Continued research and development of new therapies and the funding necessary to do so are imperative, not

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients Fulvestrant 500 mg N=361

Fulvestrant 250 mg N=374

Injection Site Pain

42 (11.6)

34 (9.1)

Headache

28 (7.8)

25 (6.7)

DOSAGE AND ADMINISTRATION

Back Pain

27 (7.5)

40 (10.7)

Recommended Dose

Fatigue

27 (7.5)

24 (6.4)

Pain in Extremity

25 (6.9)

26 (7.0)

Asthenia

21 (5.8)

23 (6.1)

24 (6.6)

22 (5.9)

Nausea

35 (9.7)

51 (13.6)

Vomiting

22 (6.1)

21 (5.6)

Anorexia

22 (6.1)

14 (3.7)

Constipation

18 (5.0)

13 (3.5)

Bone Pain

34 (9.4)

28 (7.5)

Arthralgia

29 (8.0)

29 (7.8)

Musculoskeletal Pain

20 (5.5)

12 (3.2)

Cough

19 (5.3)

20 (5.3)

Dyspnea

16 (4.4)

19 (5.1)

BRIEF SUMMARY For full Prescribing Information, see package insert. INDICATIONS AND USAGE FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

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

Dose Modification Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Speciﬁc Populations].

Administration Technique

The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged. 2. Remove perforated patient record label from syringe. 3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.” 4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap. 5. Twist to lock the needle to the luer connector. 6. Remove needle sheath. 7. Remove excess gas from the syringe (a small gas bubble may remain). 8. Administer intramuscularly slowly in the buttock. 9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered. 10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector. 11. Repeat steps 1 through 10 for second syringe. For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

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

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

Hepatic Impairment The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration]. FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Speciﬁc Populations].

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

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

and Adverse Reaction Body as a Whole

Vascular System Hot Flash Digestive System

Musculoskeletal System

Respiratory System

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms. Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis. Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2). Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day. Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5% Body System FASLODEX 250 mg Anastrozole 1 mg N=423 N=423 and Adverse Reactiona (%) (%) Body as a Whole Asthenia Pain Headache Back Pain Abdominal Pain Injection Site Painb Pelvic Pain Chest Pain Flu Syndrome Fever Accidental Injury Cardiovascular System Vasodilatation Digestive System Nausea Vomiting Constipation Diarrhea Anorexia Hemic and Lymphatic Systems Anemia

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

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

only to continue to treat and even cure cancer in all patients, but also to meet the increased national need for improved care of older patients with this disease.” Dr. Arteaga added, “Cancer already costs the country more than $215 billion per year in direct and indirect costs, and this burden will increase as the number of cases grows.” n

The ASCO Post | JUNE 10, 2014

PAGE 28

Novel Agents Dermatologic Oncology

Phase III Study of Talimogene Laherparepvec in Patients With Metastatic Melanoma: Overall Survival Analysis Reported

mgen recently announced top-line results from the primary overall survival analysis of a phase III trial in melanoma, which evaluated the efficacy and safety of talimogene laherparepvec

(also known as T-VEC) for the treatment of unresected stage IIIB, IIIC, or IV melanoma compared to treatment with subcutaneous granulocyte macrophage colony-stimulating factor Trim: 7.625 X 10.5

(GM-CSF, Leukine). Talimogene laherparepvec, an oncolytic immunotherapy, is derived from herpes simplex virus type 1. The drug is designed to selectively replicate within tumors and to

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.

Study Details The global, randomized, open-label phase III trial enrolled patients with unresected stage IIIB, IIIC, or IV melanoma. Patients were randomized 2:1 to receive either talimogene laherparepvec every 2 weeks through direct tumor injection, or GM-CSF subcutaneously for the first 14 days of each 28-day cycle, for up to 18 months. Results showed that, while the primary endpoint of durable response rate was met (as previously reported), the secondary endpoint of overall survival was not met (P = .051). The estimated overall survival hazard ratio and improvement in median overall survival were similar to what was previously reported at the interim analysis.

Survival Trend Warrants Further Research “We remain encouraged that the study met its primary endpoint of achieving durable responses in patients with metastatic melanoma,” said Sean E. Harper, MD, Executive Vice President of Research and Development at Amgen. “We missed statistical significance on the secondary endpoint of overall survival but the strong trend in survival benefit supports further research of talimogene laherparepvec to better understand its role in melanoma, both as a single-agent and in combination with other therapies.” The most frequent adverse events observed in this trial were fatigue, chills, and pyrexia. The most common serious adverse events include disease progression, cellulitis, and pyrexia. n

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

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.

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.

produce GM-CSF to enhance systemic antitumor immune responses.

SafetyGlide™ is a trademark of Becton Dickinson and Company. FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2873001 10/13

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Society of Surgical Oncology Annual Cancer Symposium Gastrointestinal Oncology

Surveillance After Colon Cancer Surgery: Too Much of a Good Thing? By Shalmali Pal

inding salvageable colon cancer recurrence is akin to finding a needle in a haystack, rendering routine patient surveillance of little value. But finding that needle offers an opportunity for treating recurrent disease early, which makes surveillance worthwhile. These were the opposing views presented by two surgical oncology experts in a

Chang created a model of the yield of surveillance imaging with the assumption that computed tomography (CT) scanning had a 100% detection sensitivity for recurrence. He calculated that the recurrence rate after resection would be 5% for stage I disease, 15% for stage II, 30% for stage III, and 60% for stage IV disease.

Follow-up does not improve cancerrelated survival, is resource-inefficient, and does not improve quality of life, but may be a frequent source of inconvenience and anxiety [for patients]. —George J. Chang, MD, MS, FACS, FASCRS

“Great Debate” at the 2014 Society of Surgical Oncology (SSO) Annual Cancer Symposium in Phoenix.1 George J. Chang, MD, MS, FACS, FASCRS, made the case for colorectal cancer surveillance as a waste of resources, while Elin R. Sigurdson, MD, PhD, FACS, defended the value of such surveillance.1 Dr. Chang is Associate Professor of Surgical Oncology, Chief of Colon and Rectal Surgery, Director of Clinical Operations, Minimally Invasive and New Technologies in Oncologic Surgery Program, and Associate Medical Director of the Colorectal Center at The University of Texas MD Anderson Cancer Center in Houston. Dr. Sigurdson is Chief of the Division of General Surgery at Fox Chase Cancer Center in Philadelphia.

Three Strikes Against Surveillance Dr. Chang listed the three main goals of colorectal cancer surveillance: • Improve patient survival through detection of of potentially curable recurrence and metachronous tumors. • Detect asymptomatic recurrence for palliative therapy. • Offer psychological support and improve quality of life. However, Dr. Chang argued, surveilling these patients is expensive, does not improve survival, and does not lead to a better quality of life.

Cost Issues To address the issue of cost, Dr.

With a 15% salvage rate following recurrence and 5 years of follow-up, “the yield of a CT scan in stage I disease is 1%,” Dr. Chang explained. “The yield of a CT scan in stage III disease is 6% for recurrence. And if we look at the yield of salvageable recurrence, it’s 0.9% of all the imaging tests performed in stage III disease.” Working with this same model and calculating what he called “back of the envelope” figures, Dr. Chang said the total cost for the recommended chest, abdomen, and pelvic CTs would be $6,300 per patient per surveillance episode. The combined cost for other components of surveillance—carcinoembryonic antigen (CEA) testing, colonoscopy, and the office visit— would come in at $2,700. “Assuming a 5-year follow-up, we can see the total cost … is $38,500, assuming one CT scan per year. Assuming two CT scans per year—we know that a lot more imaging is performed than what I’ve indicated in this model—the cost is $70,000 for stage IV disease,” he said. “The cost of recurrence based on the numbers that I presented earlier is almost $1 million in stage I. The cost of one salvage is almost $4 million. In stage II, it’s not that much better; it’s $1.3 million for salvage and that’s not to say that the person survived.”

Survival Not Improved In terms of improving survival, multiple studies have demonstrated surveillance does not do the job, Dr. Chang said.

A Cochrane systematic review of intensive vs minimal follow-up in nonmetastatic colorectal cancer showed no effect on overall survival, no difference in disease-specific survival, and no difference in recurrence detection.2 A more recent study looked at the effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer. Those investigators reported that the number of deaths was not significantly different in the combined intensive monitoring groups (18.2%) vs the minimum follow-up group (15.9%). “If there is a survival advantage to any strategy, it is likely to be small,” they concluded.3 Dr. Chang cited interim analysis from the ongoing Gruppo Italiano di Lavoro per la Diagnosi Anticipata (GILDA) trial, which is evaluating follow-up of colon cancer patients after resection with curative intent. At a mean duration of follow-up of 14 months, the investigators found similar rates of relapse (15% vs 13%) and death (7% and 5%) in the intensive and less-intensive follow-up arms.4

Quality of Life “If we can’t find a difference in recurrence, and we can’t find a difference in cancer-specific survival, and we can’t find a difference in overall survival, can we at least improve the quality of life?” Dr. Chang asked. The answer is “no,” according to Dr. Chang, who relied on data from two

patients’ attitudes toward follow-up and what it meant to their quality of life turned in less-than-positive results. “Follow-up exams were burdensome for one in two patients,” Dr. Chang said in summarizing the findings. “One in three patients found that follow-up reminded them too much of their disease. There are potential harms to follow-up.”6 Dr. Chang concluded that “expending resources to find the needle in the haystack does not result in a clinically meaningful increase in the rate of detection of recurrence. Follow-up does not improve cancer-related survival. Follow-up is resource-inefficient. Follow-up does not improve quality of life, but may be a frequent source of inconvenience and anxiety [for patients].”

Surveillance: Worth Every Penny Dr. Sigurdson also began her talk by outlining why surveillance is done after colon cancer resection: • For early detection of recurrence, to increase incidence of resectable recurrence, and to improve survival with early initiation of therapy • To assess shared risk factors that may increase risks of second primary cancers • To assure patients they are “disease free” • As a mark of good practice Early detection means determining yearly recurrence risk and the natural tumor history. That way, surveillance

Early recognition of distant disease is beginning to make a difference. These early, intensive surveillance projects allow us to find those patients. —Elin R. Sigurdson, MD, PhD, FACS

studies—one in breast cancer and one in colon cancer—to prove his point. A study published in 1994 sought to determine the impact of follow-up testing on survival and health-related quality of life in patients with breast cancer. “The summary is that there’s no difference in quality of life among patients who received intensive surveillance and those who got minimalist care,” Dr. Chang stated.5 Finally, a study of colorectal cancer

can be directed at the most likely times and sites of recurrence. “You want to limit your resource expenses by focusing on the high-risk time,” Dr. Sigurdson stated. She cited data from two studies to demonstrate that the time and sites of recurrence in colorectal cancer are well known. A 2002 study found that the risk for second primary colon cancer was 1.5% at 5 years.7 Another study noted continued on page 30

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Society of Surgical Oncology Annual Cancer Symposium Surveillance After Colon Cancer Surgery continued from page 29

that distant recurrence in stage II and stage III disease was most likely in the first 3 years, and that risk tapered down by year 8. Having these data “allows us to modify the number of colonscopies that are done,” she explained. “When I was training, they were being done annually. We have been able to extend that out to 3, 5, and 10 years.”8

COST Trial An analysis of the Clinical Outcomes of Surgical Therapy (COST) trial looking at sites of recurrence found that liver and lung metastases, as well as locoregional recurrence, were the main areas of concern. The authors reported that patients with early-stage colon cancer have similar sites of recurrence and receive benefit from postrecurrence therapy similar to that seen in patients with latestage disease.9 Most important, according to Dr. Sigurdson, salvage resection was similar in both arms of COST (36% vs 37%), with about one-third of patients having resectable disease at recurrence. In a trial that focused on liver resection, about 40% of patients were alive at 5 years, with a median survival of 3.6 years.10 Moving on to the benefits of the early initiation of therapy, Dr. Sigurdson noted that median overall survival was 6 months when best supportive care was the only option. Survival rates jumped to 1 year after the introduction of fluorouracil chemotherapy. Now, with newer chemotherapy agents, survival is in the 30-month vicinity, she said. Dr. Sigurdson explained that these survival figures apply to patients with “a very good performance status. Patients who are identified with advanced disease and poor performance status, picked up by symptomatology, have a median survival of 2 years. So early recognition of distant disease is beginning to make a difference. These early, intensive surveillance projects allow us to find those patients.” Finally, surveillance allows clinicians to look for other cancers in colorectal cancer patients who have certain risk factors such as diabetes, obesity, and alcohol consumption.

Best Test? Dr. Sigurdson finished her argument with a question: What is the best test for surveillance? She also highlighted results from the FACS randomized trial led by John Primrose, MD, FRCS, indicating that patients with resectable disease were found by imaging or CEA testing. Most of the recurrences were detected by routine investigation, and among patients who had recurrence resected, 69% were still alive at a median follow-up of 4.4 years, she pointed out. Dr. Sigurdson concluded that colorectal cancer surveillance with CEA testing and at least one annual CT scan improved the chances of curative-intent surgery and overall survival. In addition,

John Primrose, MD, FRCS

[recurrence] is the same.… Our ability, therefore, to salvage is not that different.” Instead, Dr. Chang suggested a compromise. “We know that the risk of recurrence is the highest early on and that ‘very early’ recurrence is probably preexisting disease…. In fact, [surveillance at] a single point in time, such as

Pros and Cons of Postsurgical Surveillance in Colon Cancer Pros of Surveillance ■■ Colorectal cancer surveillance with CEA testing and at least one annual CT scan improved the chances of curative-intent surgery and overall survival. ■■ To optimize early detection, the clinician should determine yearly recurrence risk and the natural tumor history so that surveillance can be directed at the most likely times and sites of recurrence. Cons of Surveillance ■■ Studies have shown that intensive vs minimal follow-up in nonmetastatic colorectal cancer had no effect on overall survival, led to no difference in disease-specific survival, and made no difference in recurrence detection. ■■ Surveilling colon cancer patients is expensive and does not improve quality of life.

no studies have adequately demonstrated a negative impact on quality of life with colorectal cancer surveillance. Indeed, National Comprehensive Cancer Network (NCCN) guidelines call for CEA testing every 3 to 6 months for 2 years and then annual CT scanning up to 5 years, she said.

Debate Rebuttals In his response, Dr. Chang asked if surveillance was worth the cost. He emphasized, “I’m not arguing that we shouldn’t attempt salvage in patients in whom recurrence is identified. I’m certainly not arguing that salvage of recurrent disease [lacks benefit]. The point is, regardless of how we look for it—or don’t look for it—our ability to detect

at 1 or 2 years, may be enough to get the highest yield and greatest value on our investment.” Dr. Sigurdson argued that the best way to offer optimal care is to follow the guidelines for surveillance. She cited a study done by Dr. Chang and colleagues that found “survival benefit for patients with stage III and high-risk stage II colon cancer who received treatment that adhered to NCCN guidelines.”11 n

Disclosure: Dr. Chang reported relationships with Ethicon Endo-Surgery and Agendia. Drs. Sigurdson and Primrose reported no potential conflicts of interest.

References 1. Chang GJ, Sigurdson ER: Follow-up after colorectal surgery: Wasting resources? 2014 SSO Annual Cancer Symposium.

Presented March 15, 2014. 2. Jeffery M, Hickey E, Hider PN, et al: Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev (1):CD002200, 2007. 3. Primrose MD, Perera R, Gray A, et al: Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: The FACS randomized clinical trial. JAMA 311:263-270, 2014. 4. Grossmann EM, Johnson FE, Virgo KS, et al: Follow-up of colorectal cancer patients after resection with curative intent—the GILDA trial. Surg Oncol 13:119-124, 2004. 5. Ghezzi P, Magnanini S, Rinaldini M, et al: Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators. JAMA 271:1587-1592, 1994. 6. Stiggelbout AM, de Haes JC, Vree R, et al: Follow-up of colorectal cancer patients: Quality of life and attitudes towards follow-up J Cancer 75:914-920, 1997. 7. Green RJ, Metlay JP, Propert K, et al: Surveillance for second primary colorectal cancer after adjuvant chemotherapy: An analysis of Intergroup 0089. Ann Intern Med 136:261-269, 2002. 8. Sargent DJ, Patiyil S, Yothers G, et al: End points for colon cancer adjuvant trials: Observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 25:4569-4574, 2007. 9. Tsikitis VL, Malireddy K, Green EA, et al: Postoperative surveillance recommendations for early stage colon cancer based on results from the clinical outcomes of surgical therapy trial. J Clin Oncol 27:3671-3676, 2009. 10. Kanas GP, Taylor A, Primrose JN, et al: Survival after liver resection in metastatic colorectal cancer: Review and metaanalysis of prognostic factors. Clin Epidemiol 4:283-301, 2012. 11. Boland GM, Chang GJ, Haynes AB, et al: Association between adherence to National Comprehensive Cancer Network treatment guidelines and improved survival in patients with colon cancer. Cancer 119:1593-1601, 2013.

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Journal Spotlight Survivorship

Study Calls for Revisiting Guidelines for Screening Childhood Cancer Survivors at Risk of Congestive Heart Failure

ne of the first studies to analyze the effectiveness of screening survivors of childhood cancer for early signs of impending congestive heart failure found improved health outcomes but

suggests that less frequent screening than currently recommended may yield similar clinical benefit. The researchers, in a study published in the Annals of Internal Medicine,1 utilized a simulation-based

GAZYVATM (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 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 pre-existing 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 mgs 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

model to estimate the long-term benefits associated with routine screening. The current guidelines recommend that survivors treated with chemotherapy agents known to affect long-term heart

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)]. For 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 pre-existing 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 hypertensive medication as is suggested here.

health be screened as often as every year, with a schedule dependent on their level of congestive heart failure risk. The new study suggests that screening survivors less continued on page 32

The most common adverse reactions (incidence ≥10%) were: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in Tables 3 and 4 below are based on a total of 356 previously untreated patients with CLL during treatment with GAZYVA in combination with chlorambucil or with chlorambucil alone. 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 45 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 with ≥5% Incidence and ≥2% Greater in the GAZYVA Treated Arm Adverse Reactions (MedDRAa) System Organ Class

Injury, Poisoning and Procedural Complications

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. 5.5 Infection 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. 5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% 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. 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. 5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 12% of patients in the trial. In 5% of patients, GAZYVA caused an acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution. Transfusion of blood products (i.e., platelet transfusion) may be necessary. 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 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 GAZYVA n =116 + Chlorambucil n =240 All Grades All Grades Grades % 3-4b % Grades % 3-4b %

Infusion related reactions

Blood and lymphatic system disordersc Neutropenia

Thrombocytopenia

Anemia

Leukopenia

General disorders and administration site conditions Pyrexia

Respiratory, thoracic and mediastinal disorders Cough

a MedDRA coded adverse reactions as reported by investigators. b c

No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms. Adverse events reported under ‘Blood and lymphatic system disorders’ reflect those reported by investigator as clinically significant.

Table 4 Post-Baseline Laboratory Abnormalities by CTCAE Grade with ≥5% Incidence and ≥2% Greater in the GAZYVA Treated Arm

Investigations

GAZYVA + Chlorambucil n =240

Chlorambucil n =116

All Grades All Grades Grades % 3-4 % Grades % 3-4 % Hematology Neutropenia Lymphopenia Leukopenia Thrombocytopenia Chemistry Hypocalcemia Hyperkalemia Hyponatremia AST (SGOT increased) Creatinine increased ALT (SGPT increased) Hypoalbuminemia Alkaline Phosphatase increased Hypokalemia

77 80 84 47

46 40 36 14

53 9 12 50

27 2 <1 11

22 16

<1 0

14 11

<1 0

The ASCO Post | JUNE 10, 2014

PAGE 32

Journal Spotlight CHF Screening continued from page 31

often may be nearly as effective in detecting heart disease early. “It is important to monitor survivors so we can reduce the late effects of treatment whenever possible, but we may be asking them to be tested too often, which burdens both individuals and the health-

care system,” said senior author Lisa Diller, MD, Chief Medical Officer of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “We think it is worthwhile to review the current [congestive heart failure] screening guidelines.” “Our findings suggest that there is a long-term benefit in screening survivors at elevated risk for [congestive heart failure],”

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% 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 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and <2% thereafter [see Dosage and Administration (2)]. Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). 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 chlorambucil alone arm. Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3-4, and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. 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 Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of Pre-Existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 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. 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

said lead author Jennifer Yeh, PhD, of the Center for Health Decision Science at Harvard School of Public Health. “Yet less frequent screening than currently recommended may be reasonable when other factors are considered. We hope these results Jennifer Yeh, PhD can help inform the ongoing Lisa Diller, MD discussion about screening childhood cancer survivors.” The Children’s Oncology Group effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at (COG) currently recommends that surthe recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring vivors undergo screening by echocardiogand B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was raphy for asymptomatic left-ventricular restored within 6 months after birth. dysfunction. If left untreated, this clinical8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in ly silent condition can progress to congeshuman milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG tive heart failure. COG recommends that is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the patients at high risk of developing congespotential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to tive heart failure be screened every 1 or discontinue nursing, or discontinue drug, taking into 2 years and those at low risk be screened account the importance of the drug to the mother. every 2 or 5 years. 8.4 Pediatric Use

The safety and effectiveness of GAZYVA in pediatric patients has not been established.

8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. 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%) an adverse event leading to death. Similar rates were observed in the comparator arm. 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 (CLcr) >30mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr<30mL/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] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

Virtual Cohort To estimate the clinical benefits and cost-effectiveness of the current heart screening guidelines, Drs. Diller and Yeh and their coauthor, cardiologist Anju Nohria, MD, of Brigham and Women’s Hospital, constructed a computer model of a virtual cohort of 15-year-olds who had survived cancer at least 5 years. Using data from the Childhood Cancer Survivors Study and the Framingham Heart Study, the researchers modeled the cohort’s congestive heart failure risk and clinical progression over the course of survivors’ lifetimes. Their analysis suggests that routine screening may prevent as many as 1 in 12 cases of congestive heart failure. The authors then used Medicare data to estimate the costs and value (expressed in cost per quality-adjusted life year [QALY]) of different screening schedules (ie, every 1, 2, 5 or 10 years) and methods (echocardiography vs cardiac magnetic resonance imaging [MRI]) for the different congestive heart failure risk groups (ie, low, high). At a cost-effectiveness threshold of $100,000/QALY, the model’s results indicate that echocardiographic screening might not be the best value for resources invested to reduce lifetime congestive heart failure risk among survivors at low risk of developing the disease. On the other hand, the data suggest that biennial echocardiography screening may be a high-value strategy for high-risk survivors. n

Reference 1. Yeh JM, et al: Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors. Ann Intern Med 160:661-671, 2014.

ASCOPost.com | JUNE 10, 2014

PAGE 33

National Comprehensive Cancer Network Annual Conference

NCCN Scientific Posters Include New Findings in Bladder Cancer, Survivorship Care, and Antiemetic Therapy By Caroline Helwick

he 19th Annual Conference of the National Comprehensive Cancer Network (NCCN), recently held in Hollywood, Florida, featured a number of scientific posters by member organizations and meeting sponsors. The ASCO Post captured some of the most interesting findings for our readers, including these news briefs. The results of these studies support the use of NCCN Guidelines in patient care.

Cisplatin in Bladder Cancer For muscle-invasive bladder cancer patients opting for radical cystectomy, current guidelines strongly recommend neoadjuvant cisplatin-based chemotherapy, and eligibility for this treatment is based on creatinine clearance as estimated by the CockcroftGault equation. In 2009, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) proposed a more precise equation. Sumanta K. Pal, MD, and colleagues at City of Hope Comprehensive Cancer Center, Los Angeles,

Sumanta K. Pal, MD

evaluated eligibility for the receipt of cisplatin on the basis of the CKD-EPI equation, vs the Cockcroft-Gault equation and other conventional methods and found the two approaches identified the same proportion of patients, approximately 70%.1 In the subset of patients ≥ 80 years old, the CKD-EPI equation found that a much smaller percentage were eligible—25% compared to 50% by the Cockcroft-Gault equation. Of 126 patients, only 34 (27%) received neoadjuvant cisplatin-based chemotherapy, and of the 92 who did not, 64% had a creatinine clearance > 60 mL/min by CockcroftGault. “In contrast to previous reports, the CKD-EPI equation does not appear to characterize a broader span of patients as cisplatin-eligible,” the authors concluded. “The discordance between ac-

tual rates of neoadjuvant chemotherapy use and rates of cisplatin eligibility suggest that other factors may guide clinical decision-making.”

Gaps in Survivorship Care Most colorectal cancer and non– small cell lung cancer (NSCLC) patients receive surveillance care and coordinated care as per NCCN Guidelines. However, only a minority receive a comprehensive assessment of treatment-associated effects, preventive cancer screening, or healthy behavior counseling, according to a study led by Crystal S. Denlinger, MD, of Fox

From a managed care perspective, it is important to promote utilization of resources toward the most costeffective option. —Edward Li, PharmD

• Few survivors receive full assessment of late and long-term effects. • Many NSCLC survivors do not have documentation of recommended vaccination. • Differences in the assessment of NSCLC survivors exist among practice settings. The researchers will assess the impact of an educational initiative for the providers in future analyses.

Palonosetron Overutilized? Crystal S. Denlinger, MD

Chase Cancer Center, Philadelphia.2 “NCCN Guidelines for Non-Small Cell Lung Cancer, Colon Cancer, and Rectal Cancer have included survivorship care guidelines since 2009, but it is unclear whether survivorship guidelines are used in follow-up care of survivors. Evaluating adherence may improve survivorship care by raising oncology providers’ awareness of appropriate survivorship care,” Dr. Denlinger suggested. The study involved a review of 374 patient charts at 10 sites encompassing 19 oncology practices affiliated with Fox Chase. The main finding was that patients are receiving appropriate cancer surveillance care and coordinated care with primary physicians, but survivors are not likely to receive comprehensive preventive care, and comprehensive intervention for the effects of cancer is uncommon. The researchers reported: • Fewer than half of survivors receive recommended cancer screenings, but academic centers perform better than nonacademic centers in this respect. • Few survivors receive counseling on physical activity and diet, and counseling is significantly more likely in nonacademic settings.

Palonosetron (Aloxi) is an effective antiemetic for chemotherapy-induced nausea and vomiting (CINV), but it may not be the most cost-effective option for regimens with low emetogenic potential, considering that other lower-cost 5HT3 antagonists are available. This was the conclusion of pharmacists from New Century Health, a healthcare management organization, who reported results from a quality management program.4 “From a managed care perspective, it is important to promote utilization of resources toward the most cost-effective option, and thus it is important to understand the patterns of inappropriate use of palonosetron,” said lead author Edward Li, PharmD. “Other treatment options may be equally efficacious and more cost-effective in lowemetogenic regimens.” The study examined a cohort of denied chemotherapy treatment authorization requests containing palonosetron to determine trends in demographics, authorization request patterns, and cost. The information was reviewed by the oncology quality management program at New Century Health from January 2013 to October 2013. A total of 378 cases of denied authorization requests were identified; most involved single-agent chemo-

therapy. The reasons for denial included lack of compendia support (81%), availability of a therapeutic alternative (42%), clinical criteria not met (15%), and dosing/frequency errors (10%). The program prompted chemotherapy regimen changes in 156 cases and supportive care treatment changes in 222 cases. Palonosetron was removed in 82% of all final, approved chemotherapy treatment authorization requests and retained in just 18% of cases. The total net cost savings based on all the changes within the cohort was $1,087,073. Evidence-based changes in therapy that resulted in enhanced care quality but increased cost totaled $757,473, according to Dr. Li and colleagues. n

Disclosure: Drs. Pal and Saam reported no potential conflicts of interest. Dr. Li is on the advisory board of Amgen and Hospira and is on the speakers bureau for Pfizer.

References 1. Chang M, Ruel N, Villegas S, et al: Chronic kidney disease epidemiology and Cockcroft-Gault equations identify similar candidates for neoadjuvant chemotherapy in muscle-invasive bladder cancer. 19th NCCN Annual Conference. Abstract AB2014-11. Presented March 13, 2014. 2. Denlinger CS, Filchner K, O’Grady M, et al: Adherence to NCCN survivorship care guidelines in lung and colorectal cancer patients. 19th NCCN Annual Conference. Presented March 13, 2014. 3. Saam J, Arnell C, Moyes K, et al: Evaluating the personal and family history overlap between hereditary cancer syndromes. 19th NCCN Annual Conference. Abstract AB2014-29. Presented March 13, 2014. 4. Li E, Tran C, Peterson B, et al: Palonosetron for chemotherapy-induced nausea and vomiting: Description and report of a quality management program. 19th NCCN Annual Conference. Abstract AB2014-17. Presented March 13, 2014.

XOFIGO® IS INDICATED

for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Not an actual patient. Models used for illustrative purposes only.

Important Safety Information1 for patients treated with Xofigo and placebo. Myelosuppression— notably thrombocytopenia, neutropenia, pancytopenia, and • Contraindications: Xofigo is contraindicated in women who are or leukopenia—has been reported in patients treated with Xofigo. may become pregnant. Xofigo can cause fetal harm when administered Monitor patients with evidence of compromised bone marrow reserve to a pregnant woman closely and provide supportive care measures when clinically indicated. • Bone Marrow Suppression: In the randomized trial, 2% of patients Discontinue Xofigo in patients who experience life-threatening in the Xofigo arm experienced bone marrow failure or ongoing complications despite supportive care for bone marrow failure pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with • Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo bone marrow failure was ongoing at the time of death. Among Xofigo, the absolute neutrophil count (ANC) should be the 13 patients who experienced bone marrow failure, 54% required ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin blood transfusions. Four percent (4%) of patients in the Xofigo arm ≥10 g/dL. Prior to subsequent administrations, the ANC should and 2% in the placebo arm permanently discontinued therapy due to be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue bone marrow suppression. In the randomized trial, deaths related Xofigo if hematologic values do not recover within 6 to 8 weeks to vascular hemorrhage in association with myelosuppression were after the last administration despite receiving supportive care observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), • Concomitant Use With Chemotherapy: Safety and efficacy of serious infections (10%), and febrile neutropenia (<1%) was similar concomitant chemotherapy with Xofigo have not been established.

600-10-0009-13c

05/14

Printed in USA

Prolong life. Treat bone metastases.

30%

reduction in the risk of death vs placebo (hazard ratio [HR]=0.695)1

The first agent to extend overall survival by exerting an antitumor effect on bone metastases in CRPC1,2 • Exploratory updated analysisa: 3.6-month increase in median overall survival vs placebo (HR=0.695; 95% confidence interval [CI]: 0.581-0.832)1 —14.9 months for Xofigo (95% CI: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8)1

• Prespecified interim analysis: 2.8-month increase in median overall survival vs placebo, P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)1 —14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1

• Overall survival benefit supported by delay in time to first symptomatic skeletal event (SSE), favoring Xofigo.b The majority of events consisted of external beam radiation therapy to bone metastases1 • 1-minute intravenous injection every 4 weeks for 6 injections1

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis. b SSEs defined as external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention.

To learn more, visit www.xofigo-us.com

Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations • Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients.

The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see following pages for brief summary of full Prescribing Information.

radium Ra 223 dichloride INJECTION

Xoﬁgo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations. Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination. Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing. 19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the Renal and urinary disorders As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. 3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go. 8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go. Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies. There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination. When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. ÂŠ 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: 05/2013 "3

The ASCO Post | JUNE 10, 2014

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National Comprehensive Cancer Network Annual Conference

NCCN Roundtable: When a Parent Has Cancer By Caroline Helwick

ttendees at this year’s annual conference of the National Comprehensive Cancer Network (NCCN) not only got up to date on the Guidelines but left with a better understanding of how children deal with a parent’s cancer, and how oncology providers can best help. Panelists for the NCCN roundtable discussion, The Child’s Experience When a Parent Has Cancer, concluded that honest, caring communication, appropriate to the child’s age and temperament, is essential, and that oncology providers should institute programs that help families deal with the illness. The session was moderated by Lillie D. Shockney, RN, Director of the Cancer Survivorship Program at Johns Hopkins Medicine, Baltimore, who introduced the conversation by sharing

talking about death does not raise their anxiety,” explained Martha Aschenbrenner, MA, a palliative care counselor at The University of Texas MD Anderson Cancer Center, Houston, who is also a child life specialist, a pastoral counselor, and a cancer survivor herself. While the natural instinct is to keep frightening information out of the reach of children, those who receive “honest information” are actually better able to understand, to cope, and to trust in the people caring for them, than children who are shielded, she explained.

Tailor the Conversation Conversations about cancer should be tailored to the child’s age and temperament. This is the foundation for work that is done at Massachusetts General Hospital Cancer Center, Boston, with its program, the Marjorie E. Korff Parenting at a Challenging Time (PACT) Program (www. MGHPACT.org). PACT, which is staffed by child psychiatrists and psychologists, is a “parent guidance consultation model” that is individualized based on the parent’s description of the child.

way he educated himself, and his ability to create a support network among his friends. “My son chose to walk the journey with me. It taught me that kids can handle a lot more than we think they can and that when he faces adversity, he is going to be able to handle it,” she added. Martha Aschenbrenner, MA

younger than age 6 have a poor concept of time and do not understand the meaning of “forever.” A good way to explain death is that the parent “will not breathe, eat, hurt, or come back.” When the parent is terminally ill, this conversation should begin early on to prepare the child. School-age children express their thoughts more easily, understand that sickness can lead to death, and are likely to ask blunt questions. These should be answered honestly, and repeated affirmations that “everything will be okay” should be avoided. Virtually all school-age children worry about their parent dying, and their fears should be openly addressed. For teenagers, dealing with a parent’s cancer diagnosis can actually be charac-

Lillie D. Shockney, RN

her own experience as the mother of a 12-year-old when diagnosed with breast cancer. She was diagnosed with cancer in the contralateral breast 3 years later. Her daughter reacted with a mixture of fear, misunderstanding, and—fortunately—unintentional humor that the family continues to harness to this day, balancing the distress and insecurity of a cancer diagnosis. “Without realizing it, our daughter found our sense of humor, and every day my husband and I make sure we find something funny about the fact that I have been diagnosed with cancer,” Ms. Shockney shared. She said she learned the importance of referencing “hope” in those early conversations. Hope can take many forms but always incorporates the future well-being of the family and is not eroded by honesty, she emphasized.

Openness Is Important The panelists strongly agreed that, as hard as it may seem, children need honest information about the cancer diagnosis and even the possibility of death. This means that parents, caregivers, and providers should address all questions, thoughts, and emotions, with clear language, avoiding confusing euphemisms. “When children are forewarned,

Our program respects that the parent is the expert on his or her own children but needs help in addressing the challenges of living with cancer. —Paula K. Rauch, MD

“Our program respects that the parent is the expert on his or her own children but needs help in addressing the challenges of living with cancer,” said Paula K. Rauch, MD, Founding Director of PACT and Associate Professor of Psychiatry at Harvard Medical School, Boston. PACT clinicians provide individual consultations with parents and seek to learn about the child’s age, temperament, behavior, and concerns he or she may have expressed. These consultations help prepare parents for talking with their children and dealing with issues and needs that might arise.

Child Development Principles Aside from a child’s unique personality, perspective, and situation, there are certain child development principles that should be appreciated when talking to children about cancer, the experts said. Children

ter-building. A prompt, honest, but sensitive discussion was advised by Maya Silver, who coauthored with her father, My Parent Has Cancer and It Really Sucks. “Withholding the news often results in teenagers hearing the news accidentally, and this creates a perceived breach in trust,” she noted. She reminded listeners that teenagers view dishonesty as a lack of respect and trust, and are resentful of being misled, or “lied to.” Since teenagers will search the Internet for information, caregivers and providers should ensure that their information is accurate. While teenagers like to be up to date on the parent’s treatment and condition, she cautioned, “Be honest within reason.” Zoraida Sambolin, former anchor of CNN’s Early Start, was diagnosed with breast cancer when her son was 14. She was surprised by his resiliency, the

Responsibility of Oncology Providers Unfortunately, despite the need for specialists in this area, most communities and hospitals offer little guidance for families impacted by cancer. In the absence of structured programs, the person usually charged with speaking to the children “is you,” Ms. Aschenbrenner told NCCN attendees. Bruce Ham, who wrote about his experience of being widowed with three young daughters in Laughter, Tears, and Braids, also urged providers to be proactive. “You, more than anyone, are in the position to prepare families for what could come to be,” he emphasized. At 39, his wife lived only 6 months after her metastatic colon cancer diagnosis—leaving Mr. Ham surprised and unprepared. “It’s great that we maintained hope,” he said, “but I wish I would have had more time to ask my wife questions, to get her perspective on life, for her to make memories for my girls. I wish I had her counsel before she was so riddled with drugs that these conversations were trying for both of us.” In the aftermath of her death, Mr. Ham joined a support group, Single Fathers Due to Cancer, part of the University of North Carolina at Chapel Hill. He now blogs about the experience of raising three daughters as a single father on his website, www .therealfullhouse.wordpress.com.

Creating a Legacy Part of being mindful of the child’s experience, and of honoring the parent dying of cancer, is to create a legacy for the children, the panel agreed. This can be in the form of letters, videos, scrapbooks, and cards to be opened on significant occasions—and the process should be initiated while the parent is still up to the task, they said. “Write a letter about what you see in your child that is special; share a unique parenting memory,” Dr. Rauch tells patients. n Disclosure: Ms. Shockney, Ms. Aschenbrenner, Dr. Rauch, Ms. Silver, Mr. Sambolin, and Mr. Ham reported no potential conflicts of interest.

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National Comprehensive Cancer Network Annual Conference Hematology

Looking Ahead in Treating Chronic Lymphocytic Leukemia By Caroline Helwick

t’s the dawn of a new era in the treatment of chronic lymphocytic leukemia (CLL), largely due to the development of agents targeting the BCR signaling pathway, according to John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center, Columbus. At the 19th Annual Conference of the National Comprehensive Cancer Network (NCCN) in Hollywood, Florida, Dr. Byrd presented new standards of care, and looked to the future, in the treatment of CLL.

Key Considerations Among the adult leukemias, CLL is the most prevalent, is generally diagnosed early, is associated with the longest life span, and is a disease of the elderly—“factors that are important, as we think of new therapies,” he noted. Treatment is initiated only when patients become symptomatic. “There is no advantage to treating CLL before symptoms develop, irrespective of genomic features,” he emphasized. “The biggest disaster I see is the patient with stage 0 to 1 disease who was started on treatment based on a lymphocyte count changing, in the absence of symptoms, and he experiences treatment-related toxicity,” Dr. Byrd said. “You treat the disease in the setting of symptoms.” Treatment choice is differentiated by age or functional status and by genomic features. New to the NCCN Guidelines is an emphasis on considering del(17p), which indicates patients who are predicted to have worse outcomes and who require different management strategies. “Rather than treat low-risk patients with less chemoimmunotherapy, if you treat any group, this is the one,” he said.

Symptomatic Patients The value of adding rituximab (Rituxan) to fludarabine/cyclophosphamide (FC) was solidly established by the updated, 6-year analysis of the German CLL Study, where the addition of rituximab to FC (FCR) significantly improved response rates, progression-free survival, and overall survival.1 Most genetic subgroups (except for del 17p) benefited from FCR and patients negative for minimal residual disease or disease in the nodes had a very long remission from chemoimmunotherapy—out to 10 years, he noted. Less evidence-based, but commonly used in practice, is bendamustine (Treanda) plus rituximab in young patients. However, the CLL10 study found this

doublet to be inferior to FCR, though easier to administer.2 “For a chance at cure, it’s worth considering FCR. This is one area where the field is changing,” he said. Summarizing his treatment paradigm, Dr. Byrd said that fludarabine/ rituximab may be preferred for low-risk patients, with cyclophosphamide added for patients with del(11q). Patients with del(17p) can receive FCR or high-dose methylprednisolone plus rituximab, or be enrolled in a clinical trial. Elderly patients should not receive fludarabine, as it carries no benefit over chlorambucil (Leukeran). These patients can be treated with benda-

Novel Agents for Relapsed Disease Even with relapsed disease, only the presence of symptoms should dictate treatment, and patients with unfavorable risk factors should be evaluated for transplant, Dr. Byrd said. With the approval of ibrutinib (Imbruvica), the traditional second-line therapies have largely become irrelevant. Response to ibrutinib has been independent of all features except IgVH mutation status, he said, and while del(17p) and del(11q) patients “do drop off,” relapsed/refractory patients lacking these mutations have a progression-free survival time that is simi-

There is no advantage to treating CLL before symptoms develop, irrespective of genomic features. —John C. Byrd, MD

mustine/rituximab (which is more toxic but feasible). Early data suggest chlorambucil/rituximab is also a good treatment option here.

New Standard of Care The NCCN Guidelines have added a new standard-of-care regimen, obinutuzumab (Gazyva) plus chlorambucil. Obinutuzumab is a humanized monoclonal antibody targeting CD20, with novel properties as compared to rituximab. In the German CLL11 study, chlorambucil plus obinutuzumab was superior to chlorambucil plus rituximab in multiple endpoints.3 Progression was reduced by 81% (P < .001), and vs chlorambucil alone, mortality was reduced by 59% (P = .002). Obinutuzumab/chlorambucil is indicated as first-line treatment in CLL patients (1) without del(11q) or del(17p), both those < 70 years old (with or without comorbidities) and those ≥ 70, (2) with del(17p) (any age), and (3) with del(11q) if ≥ 70 or younger with comorbidities. “Importantly, for the first time in the elderly, infirm population, we see a survival advantage [over monotherapy]. The additional cost is probably justified by more than 1 year additional progressionfree survival. For the elderly, this is a better drug, and we should incorporate it,” he maintained.

lar to what is seen in treatment-naive patients. With additional follow-up, very few patients have shown disease progression, he noted. Several ongoing studies are evaluating ibrutinib in combination with ofatumumab, rituximab, and bendamustine/ rituximab, and clinicians are encouraged to enroll patients on trials that are still accruing, including ECOG 1912 and Alliance 041202. Noting that resistance to ibrutinib has been “rumored,” he countered that of 267 patients treated at Ohio State University, 201 are still on treatment at a median follow-up of 16 months. “We have patients who are out close to 4 years. There were 42 who went off treatment for reasons other than progressive disease, and only 24 have [had progression] on drug,” he noted. “If a relapsed/refractory patient does not respond to ibrutinib, the patient probably has something else going on and should be biopsied,” he suggested. Most patients who relapse typically do so between years 1 and 2, and they should be retreated. Excitement is also building over idelalisib, an inhibitor of PI3K-delta, which both targets the BCR signaling pathway and inhibits B-cell signaling in CLL. In combination with rituximab, ofatumumab, or bendamustine, response rates have been higher than seen with single-agent

idelalisib, and a pivotal study of the idelalisib/rituximab combination may lead to the drug’s approval.4 This study evaluated this regimen in 220 relapsed patients with diminished renal function, previous therapy-induced myelosuppression, or major coexisting illness. Median progression-free survival was 5.5 months with rituximab only and was not reached in the idelalisib group— a 50% reduction in risk (P < .001). Response rates were increased 30-fold (P < .001) and mortality was reduced 72% (P = .02).

Complementary Agents? “Clearly, idelalisib in relapsed disease is more active than rituximab. As monotherapy, it is probably not as good as ibrutinib, but the study populations were not the same. I believe these drugs are complementary,” Dr. Byrd commented. Phase II and III studies of idelalisib in combination with bendamustine, ofatumumab, and rituximab are in progress in untreated CLL and in relapsed/refractory disease. Other PI3K inhibitors (eg, IPI145) are also in late-stage development, as are other experimental BCR-signaling agents and second-generation Bruton’s tyrosine kinase inhibitors. The hope is that these novel agents will be effective, even in the presence of newly defined mutations related to resistant disease. n

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

References 1. Fischer K, Bahlo J, Fin A-M, et al: Extended followup of the CLL8 protocol, a randomized phase III trial of the German CLL Study Group comparing fludarabine and cyclophosphamide to FC plus rituximab for previously untreated patients with chronic lymphocytic leukemia. 2012 American Society of Hematology Annual Meeting. Abstract 435. Presented December 10, 2012. 2. Eichhorst B, Fink A-M, Busch R, et al: Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia. 2013 American Society of Hematology Annual Meeting. Abstract 526. Presented December 9, 2013. 3. Goede V, Fischer K, Busch R, et al: Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370:1101-1110, 2014. 4. Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:9971007, 2014.

The ASCO Post | JUNE 10, 2014

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Issues in Oncology Health-Care Policy

Patients Benefit From Faster FDA Drug Approval Process By Margot Fromer

n an increasing spirit of cooperation, U.S. Food and Drug Administration (FDA) and several pharmaceutical companies are bringing to fruition the newest in a series of ways to expedite drug development and review. Breakthrough therapy is the designation instituted in 2012 by the FDA Safety and Innovation Act. It is intended for a drug, alone or in combination, to treat a serious or life-threatening disease and for which preliminary clinical evidence indicates substantial improvement over existing therapies on one or more clinically significant endpoints—for example, treatment effects observed early in clinical development. If a sponsor applies for breakthrough designation, FDA will expedite its review and will grant or reject the designation within 60 days. In early May, the Friends of Cancer Research (FOCR) held a briefing in the Hart Senate Office Building in Washington, DC, to mark the successful launch of the breakthrough designation.1 It was

sponsored by Sens. Michael Bennett (D-CO), Orrin Hatch (R-UT), and Richard Burr (R-NC), who were also the primary sponsors of the original breakthrough legislation, along with Rep. Diana DeGette (D‑CO) and Fmr. Rep. Brian Bilbray (R-CA) in the House.

mab/GlaxoSmithKline to treat chronic lymphocytic leukemia • ceritinib (Zykadia) from Novartis to treat non–small cell lung cancer (NSCLC) In her opening remarks at the briefing,

Development, Genentech—and former ASCO President, agreed. “We had the first drug approved through this program, for CLL, an incurable and difficult-to-treat cancer that usually occurs in patients aged 70 and over. These patients tend to have

Progress to Date In the past 2 years, there have been 184 requests for breakthrough therapy designation. A total of 48 of those requests were granted, and 6 such drugs have been approved: • obinutuzumab (Gazyva) from Genentech to treat chronic lympocytic leukemia (CLL) • ibrutinib (Imbruvica) from Pharmacyclics/Johnson & Johnson to treat mantle cell lymphoma • sofosbuvir (Sovaldi) from Gilead to treat hepatitis C • ivacaftor (Kalydeco) from Vertex to treat cystic fibrosis • ofatumumab (Arzerra) from Gen-

Ellen Sigal, PhD

Sandra Horning, MD

Ellen Sigal, PhD, Chair and Founder of FOCR, said, “The idea for this new designation came from FDA, and there has been a lot of support from that agency and also from manufacturers, Congress, and advocacy groups. Everyone thinks it’s a good thing.” Sandra Horning, MD, Chief Medical Officer and Head of Global Product

Urte Gayko, PhD

other medical conditions that make treatment especially difficult, and many are not candidates for standard combination therapy. Obinutuzumab combined with mild chemotherapy is an important new option for these patients.” She added that working with FDA in such a speeded-up and intense envi-

ASCOPost.com | JUNE 10, 2014

PAGE 41

Issues in Oncology

ronment requires a certain mindset, a “can-do” attitude. Urte Gayko, PhD, Senior Vice President of Global Regulatory Affairs, Pharmacyclics, sponsor of ibrutinib, the second drug approved through the program, added positive feelings about working with FDA in a highly charged and concentrated atmosphere. “Mantle cell lymphoma is a true orphan disease, associated with a life expectancy of only a year or two. Patients are in desperate need of a drug that works, and they need it quickly. The breakthrough program provided that, and FDA was very supportive of our efforts.”

plete one, known as “rolling review.” Accelerated approval speeds development of a drug that can provide meaningful therapeutic benefit over available therapies and allows approval based on a surrogate endpoint. Accelerated approval is useful when the course of a disease is long, and it takes an extended amount of time to demonstrate and measure clinical benefit. For these reasons, sponsors are usually required to conduct postmarket studies after approval. Priority review shortens the review time to 6 months from the standard 10 months. Any drug can be granted priority review.

It Can Get Confusing

How Breakthrough Works

There are three other ways to expedite drug development, review, and approval, each of which contains subtle differences, which can be confusing. Fast track is intended to expedite review of drugs that treat serious conditions and fill an unmet medical need. Designation is granted on the basis of preclinical data. The sponsor will have more frequent contact with FDA reviewers than usual and can submit portions of a marketing application before submitting the com-

If FDA grants a designation of breakthrough therapy, it will provide advantages to the sponsor by: • holding frequent meetings with drug reviewers • providing advice about the drug’s efficacy as demonstrated by clinical and nonclinical data • ensuring that the clinical trial design is practical and appropriate, especially in minimizing the number of patients • involving senior agency managers

THE SIDE OF CANCER YOU’RE NOT SEEING

There has been remarkable unanimity among FDA reviewers about the appropriateness of breakthrough therapy designation. They almost never disagree about which drugs should make it into the program. —Janet Woodcock, MD

and staff in the collaboration Since the inception of the program, said Janet Woodcock, MD, Director, FDA Center for Drug Evaluation and Research, “There has been remarkable unanimity among FDA reviewers about the appropriateness of breakthrough therapy designation. They almost never disagree about which drugs should make it into the program.” A bit more problematic has been the need for sponsors to “get their act together” regarding drug manufacture. “They’re used to the approval process taking about 7 years, so the speed with which we’re working surprises them, and they’re having trouble making the drug available.”

What This Means for Patients Breakthrough therapy can bring drugs to market fast. It has the potential to save lives. Bayard “Chip” Kennett, advocate and former Congressional staffer, is glad of that. He was diagnosed with stage IV NSCLC at age 31 and had had initial success with standard chemotherapy, which then stopped working. “My oncologist at Hopkins told me about the trial of [ceritinib] that Novartis was conducting in Philadelphia, and since I was driving to Baltimore from my home in Virginia, it didn’t seem like much more of an effort to go north a continued on page 42

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The ASCO Post | JUNE 10, 2014

PAGE 42

Issues in Oncology Health-Care Policy

Unprecedented Release of Medicare Data Raises Concerns About Lack of Context: Statements From COA and ASTRO

n April, as part of the Obama administration’s work to make the U.S. health-care system more transparent, affordable, and accountable, the Centers for Medicare & Medicaid Services (CMS) released a vast amount of privacy-protected data on services and procedures provided to Medicare beneficiaries by physicians and other health-care professionals. The data, which is available at www. cms.gov, also shows payment and

leased the data. The data is incomplete, biased, without context, and an unrepresentative sample of Medicare reimbursement to oncologists.… Further, CMS did not allow physicians an opportunity to confirm the accuracy of individual data and did not conduct any studies to assess how the data will potentially influence consumers, especially senior beneficiaries, about their medical care decision-making.

The [Medicare reimbursement claims] data is incomplete, biased, without context, and an unrepresentative sample of Medicare reimbursement to oncologists.… —COA

lently billing Medicare, which should be a top priority of CMS independent of releasing Medicare reimbursement claims data to the general public. COA also equally supports more transparency and accountability in medical care, especially in measuring the quality and value of cancer care. This is evidenced by COA’s Oncology Medical Home initiative and associated payment reform model based on quality and value metrics. Community oncology practices across the country are providing cost-effective cancer care that substantially reduces spending by Medicare and seniors, as documented by numerous national studies. CMS should be empowering cost-effective cancer care in the community setting and providing consumer-friendly quality and value data that will truly help in more informed decision-making. The release of Medicare reimbursement claims data is not a step in that direction.

submitted charges for those services and procedures by provider. In the May 1 issue of The ASCO Post, we published statements from the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) on the release of the Medicare physician payment data. Both societies emphasized the need for greater context to appropriately interpret the data and cautioned that the numbers, as provided, could be misleading. Statements by the Community Oncology Alliance (COA) and American Society for Radiation Oncology (ASTRO), also issued at the time of the data release, sounded a similar note and are presented below.

CMS has stated that “this data release will help beneficiaries and consumers better understand how care is delivered through the Medicare program.” That is impossible given that the data is simply an unscientific and inconsistent sample of reimbursement claims data—it provides no metrics on quality and value. COA believes that the data may well confuse seniors and others with cancer, adding unnecessary angst to an already emotional situation. As physi-

Community Oncology Alliance Statement

cians we are first taught to do no harm to our patients. The release of Medicare physician reimbursement claims data may possibly result in inaccurate, misunderstood, and even harmful conclusions by cancer patients. COA strongly supports identifying physicians who may be fraudu-

data from Medicare released [recently] did not have the necessary context and details to provide an accurate picture of radiation oncology care…. The Medicare claims data released is limited and creates significant challenges to interpreting its meaning because it is not integrated with clinical

phy [significantly more work in a good deal less time] to which both FDA and pharmaceutical companies are committed. However, it is also wildly expensive, and FDA needs a big new chunk of money to support it. There are very sick patients out there waiting for help.” Nevertheless, she added, the issue is more about curative treatment and improved quality of life than it is about money. “Of course, price is important to

patients, but efficacy is at the forefront.” Dr. Woodcock was equally enthusiastic. “Getting effective drugs to patients is the reason why people work at FDA, and this program has been very inspiring—a serious commitment. We need all the drug development avenues we can think of and are willing to expend as much effort as necessary. Some of the products may not last over the long haul, but it’s worth the work.” n

The Community Oncology Alliance strongly disagrees with the release of physician-specific Medicare reimbursement claims data and the manner in which the Centers for Medicare & Medicaid Services re-

FDA Drug Approval Process continued from page 41

few more hours—especially since I was out of options,” he said. He responded almost immediately and now feels well and believes that the breakthrough drug is keeping him alive. Dr. Sigal said there are a number of patients who feel the same. “This program is wildly popular, especially in view of the all-hands-on-deck philoso-

American Society for Radiation Oncology Statement The American Society for Radiation Oncology (ASTRO) is committed to transparency of Medicare information; however, ASTRO is troubled that individual physician payment

The amount that a physician bills and is reimbursed does not directly correlate to his or her personal income. —ASTRO

data about how the care is provided and billed. As a specialty that effectively utilizes highly advanced, sophisticated technology that can cost millions of dollars, the claims data alone offers a distorted view of the revenue generated by radiation oncology practices. For instance, the reimbursement data does not reflect the substantial expenses associated with operating a radiation oncology center, including the costs of expensive equipment and maintaining a welltrained and specialized team, including radiation oncology doctors, medical physicists, dosimetrists, radiation therapy technicians, nurses and other health professionals such as dieticians and social workers…. As context, radiation oncology accounts for only about 2% to 3% of the almost $87 billion paid (approximately $2.4 billion) by Medicare via the Medicare Physician Fee Schedule, based on the 2012 claims data. The contributions radiation oncology has made to improving cancer cure rates indicates that Medicare is getting strong value for the relatively little it spends. The amount that a physician bills and is reimbursed does not directly correlate to his or her personal income. Preliminary analysis of the data estimates that approximately 82% of radiation oncology billing dollars pay for the physical and practical overhead expenses, and approximately 18% represents the physician’s work…. ASTRO shares CMS’s commitment to transparency, particularly as the health-care payment system shifts away from the fee-for-service model to one based on value. ASTRO is proud to continue to participate in a thorough dialogue with CMS as new payment models are developed and patients can become better-informed health-care consumers. n Disclosure: Drs. Sigal and Woodcock reported no potential conflicts of interest. Dr. Horning is an employee of Genentech/Roche and has stock in Roche.

Reference 1. Science and Progress at the FDA: A Friends of Cancer Research Congressional Briefing on the Progress of the FDA’s Breakthrough Therapy Program. Washington, DC, May 6, 2014.

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The ASCO Post | JUNE 10, 2014

PAGE 44

JCO Spotlight Breast Cancer

ASCO Clinical Practice Guideline Update: Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer By Matthew Stenger

SCO recently convened an update committee of experts in medical oncology, pathology, radiation oncology, surgical oncology, guideline implementation, and advocacy to develop evidence-based recommendations that update the ASCO 2005 clinical practice guideline on use of sentinel node biopsy in patients with early-stage breast cancer.1 The update is provided for medical oncologists, radiation oncologists, pathologists, surgeons, oncology nurs-

Gary H. Lyman, MD, MPH, FASCO

es, patients/caregivers, and guideline implementers. Gary H. Lyman, MD, MPH, FASCO, of Fred Hutchinson Cancer Research Center, University of Washington, and Armando E. Giuliano, MD, of the John Wayne Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, were the co-chairs of the update committee.

Methods The update committee performed a systematic review of the literature from February 2004 through January 2013 to review new evidence bearing upon three primary clinical questions: (1) How should the results of sentinel node biopsy be used in clinical practice? (2) What is the role of sentinel node biopsy in special circumstances in clinical practice? (3) What are the potential benefits and harms associated with sentinel node biopsy? Nine randomized clinical trials met the systematic review criteria for clinical questions 1 and 2, and 13 cohort studies provided evidence pertaining to clinical question 3. No phase II studies, meta-analyses, or other systematic reviews were identified that met the systematic review criteria for the guideline update.

Summary of Update In brief, recommendations based on new information from randomized clinical trials include the following: women

without sentinel lymph node metastases should not receive axillary lymph node dissection. Women with one to two metastatic sentinel lymph nodes planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo axillary lymph node dissection (in most cases). Women with sentinel lymph node metastases who are to undergo mastectomy should be offered axillary lymph node dissection. Recommendations based on new information from cohort studies or informal consensus are as follows: Women with operable breast cancer and multicentric tumors, with ductal carcinoma in situ who will undergo mastectomy, who previously underwent breast or axillary surgery, or who received preoperative/neoadjuvant systemic therapy may be offered sentinel node biopsy. Women who have large or locally advanced invasive breast cancer (T3/T4), inflammatory breast cancer, or ductal carcinoma in situ (when breastconserving surgery is planned) or who are pregnant should not undergo sentinel node biopsy. In some cases, updated evidence was not sufficient to warrant updating of previous recommendations.

Recommendations The individual recommendations, type and strength of supporting evidence, and strength of recommendation are provided below. Recommendation 1: Clinicians should not recommend axillary lymph node dissection for women with earlystage breast cancer who do not have nodal metastases. Type of recommendation = evidence-based, benefits outweigh harms. Evidence quality = high. Strength of recommendation = strong. Recommendation 2.1: Clinicians should not recommend axillary lymph node dissection for women with earlystage breast cancer who have one or two sentinel lymph node metastases and are to receive breast-conserving surgery with

conventionally fractionated whole-breast radiotherapy. Type of recommendation = evidence-based, benefits outweigh harms. Evidence quality = high. Strength of recommendation = strong. Recommendation 2.2: Clinicians may offer axillary lymph node dissection to women with early-stage breast cancer with nodal metastases found on sentinel node biopsy who are to receive mastectomy. Type of recommendation = evidencebased, benefits outweigh harms. Evidence quality = low. Strength of recommendation = weak. Recommendation 3: Clinicians may offer sentinel node biopsy to women who have operable breast cancer and who have the following characteristics/ circumstances: Recommendation 3.1: Multicentric tumors. Type of recommendation = evidence-based, benefits outweigh harms. Evidence quality = intermediate. Strength of recommendation = moderate. Recommendation 3.2: Ductal carcinoma in situ when mastectomy is performed. Type of recommendation = informal consensus, benefits outweigh harms. Evidence quality = insufficient. Strength of recommendation = weak. Recommendation 3.3: Prior breast and/or axillary surgery. Type of recommendation = evidence-based, benefits outweigh harms. Evidence quality = intermediate. Strength of recommendation = strong. Recommendation 3.4: Preoperative/ neoadjuvant systemic therapy. Type of recommendation = evidence-based, benefits outweigh harms. Evidence quality = intermediate. Strength of recommendation = moderate. Recommendation 4: There are insufficient data to change the 2005 recommendation that clinicians should not perform sentinel node biopsy for women who have early-stage breast cancer and meet the following criteria: Recommendation 4.1: Large or locally advanced invasive breast cancers

Updated Recommendations for Sentinel Lymph Node Biopsy ■■ Women without sentinel lymph node metastases should not receive axillary lymph node dissection. ■■ Women with one to two metastatic sentinel lymph nodes planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo axillary lymph node dissection in most cases. ■■ Women with sentinel lymph node metastases who are to undergo mastectomy should be offered axillary lymph node dissection.

(tumor size T3/T4). Type of recommendation = informal consensus. Evidence quality = insufficient. Strength of recommendation = weak. Recommendation 4.2: Inflammatory breast cancer. Type of recommendation = informal consensus. Evidence quality = insufficient. Strength of recommendation = weak. Recommendation 4.3: Ductal carcinoma in situ when breast-conserving surgery is planned. Type of recommendation = informal consensus. Evidence quality = insufficient. Strength of recommendation = strong. Recommendation 4.4: Pregnancy. Type of recommendation = informal consensus. Evidence quality = insufficient. Strength of recommendation = weak.

Qualifying Statements As a qualifying statement, the guideline update notes that clinicians may perform sentinel node biopsy for ductal carcinoma in situ diagnosed by minimally invasive breast biopsy under three conditions: (1) when mastectomy is planned, because this precludes subsequent sentinel node biopsy at a second operation; (2) when physical examination or imaging reveals a lesion highly suggestive of invasive cancer; and (3) when the area of ductal carcinoma in situ on imaging is large (≥ 5 cm). It is also noted that sentinel node biopsy may be offered before or after neoadjuvant systemic therapy, although results appear to be less accurate for sentinel node biopsy performed after neoadjuvant therapy. The committee also notes that the current update deletes a 2005 recommendation regarding patients who had undergone prior nononcologic breast surgery or axillary surgery, due to insufficient data on which to base a recommendation. A data supplement with additional evidence tables, a methodology supplement with information about evidence quality and strength of recommendations, slide sets, and clinical tools and resources are available at www.asco.org/guidelines/ breastsnb. Patient information is available at www.cancer.net. n

Disclosure: The Update Committee reported no potential conflicts of interest.

Reference 1. Lyman GH, Temin S, Edge SB, et al: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. March 24, 2014 (early release online).

ASCOPost.com | JUNE 10, 2014

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Perspective

ASCO Guideline Update Extends Sentinel Node Biopsy Indications in Breast Cancer By Armando E. Giuliano, MD

he American Society of Clinical Oncology (ASCO) published its first guideline for sentinel lymph node biopsy in 2005.1 Since that time, many new randomized and cohort studies have been published investigating the indications and outcomes of the procedure. The updated 2014 guideline, recently published in Journal of Clinical Oncology and reviewed in this issue of The ASCO Post, considers new evidence from recent studies including 13 cohort studies and 9 randomized trials.2 It is clear from these studies that more patients are suitable candidates for sentinel lymph node biopsy without completion of axillary lymph node dissection.

Associated Morbidity The importance of adequate use of this procedure cannot be overemphasized. Axillary dissection is associated with significant transient and permanent morbidity. Further, axillary dissection results in significant time away from routines of daily life and can lead to permanent symptomatic lymphedema, numbness, decreased shoulder mobility, and pain. While sentinel lymph node biopsy can result in the same complications, the prevalence of these sequelae is much lower after sentinel lymph node biopsy than after axillary lymph node dissection. This is clear from the randomized studies in which complications of the two procedures can be directly compared. Every study shows lower complication rates for sentinel lymph node biopsy than axillary lymph node dissection and high axillary staging accuracy for sentinel lymph node biopsy alone. The prospective randomized trials show no increased recurrence rates or mortality when sentinel lymph node biopsy alone is performed with omission of axillary lymph node dissection for patients whose sentinel lymph nodes are tumor-free. These studies support the important recommendation that patients whose sentinel lymph nodes are free of metastasis not undergo axillary lymph node dissection. Dr. Giuliano is Executive Vice Chair, Surgery, Cedars-Sinai Medical Center, Los Angeles. He was Co-Chair of the Update Committee on sentinel node biopsy with Gary H. Lyman, MD, MPH, FASCO.

Key New Recommendation A major change from the 2005 guideline is the additional recommendation that axillary lymph node dissection can be omitted for some sentinel lymph node–positive patients. The impetus for this recommendation was a careful evaluation of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, which randomly assigned clinically node-negative patients who had clinical T1 or T2 tumors and only one or two positive sentinel lymph nodes to either completion of axillary lymph node dissection or sentinel lymph node biopsy only.3 All patients underwent whole-breast irradiation with opposing tangential fields. Prone irradiation, accelerated partial-breast irradiation, and third-field nodal irradiation were prohibited. Nearly all patients in both arms received adjuvant chemotherapy or endocrine therapy. At a median follow-up of 6.3 years, 0.9% of the sentinel lymph node biopsy–only group developed axillary recurrence compared to 0.5% of the group receiving sentinel lymph node biopsy followed by axillary lymph

with either sentinel lymph node micrometastases or macrometastases. This single important change will affect most women with early breast cancer and nodal metastasis since most women with tumor-involved sentinel nodes have only one or two involved nodes. The recommendation does not apply to patients treated with accelerated partial-breast irradiation or irradiation in the prone position. Those whose axillary nodal disease is documented by fine-needle aspiration may still undergo sentinel lymph node biopsy if the abnormal lymph node is removed. The panel still advises completion of axillary lymph node dissection for women with early-stage breast cancer undergoing mastectomy.

Unconsidered Study Results of the randomized AMAROS trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) were presented at the 2013 ASCO Annual Meeting but were not fully published and, therefore, were not considered for the guideline update.4 Clinicians should be aware of this study, since it

A major change from the 2005 guideline is the additional recommendation that axillary lymph node dissection can be omitted for some sentinel lymph node–positive patients. —Armando E. Giuliano, MD

node dissection. There was no significant difference in overall survival or disease-free survival between the two groups. This trial illustrated that completion of axillary lymph node dissection may be omitted in a select group of patients with sentinel lymph node metastases and led to this significant change in the 2014 ASCO guideline. In the opinion of the ASCO expert panel, axillary lymph node dissection can be avoided in patients with one or two nodes involved with metastatic cancer but only when conventionally fractionated wholebreast irradiation is planned and adjuvant systemic therapy is given. This recommendation applies to patients

offers an additional option for sentinel lymph node–positive patients, even those treated with mastectomy. The AMAROS trial randomly assigned patients with a tumor-involved sentinel lymph node to axillary irradiation or axillary lymph node dissection. The 5-year axillary recurrence rates were very low in both the axillary irradiation and axillary lymph node dissection groups. The disease-free survival rates were similar in the two groups, and there was no statistical difference in overall survival. However, there were fewer complications in the axillary irradiation patients, including a lower frequency of lymphedema (P < .0001). The decreased rate of lymph-

edema after nodal irradiation was still seen at 1, 3, and 5 years. The study will likely prove to be an important one, but determination of its full impact awaits careful evaluation of published results.

Additional Change An additional change from the prior guidelines relates to patients treated with neoadjuvant systemic therapy, who may now be offered sentinel lymph node biopsy before or after their treatment. Women with large or locally advanced breast cancer or inflammatory breast cancer should not receive sentinel lymph node biopsy. Most patients with ductal carcinoma in situ undergoing breast-conserving surgery should not undergo sentinel lymph node biopsy, nor should pregnant patients. The new ASCO guideline extends sentinel lymph node biopsy to more patients and confirms its clinical utility. The guideline suggests that sentinel lymph node biopsy is appropriate for most patients with early operable breast cancer. The ASCO committee encourages patients to speak with their multidisciplinary care team in order to fully understand their options and determine whether sentinel lymph node biopsy is appropriate for them. n

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

References 1. Lyman GH, Giuliano AE, Somerfield, MR, et al: American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 23:7703-7720, 2005. 2. Lyman GH, Temin S, Edge SB, et al: Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 32:1365-1383, 2014. 3. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis—a randomized clinical trial. JAMA 305:569-575, 2011. 4. Rutgers EJ, Donker M, Straver ME, et al: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023). 2013 ASCO Annual Meeting. Abstract LBA1001. Presented June 3, 2013.

The ASCO Post | JUNE 10, 2014

PAGE 46

Perspective Carolyn B. Hendricks, MD continued from page 1

the proportion of medical oncologists aged 64 and older surpassed the proportion of oncologists under the age of 40.) Another factor exacerbating the predicted oncology workforce shortage is physician burnout. While most medical oncologists feel that their practices are extremely rewarding and they really enjoy taking care of patients, the increased workload and administrative burdens placed on oncologists—especially those in small or solo private practices, who deliver 50% more clinical services than those in academic settings—are driving some to leave their current position or retire early.

I really want to preserve the small, nurturing, highquality practice environment that I have cultivated over the years, so I’m truly hoping that the changes outlined in ASCO’s The State of Cancer Care in America report will be enacted. —Carolyn B. Hendricks, MD

As outlined in the report, ASCO has developed significant initiatives to mitigate these issues and ensure that highquality cancer care for patients continues over the next decade and beyond. (A copy of The State of Cancer Care in America: 2014 can be downloaded at www.asco.org/stateofcancercare)

Making Hard Business Choices Another important medical oncology trend discussed in ASCO’s report is the demise of small and midsize community practices. According to ASCO’s 2013 census of U.S. oncology practices, nearly two-thirds of small practices reported that they were likely to merge, sell, or close operations in the next year. In addition to the impact these choices have on oncologists’ professional careers, they also present a significant hardship for patients.

Soon I may have to make some difficult business decisions of my own. Since 2001, I have been in a small solo practice in suburban Maryland that is dedicated to treating patients with breast cancer. I have a terrific staff and phenomenal patients and I really love my work, but right now I am seriously considering closing my practice.

Over the past several years, the cost of chemotherapy drugs has risen and reimbursement for chemotherapy drugs has fallen, taking my practice to the tipping point. In addition to the high drug costs, administering chemotherapy in the practice settingS:6.875” is very complex. In my small practice, chemotherapy administration requires the presence

of two highly trained oncology nurses, a highly skilled nurse practitioner, and a top-notch administrator to make sense of all the billing. Because chemotherapy drug pricing is directly tied to the amount purchased, in a really small practice like mine, or in any small practice across the United States that doesn’t buy these drugs in large quanti-

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ASCOPost.com | JUNE 10, 2014

PAGE 47

Perspective

ties, we pay more for the same chemotherapy drugs than larger practices do, and we have the same safety and staffing requirements as larger practices, so our expenses are proportionally greater.

Breaking the Bank In 2013, I had to purchase $3.4 million of chemotherapy drugs for my

patients. This is an average amount for medical oncologists, but in my small practice, the high cost covered the price of only a handful of drugs. Ensuring high-quality oncology care for patients is very time-intensive, so I can’t reduce my overhead expenses by seeing more S:6.875” patients, which would compromise the quality of the care I give.

As a result, for the past 2 years my practice has lost a significant amount of revenue. Community oncologists like me who have to purchase chemotherapy on credit then have to scramble to get reimbursed, which has led me to incur a significant amount of debt and a significant reduction in income. My income now approximates

WITHIN

what it was 10 years ago. In addition, I’ve experienced a significant staff shortage this year, which is also having a negative impact on my practice. I have a small staff, and two staff members were on maternity leave for 3 months at the same time. As a result, I had to transfer my patients to the local hospital for care during that time. In fact, my patients got very good care, but they were distressed at having to go to another facility. Moreover, they incurred much higher out-of-pocket expenses for their chemotherapy compared to their out-of-pocket costs for the exact same chemotherapy that was administered in my office.

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So what are my options? Should I purchase greater amounts of chemotherapy at a reduced cost or should I merge, sell, or close my practice? For more than a year, I was actually in negotiations with an academic medical center interested in either merging with my practice or purchasing it altogether. But the center withdrew from negotiations, claiming that the economic climate for outpatient oncology care is too precarious at this time to go forward with those plans. I’m now considering the possibility of merging with other local or regional oncology groups, which is the current trend. But that prospect is a bit daunting, and I’m deciding whether I instead need to close my practice. In either case, the impact on my staff and my patients would be significant. I really want to preserve the small, nurturing, high-quality practice environment that I have cultivated over the years, so I’m truly hoping that the changes outlined in ASCO’s The State of Cancer Care in America report will be enacted. Small practices like mine would benefit financially from those changes in multiple ways, keeping us solvent. For example, repealing the sustainable growth rate formula and reversing Medicare cuts caused by sequestration; aligning payment systems with the goal of delivering high-value, patient-centered care; and providing funding and support to help struggling practices make the transition to valuedriven payment models would all be extremely helpful measures. Steps along these lines would go a long way toward alleviating the workforce issues that I have described. Hopefully, these changes can be made rapidly enough, before I have to close my practice doors. n

The ASCO Post | JUNE 10, 2014

PAGE 48

Journal Spotlight Breast Cancer

Postmastectomy Radiotherapy Reduces Breast Cancer Recurrence and Mortality in Women With One to Three Positive Nodes By Matthew Stenger

eta-analyses have shown that postmastectomy radiotherapy reduces risks of recurrence and breast cancer mortality in the population of all women with node-positive disease, but outcomes in those with only one to three positive nodes have not been specifically examined. As reported by Paul McGale, PhD, and colleagues in The Lancet, an individual patient data meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group has shown that postmastectomy radiotherapy in this setting is associated with significantly reduced 10year risk of recurrence and 20-year risk of breast cancer mortality.1

Study Details The meta-analysis included individual data for 8,135 women randomly assigned to treatment groups between 1964 and 1986 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery vs the same surgery without radiotherapy. Follow-up was 10 years for breast cancer recurrence and through January 1, 2009, for mortality. The extent of axillary surgery was known for all but 183 women (2%). In total, 1,594 women (20%) had pathologically node-negative disease, 5,821 (72%) had pathologically node-positive disease, and pathologic nodal status was unknown for 720 (8%). A total of 3,831 women with known pathologic nodal status and known number of affected nodes had axillary dissection to at least level II and had zero, one to three, or at least four positive nodes. All of these patients were from trials in which radiotherapy included the chest wall, supraclavicular or axillary fossa (or both), and internal mammary chain.

Node-Negative Disease Of the 1,594 women with nodenegative disease, 700 (44%) had axillary dissection, 870 (55%) had axillary sampling, and extent of axillary surgery was unknown for 24 (1%). Among the 700

with axillary dissection, radiotherapy vs no radiotherapy was associated with no significant differences in proportions of women who had a locoregional recurrence prior to a distant recurrence over 10 years (3.0% vs 1.6%, (2P > .1), 10year overall recurrence (22.4% vs 21.1%, rate ratio [RR] = 1.06, 2P > .1), or 20year breast cancer mortality (28.8% vs 26.6%, RR = 1.18, 2P > .1). However, radiotherapy was associated with significantly greater 20-year overall mortality (RR = 1.23, 2P = .03). Among the 870 women with only ax-

Postsurgical Radiotherapy in Breast Cancer ■■ Among women undergoing axillary dissection who had one to three positive nodes, radiotherapy vs no radiotherapy was associated with significantly reduced risk of 10-year locoregional recurrence before distant recurrence, 10-year overall recurrence, and 20-year breast cancer mortality. ■■ These risk reductions remained significant when analysis was limited to women receiving systemic therapy.

fluorouracil, or tamoxifen) was given in both the radiotherapy and no-radiotherapy groups. Among these women, radiotherapy was associated with significantly

[T]he absolute risks of breast cancer recurrence and mortality have reduced in many countries because of advances in detection and treatment of breast cancer, so the absolute benefits from postmastectomy radiotherapy today are likely to be smaller than those reported here. —Early Breast Cancer Trialists’ Collaborative Group

illary sampling [vs axillary dissection], radiotherapy was associated with reduced 10-year risk of locoregional recurrence (ie, locoregional recurrence before distant recurrence) (2P < .00001) and 10-year overall recurrence (RR = 0.61, 2P = .0003) but had no significant effect on 20-year breast cancer mortality (RR = 0.97, 2P > .1) or overall mortality (RR = 1.00, 2P > .1).

One to Three Positive Nodes Of the 5,821 women with node-positive disease, 3,131 (54%) had axillary dissection, 2,541 (44%) had axillary sampling, and extent of axillary surgery was unknown for 149 (2%). Among the 1,314 women with axillary dissection and one to three positive nodes, radiotherapy was associated with significant reductions in risk for 10-year locoregional recurrence (3.8% vs 20.3%, 2P < .00001), 10-year overall recurrence (34.2% vs 45.7%, RR = 0.68, 2P = .00006), and 20-year breast cancer mortality (42.3% vs 50.2%, RR = 0.80, 2P = .01). A total of 1,133 of these women were in trials in which systemic therapy (cyclophosphamide, methotrexate, and

reduced risk of locoregional recurrence (4.3% vs 21.0%, 2P < .00001), overall recurrence (33.8% vs 45.5%, RR = 0.67, 2P = .00009), and breast cancer mortality (41.5% vs 49.4%, RR = 0.78, 2P = .01).

Four or More Positive Nodes and All Node-Positive Among the 1,772 women with axillary dissection and at least four positive nodes, radiotherapy was associated with significant reductions in 10-year risk for locoregional recurrence (13.0% vs 32.1%, 2P < .00001), 10-year overall recurrence (66.3% vs 75.1%, RR = 0.79, 2P = .0003), and 20-year breast cancer mortality (70.7% vs 80.0%, RR = 0.87, 2P = .04). Among all 3,131 women with nodepositive disease who had axillary dissection, radiotherapy was associated with significant reductions in risk for locoregional recurrence (8.1% vs 26.0%, 2P < .00001), overall recurrence (51.9% vs 62.5%, RR = 0.75, 2P < .00001), and breast cancer mortality (58.3% vs 66.4%, RR = 0.84, 2P < .001). In women not receiving radiotherapy, overall recurrence rates were higher during

Commentary on Postmastectomy Radiation See perspective by Bruce G. Haffty, MD on page 52

years 0 to 4 than during years 5 to 9. There was little difference between radiotherapy and no-radiotherapy groups in breast cancer mortality during the first few years of follow-up, with a reduction among those receiving radiotherapy being observed thereafter through years 10 to 15 and possibly beyond. Radiotherapy also reduced 20-year overall mortality among all women with node-positive disease who had axillary dissection (RR = 0.89, 2P = .01). The investigators concluded: After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given…. Radiotherapy techniques have improved in the past few decades and so the proportional benefits of radiotherapy are likely to be larger than in these trials. However, the absolute risks of breast cancer recurrence and mortality have reduced in many countries because of advances in detection and treatment of breast cancer, so the absolute benefits from postmastectomy radiotherapy today are likely to be smaller than those reported here. n Disclosure: The study was funded by Cancer Research UK, British Heart Foundation, and UK Medical Research Council. The study authors reported no potential conflicts of interest.

Reference 1. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group): Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. March 19, 2014 (early release online).

FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% confidence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

EXTEND SURVIVAL WITH ZELBORAF Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)† 100

HR=0.47 (95% CI, 0.35-0.62), P<0.0001

Percentage surviving

80 60 40 20 0

7 8 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (HR=0.47; 95% CI, 0.35-0.62; P<0.0001) —78 (23%) deaths and 122 (36%) deaths in the ZELBORAF and dacarbazine arms, respectively In an updated analysis, median OS was reached at 13.6 months with ZELBORAF: 3.3-month improvement over median OS of 10.3 months with dacarbazine (95% CI, 12.0-15.3 months vs 9.1-12.8 months) —Updated based on 478 deaths (ZELBORAF median follow-up 13.4 months)

Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.

Significant improvement in PFS ≈4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis. Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | JUNE 10, 2014

PAGE 52

Perspective

Should Breast Cancer Patients With One to Three Positive Nodes Routinely Receive Postmastectomy Radiation? By Bruce G. Haffty, MD

he Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) continues to provide valuable clinically relevant and prac-

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2. Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF* Trial 1: Treatment Naïve Patients

ADRs

Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

ZELBORAF n= 336 Grade All Grades 3a (%) (%)

Trial 2: Patients with Failure of at Least One Prior Systemic Therapy Dacarbazine ZELBORAF n= 287 n= 132 Grade Grade All All Grades 3a Grades 3 (%) (%) (%) (%)

37 33 45 23 24 9 8 19 5 14

8 3 <1 1 1 2 0 0 <1 0

2 4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0 * For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

and long-term follow-up in this database provide a unique opportunity to determine small but clinically meaningful differences in outcomes be-

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)]. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment. 8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)]. • ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)]. • Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)]. • Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)]. • ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)]. • Liver laboratory abnormalities can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)]. • ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)]. • Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)]. • ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

tween the treatment arms, which the smaller individual trials may be underpowered to detect. Over the years, due to the very long-term, detailed followup, sophisticated statistical methods, and meticulous processing of individual patient-level data from randomized trials, the EBCTCG has not only demonstrated improvements in outcomes associated with radiation therapy,1,2 but also has uncovered subtle but clinically important toxicities, including heart disease and second malignancies, associated with radiation.

Continuing Controversy The benefits of postmastectomy radiotherapy in reducing local-regional relapse rates and improving breast cancer mortality for nodepositive breast cancer patients has been clearly demonstrated in individual randomized trials, as well as in previous meta-analysis. While the benefits of postmastectomy radiation in patients with more advanced disease and/or at least four involved nodes has been widely embraced and accepted as the standard of care, the routine use of postmastectomy radiotherapy in patients with one to three involved nodes continues to be controversial. A previous effort by the Radiation Therapy Oncology Group evaluating postmastectomy radiation in patients specifically with one to three positive nodes closed due to poor accrual, though ongoing trials continue to address this issue. Advocates of postmastectomy radiation point to the local-regional control and breast cancer mortality rates demonstrated in several randomized trials. However, others argue that local-regional relapse rates with earlier detection, current surgical approaches, and more detailed pathologic processing—and with more powerful and effective systemic therapies—are currently much lower. These authors question the risk/ benefit ratio, given the potential toxicities of postmastectomy radiation.

Safety:10"

ZELBORAF ® (vemurafenib) tablet for oral use Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)]. 5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)]. 5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

tice-influencing information garnered from individual patient-level data from Safety:7" numerous randomized trials in breast cancer. The large numbers of patients

Dr. Haffty is Professor and Chair, Department of Radiation Oncology, RutgersCancer Institute of New Jersey, Robert Wood Johnson Medical School and New Jersey Medical School, New Brunswick.

ASCOPost.com | JUNE 10, 2014

PAGE 53

Perspective

The disagreement has resulted in wide variations in the application of postmastectomy radiotherapy for one to three positive nodes, continued debate, and, most important, confusion among patients and referring physicians regarding the benefit of postmastectomy radiotherapy in this group at mastectomy. Appropriately, the majority of clinicians selectively use postmastectomy radiation based on a number of clinical factors, including patient age and comorbidities, primary tumor size, receptor status, lymphovascular space invasion, grade, and other factors.

Valuable Update The current EBCTCG updated meta-analysis,3 reported in Lancet and reviewed in this issue of The ASCO Post, focuses on patients with one to three positive nodes and provides valuable information regarding the risk/benefit ratio of postmastectomy radiotherapy. The investigators clearly demonstrate a statistically significant and clinically meaningful impact of postmastectomy radiation on local-regional relapse, overall recurrence, and breast cancer mortality in patients with one to three nodes. While some of the trials included in the meta-analysis were older and in the pre–systemic therapy era, the study did involve more than 1,000 women in trials where systemic therapy was administered to both the radiotherapy and no-radiotherapy groups, in which radiotherapy was associated with a significantly reduced risk in local-regional recurrence, overall recurrence, and breast cancer mortality (41.5% vs 49.4%, rate ratio = 0.78, 2P = .01). Furthermore, there was no difference in the proportional reduction in breast cancer mortality associated with postmastectomy radiation based on whether there were one, two, or three nodes involved. Therefore, it appears that even patients with one involved node derived a significant benefit from postmastectomy radiation.

Current Considerations Although the reductions in localregional relapse and breast cancer mortality are impressive, patients in

the meta-analysis with one to three nodes randomly assigned to no postmastectomy radiation had relatively high rates of local-regional recurrence (21%) and overall recurrence (45%) compared to current reports. Given earlier detection of disease, improvements in surgical approaches, more detailed pathologic processing with serial sectioning (which often detects nodal micrometastasis), and more effective systemic therapy reported in more contemporary series, the absolute reduction in both local-regional recurrence and breast cancer mortality associated with postmastectomy radiation in patients with one to three involved nodes would be expected to be less in the current era than that reported in this meta-analysis. On the other hand, improvements in radiation therapy techniques with

The findings of the EBCTCG meta-analysis are also consistent with recent reports from the Canadian MA.20 trial4 and the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial.5 Patients with one to three involved lymph nodes, predominantly treated with breastconserving surgery, constituted a majority of patients in these trials, in which patients were randomly assigned to radiation directed to the breast/chest wall alone or radiation delivered to the breast/chest wall and regional lymphatics. Both of these trials also demonstrated reduced distant metastasis and reduced breast cancer mortality in addition to improved localregional relapse in the cohorts of patients randomized to regional nodal irradiation. The full publications

Given these data, it is important to consider and discuss the potential benefits of postmastectomy radiation with all patients who have node-positive disease. —Bruce G. Haffty, MD

computed tomography–based planning, lower doses to the nontarget cardiac and pulmonary structures, and more accuracy and precision in delivering radiation to the target chest wall and regional lymphatics are likely to improve the radiation treatment effect, reduce potential toxicities, and improve the therapeutic gain. Therefore, while the absolute reduction in local-regional relapse rates associated with postmastectomy radiation in patients with one to three positive nodes is likely to be smaller than that reported in the meta-analysis, the relative benefit and risk/benefit ratio of postmastectomy radiation is likely to persist for the majority of patients with one to three involved nodes.

of the MA.20 and EORTC trials in the near future will hopefully provide clinicians with further insight and details regarding the benefits of regional nodal irradiation in these patients.

Practical Implications As with the valuable previous efforts of the EBCTCG, this recent analysis demonstrating breast cancer mortality benefit with postmastectomy radiation in patients with one to three positive nodes is likely to have a significant impact on clinical practice. Appropriately, clinicians and patients are still likely to be selective in the use of postmastectomy radiation, utilizing the full spectrum of available clinical data and literature, including age, comor-

bidities, histology, grade, receptor status, primary tumor size, extent of nodal involvement, and other factors in the ultimate decision of whether to use postmastectomy radiation in patients with low nodal burdens. The currently available randomized data, however, provide a high level of evidence that postmastectomy radiation is associated with a clinically significant benefit in the majority of patients with positive nodes, including patients with one to three involved nodes. Given these data, it is important to consider and discuss the potential benefits of postmastectomy radiation with all patients who have node-positive disease. n

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

References 1. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005. 2. Early Breast Cancer Trialists’ Collaborative Group: Effect of radiotherapy after breast-conserving surgery on 10year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011. 3. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group): Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. March 19, 2014 (early release online). 4. Whelan TJ, Olivotto I, Ackerman I, et al: NCIC-CTG MA.20. An Intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol 29(suppl):Abstract LBA1003, 2011. 5. Poortmans PSH, Kirkove C, Budach V, et al: Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 years results of the EORTC radiation oncology and breast cancer groups phase III trial 22922/10925. Eur J Cancer 47(suppl 2), 2013.

The Value of Federally Funded Cancer Research ASCO has created a badge to raise awareness of the importance of federally funded biomedical research that improves the lives of people worldwide. The plenary presentations at ASCO’s Annual Meeting all were the result of federally funded research. To call attention to the value of federal funds, The ASCO Post has printed this badge alongside reports on data resulting from federally funded research (see pages 1 and 3 in this issue).

The ASCO Post | JUNE 10, 2014

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Expert’s Corner Supportive Care

Helping Young Adults Cope With Cancer A Conversation With Karen Fasciano, PsyD By Jo Cavallo

or young adults diagnosed with cancer, coping with the aftermath of the disease can be especially daunting. Although all cancer survivors share some common concerns and distress, for young adults grappling with body image, sexuality, peer pressure, dating, marriage, family planning, education, and career goals, the experience of having a life-threatening illness can be uniquely challenging and isolating. To ease the emotional burden of living with cancer for young survivors, in 2010, the Dana-Farber Cancer Institute in Boston launched a Young Adult Program. The program provides survivors between the ages of 18 and 34 being treated at the cancer institute with an array of clinical services to help them cope. This initiative includes an interactive website (www.dana-farber.org/ yap), which provides real-time online support groups, coping skill resources, educational material, and archived educational workshops. Survivors can also “friend” other survivors, have instantmessage chats, and post comments and videos on the website. The ASCO Post talked with Karen Fasciano, PsyD, Clinical Psychologist and Director of Dana-Farber’s Young Adult Program about the goals of the program, why young adults face greater emotional distress than pediatric or older cancer survivors, and what oncologists can do to ease the emotional burden of their young adult patients.

Targeted Support Why did Dana-Farber Cancer Institute launch the Young Adult Program? At Dana-Farber, we have world-class medical and pediatric oncology programs and are also committed to the emotional care of our patients during the cancer experience. As part of standard care, pediatric patients receive psychosocial support services. In the adult oncology setting, young adults had access to psychosocial programs, but most were not developmentally targeted to their needs. We were fortunate to receive philanthropic funding to change the structure of our supportive care for young adults and began our Young Adult Program. The program was created with input from medical and psychosocial clinicians who work with young adult pa-

tients, but most importantly with input from members of our young adult advisory board. The advisory board is made up of a very dedicated group of young adults who have coped with cancer and now donate their time and knowledge of the experience to guide our programmatic and clinical offerings. I can conclusively say that young adults receiving medical oncology care at Dana-Farber are offered emotional support that is targeted to their specific needs and delivered in ways that are acceptable to their life stage.

Online Resources What types of online programs do you provide? In addition to the virtual community where young adults can post a profile and messages, as well as instant-message, the website also has an overt educational component, including a skillbuilding section to help them enhance their coping skills while going through

Unique Challenges How does cancer affect young adults differently from children or older adults with the disease? Having cancer during young adulthood disrupts lives in a different way than it does the lives of pediatric or older adult patients. For example, young adults are often just starting out in their professional careers, and disruptions in that process can be more difficult to overcome than gaps in more established careers. In addition, a cancer diagnosis at this time can create a burden on forming new intimate relationships, which can be complicated by the emotional demands of having cancer, body image self-consciousness, and sexual health concerns—all the issues that are developmentally paramount to this population. Having cancer challenges young adults’ worldview and their sense of control, and exposes them to uncertainty and mortality in a way that many have

Providing young adult patients with resources for emotional support services and referrals to local and national support programs should be standard of care. —Karen Fasciano, PsyD

cancer treatment. We offer different strategies for managing issues like anxiety, communication challenges, changes in goals, and other problems arising from their cancer diagnosis. These sections are skill-based and draw from principles of cognitive behavioral therapy, but are presented in a targeted way that address concerns relevant to young adults. The website also provides educational material on such issues as exercise and sexual health. There are a number of other national social networking websites for young adults with cancer, but we wanted to create a local community at Dana-Farber that helps young adult patients feel more connected and less isolated. Preliminary results from our survey indicate that young adults feel less alone as a result of their participation on the website.

not experienced before. The diagnosis happens during a very important developmental time when many changes are taking place and normal developmental tasks are disrupted. For young patients with an incurable cancer and a shortened life expectancy, the emotional upheaval can be especially difficult. They have to discover ways to live a life that is meaningful to them, while at the same time accepting the loss of a long future—a struggle the majority of their healthy peers will not face for decades.

After Treatment Once treatment is completed, how diligent are young adults about maintaining their follow-up medical care? This is definitely an area of concern. Usually, young adults who have never

been sick prior to their cancer diagnosis don’t advocate for their health care in the same way older adults or parents of pediatric patients do. In my clinical experience, once young adults are done with their treatment, some become strong advocates for their health care and are vigorous about maintaining their routine follow-up medical care, and others may not be as vigilant, in some cases because they are not given specific survivorship care plans and do not understand what is expected of them. And young survivors want to put the experience behind them and move on with their lives? Many may want to do that, but most young survivors will not be able to leave the experience of cancer behind them, because it leaves a lasting impression on their lives. Young adults often expect that once they complete treatment, they will be physically and mentally back to normal. But then they find that there is some emotional healing that often comes with the end of treatment and that getting acclimated back into their normal day-to-day lives is not as easy as they expected it would be.

Action Points What can oncologists do to improve the emotional care of their young adult patients? Involving the patient’s family and support system in the patient’s care is essential for a young adult’s emotional well-being. Young adults may not know when or how to ask for this kind of help, but they will need emotional support. Oncologists should talk with their young adult patients about the psychosocial issues they may be experiencing and suggest appropriate solutions and referrals to mental health professionals. It is important to acknowledge the life disruptions a cancer diagnosis causes and try to limit them as much as possible, while at the same time normalizing the emotional impact of cancer. Providing young adult patients with resources for emotional support services and referrals to local and national support programs should be standard of care. n Disclosure: Dr. Fasciano reported no potential conflicts of interest.

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Awards

Demetrius H. Bagley, MD, Honored With AUA Lifetime Achievement Award

he American Urological Association (AUA) has presented D emetrius H. Bagley, MD, with its 2014 Lifetime Achievement Award for visionary leadership and education in ureteroscopy and minimally invasive surgical techniques for the upper urinary tract. Dr. Bagley is The Nathan Lewis Hatfield Professor of Urology and Professor of Radiology, Department of Urology at Jefferson Medical College in Philadelphia. The award was presented at the 2014 AUA Annual Meet-

Errata

n the May 15 issue of The ASCO Post, text was inadvertently dropped on page 4, at the end of a paragraph about novel agents for multiple myeloma, in the article, “NCCN Clinical Practice Guidelines in Oncology: 2014 Updates.” The complete paragraph should have read as follows:

ing held recently in Orlando, Florida. The AUA’s Lifetime Achievement Award is given to recognize an individual who has made outstanding contributions to advance the mission and goals of the American Urological Association. “Dr. Bagley has inspired his

colleagues with his vision and creativity. He has moved the field forward by bringing minimally invasive techniques such as ureteroscopy to the forefront of daily urologic care,” said Leonard B:7.875 in G. Gomella, MD, FACS, Chair of the T:7.625 in Department of Urology at Thomas JefS:6.625 in

ferson University and Hospitals. Dr. Bagley received his medical degree at Johns Hopkins University in Baltimore. His first faculty appointment in Urology was at the University of Chicago, and he has been at Jefferson Medical College since 1983. n

CLINICAL EVIDENCE INDICATES...

THERE ARE DISTINCT WAYS TO HELP MANAGE ADVANCED PROSTATE CANCER * INHIBIT ANDROGEN PRODUCTION

On the horizon are new classes of agents that are demonstrating very impressive gains in remission duration and survival: monoclonal antibodies (elotuzumab, which targets CS1, and daratumumab and SAR650984, which target CD38); an antibody-drug conjugate (indatuximab ravtansine, which targets CD138); histone deacetylase inhibitors (ricolinostat); a kinesin spindle protein inhibitor (filanesib); and an Akt inhibitor (afuresertib).

The complete article is available online at www.ascopost.com/ issues/may-15,-2014/nccn-clinicalpractice-guidelines-in-oncology2014-updates.aspx.

BLOCK THE ANDROGEN RECEPTOR

he article, “FGFR Inhibitors of Interest in Bladder and Lung Cancer,” which appeared in the May 15 issue of The ASCO Post, misidentified the affiliation of Lecia Sequist, MD. Dr. Sequist is a medical oncologist at Massachusetts General Hospital Cancer Center. The corrected article is available online at www.ascopost.com/ issues/may-15,-2014/fgfr-inhibitorsof-interest-in-bladder-and-lungcancer.aspx. n

EACH PLAYS AN IMPORTANT ROLE 1-3 Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990;144(4):934-941. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgensensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Expert’s Corner Technology

A Way Forward in Genomic Medicine By Ronald Piana

ver the past several decades, the convergence of scientific discovery, technology, and therapeutic developments has created an unparalleled opportunity to integrate our growing knowledge of genomics into the clinical practice of oncology. To shed light on the current state and future of genomics-driven cancer medicine, The ASCO Post recently spoke with Charis Eng, MD, PhD, FACP, ACS Clinical Research Professor, Chair and founding Director of the Genomic Medicine Institute at the Cleveland Clinic’s Lerner Research Institute.

Genomic Medicine Institute Please tell the readers a bit about the Genomic Medicine Institute (GMI). I founded the GMI about 8 years ago as a single platform for genetic and multiomics research, academic clinical activities, and education in genomic medicine as it pertains to personalized health care. Before this, there was not even the practice of traditional medical genetics at the Cleveland Clinic. Actually, I am one of only four formally trained clinical cancer geneticists in the nation. Since then, I’ve built out the clinical arm of the GMI, which we call the Center for Personalized Genetic Healthcare. It has become the nation’s most comprehensive center of genomic medicine, from the traditional prenatal and pediatric genetics to adult subspecialties like cancer genetics. Our research is very patient-oriented; the genetic and omics data we collect provides evidence-based cancer risk assessments to help guide clinical management of our patients. In the past, it could take several months for a patient to get genetic services. By standardizing the practice and actually completely disrupting the practice of medical genetics, we have sameday access. Accelerating the process has obvious clinical benefits, but it also reduces patient anxiety.

Genetic Counseling Our knowledge of genetics has rapidly expanded. Are we capable of fully using this knowledge in clinically meaningful ways? Yes, [we can make good use of this information] if clinicians know where to send their patients for genetic counseling, which is a crucial component of utilizing genetic information for clinical decision-making. My team has worked to integrate genetic services and genetic counselors throughout the Cleveland

Clinic system in the region and outside northeastern Ohio. Our genetic counselors now serve in approximately 20 clinical locations associated with nine different specialties, both on and off our main campus. In fact, last year about 4,000 new outpatients saw genetic counselors, up from about 600 in past years. Our goal is to integrate genomic medicine processes into every clinical subspecialty at Cleveland Clinic.

Decision-Making Dilemmas At the recent Society of Surgical Oncology meeting, you gave a lecture titled “GeneEnabled Surgical Decision-Making: The Agony and the Ecstasy.” Could you describe some of the highlights? The susceptibility gene PTEN that is being examined in Cowden syndrome makes a good genetics model, as many other heritable cancers flow along these lines. Generally PTEN mutations are found in 25% to 85% of people with Cowden syndrome, which confers a very high lifetime risk for several cancers— for instance, an 85% lifetime risk of developing breast cancer and a 25% lifetime risk of thyroid cancer. PTEN also confers a higher lifetime risk of developing colon, endometrial, and kidney can-

The agony part of this issue—as it’s related to Cowden syndrome with PTEN mutation—is that in doing a total thyroidectomy, it is impossible to remove every single cancer cell; therefore, we actually see thyroid grow back. When thyroids grow back, the thyroid cancer risk comes back. So even though our genetic predictors give a reason for clinical intervention, the patient still must undergo periodic lifetime surveillance. Moreover, because of the anatomic location of the thyroid, surgery is complicated and can result in scarring that makes follow-up surgery almost impossible. Again, it is great to have this genetic information, but we still need to know every clinical outcome associated with every variant (variant is used when one is not sure that it is a disease-associated mutation).

Genetic Screening Testimony In 2009, you testified at a meeting of the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) focused on evidence needed to evaluate screening genetic tests for Medicare coverage. Please explain how the federal government evaluated the potential of genetic screening.

Our goal is to integrate genomic medicine processes into every clinical subspecialty at Cleveland Clinic. —Charis Eng, MD, PhD, FACP

ing during the annual wellness visits. In retrospect, it was a good experience; however, it also gave me a good look at the challenges we face in dealing with government agencies. The bureaucracy was stifling, even to the point of the instructions, which were terribly unclear.

Personalized Medicine The term “personalized medicine” has captured the imagination of providers and payers. From your perspective, what does it mean and where are we going with it? Yes, everybody loves the term, but most don’t know the meaning. The term personalized medicine was first coined by Pharma as a way to frame genomics in the drug development process, ie, pharmacogenomics. I use personalized health care in a larger health-care context. Genetics is only one aspect of personalized health care. A human is not just one gene or even our 30,000 genes. You have to look at the whole landscape. Genomic personalized medicine should take into account the sum total of genegene interactions and gene-environment interactions. And it is one component of the continuum that moves from imaging all the way to prevention and treatment strategies. Hopefully one day soon everyone will have comprehensive knowledge of genetic and genomics-based personalized health care, not only for treatment and disease management, but also in the equally important field of disease prevention.

Closing Thoughts cers. So, we can predict a molecular diagnosis because we know the particular gene mutation. We even know the ages at which the risk rises within mutationpositive individuals. When we predict an 85% risk for developing breast cancer, it’s a no-brainer that we need to screen and also consider prophylactic prevention measures. These women may also have benign disease, making screening difficult. However, with magnetic resonance imaging, we can pretty accurately predict cancer. Deciding on a clinical course presents certain dilemmas, but it’s still better to have to make hard decisions that might save a life than to not have that information. This knowledge, although imperfect, gives us an array of options.

It was essentially a fact-finding process in that they wanted guidance on what genetic screening entailed and where we could apply it in a way that would benefit the public health system. Prenatal genetic screening is practiced worldwide, but expanding that to adult populations in order to screen for factors that predispose people to cancer and other adult-onset diseases is an area that was still confusing. The most interesting part is that all of us stood up and independently said that taking a family health history is the most effective and cost-efficient manner to screen for genetic disease. And although this meeting took place in 2009, CMS established two new “G” codes for family health history screen-

Any last thoughts on your work and what lies ahead? The principle on which I founded the Genomic Medicine Institute is the study of common genomic processes that lead to different diseases. Borrowing knowledge from other fields to inform cancer and vice versa actually makes research go faster. Finding the particular molecular switch that turns the process on in specific contexts is essential to determining who will develop the disease and, ultimately, how we can select targeted interventions to effectively treat or prevent the disease, as the situation demands. We are currently achieving small parts of genetics-based personalized health care, especially in the practice continued on page 57

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Announcements

Cancer Center at Johns Hopkins Set to Expand With $65 Million Gift

he Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins has announced it will use a $65 million gift toward the construction of a new patient care building that will be named for the late Albert P. “Skip” Viragh, Jr. Mr. Viragh, a Maryland mutual fund investment leader and philanthropist, was a patient at Johns Hopkins, where he was treated for pancreatic cancer. Mr. Viragh died of the disease in 2003 at age 62. The Skip Viragh Outpatient Cancer Building is slated for completion in 2017 and will be funded mostly by philanthropic gifts. The new facility will serve as the primary entry point for cancer care on the medical center campus.

medical, radiation, and other consultations and services. “Skip’s cancer experience taught us that having a place like Johns Hopkins is a key element in fighting the disease, and now, with Skip’s help, Johns Hopkins will be able to offer innovative,

easy-to-navigate care for many more people with cancer,” said Mark Viragh, Skip’s brother. The gift is part of Rising to the Challenge: The CampaignB:7.875 for Johns Hopkins, in an effort to raise $4.5T:7.625 billion, primarily in to support students,S:6.625 research and disin

covery, and interdisciplinary solutions to some of humanity’s most important problems. The campaign, supporting both the University and Johns Hopkins Medicine, is targeted for completion in 2017. More than $2.44 billion has been committed so far. n

IN ADVANCED PROSTATE CANCER…

DO YOUR PATIENTS HAVE

MORE ANDROGEN THAN YOU CAN CATCH WITH ANDROGEN RECEPTOR BLOCKADE?

Albert P. “Skip” Viragh, Jr

“Skip was an innovator in his world of personal finance, and, through his legacy gifts, he continues to partner with Johns Hopkins innovators in cancer care,” says William G. Nelson, MD, PhD, Director of the Johns Hopkins Kimmel Cancer Center and Professor of Oncology at the Johns Hopkins University School of Medicine. “The new building will be far more than a place for physician visits and diagnostic scans. It will be the place where we’ll explore novel ways to deliver cancer care and cures.” The Skip Viragh Building will be able to accommodate all adult medical oncology patient consultations and house multidisciplinary treatment clinics modeled on one established for pancreas cancer patients who can benefit from a wide range of coordinated surgical,

Charis Eng, MD, PhD, FACP continued from page 56

of clinical cancer genetics. So that’s the focus of my work moving forward. n Disclosure: Dr. Eng is a member of the external strategic advisory board of N-of-One, and external scientific advisory boards of the Center for Personalized Medicine, Mission Hospital, NC, CareSource and Medical Mutual of Ohio; and external scientific advisory boards of EcoEos and GenomOncology (unpaid).

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

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Direct From ASCO

ASCO Takes Aim at the Link Between Obesity and Cancer

SCO is stepping up its efforts to address the link between obesity and cancer—both as a leading cause of cancer and as a complicating factor for treatment. In recent years, research has demonstrated that a growing number of cancers are linked to obesity, and public health researchers predict that obesity will soon replace tobacco as the leading preventable cause of cancer. Yet public awareness about the connection remains low: one recent survey suggested that less than one in 10 Americans even realizes that obesity is a risk factor for cancer. “As oncologists, we have an obligation to take this challenge head on and identify ways to both reduce obesity-

be addressed in isolation from obesity’s other harmful effects, but we also need to aggressively build awareness—just as we did years ago with tobacco—that energy imbalance is a major contributor to the nation’s cancer burden,” added Dr. Hudis.

Understanding the Obesity–Cancer Link Excess weight has been linked with an increased risk for many of the most common cancers, including breast, colon, and high-grade prostate cancers. In 2007 alone, more than 50,000 new cases of cancer in women and 34,000 new cases in men were tied to obesity. By 2030, this combined figure will more than quadruple—with

As oncologists, we have an obligation to take this challenge head on and identify ways to both reduce obesity-related cancers and to ensure that obese and overweight individuals with cancer receive the very best possible care. —Clifford A. Hudis, MD, FACP

related cancers and to ensure that obese and overweight individuals with cancer receive the very best possible care,” said Clifford A. Hudis, MD, FACP, ASCO Immediate Past President. “We recognize that cancer cannot

400,000 obesity-related cancers projected annually. Researchers are also beginning to understand the biologic link between obesity and cancer. Potential causal mechanisms currently under study in-

clude the role of chronic inflammation in excess fat tissue, the influence of insulin and insulin-like growth factors, adipose tissue and estrogen production, and tumor regulators and adipokines. Obesity was a key focus of this year’s ASCO Annual Meeting. One study featured at the meeting explored the connection between obesity and breast cancer outcomes, finding that obesity raises breast cancer mortality risk by more than 30% in premenopausal and perimenopausal women with estrogen receptor–positive disease. Also at the meeting, ASCO and the American Association of Cancer Research (AACR) hosted a joint Special Session, titled “Inflammatory Cells and Cancer,” in which obesity was a key focus of discussion.

ASCO Issues New Resources ASCO is committed to helping oncologists manage the challenges associated with obesity. Given that nearly two-thirds of the U.S. adult population is now considered overweight or obese, obesity is already a critical factor in the care of many thousands of individuals diagnosed with cancer every year. ASCO also recognizes that patients with cancer need support in order to lose weight, or to maintain a healthy weight during cancer treatment and survivorship. To address these critical needs, in May, ASCO released “Obesity and Cancer: A Guide for Oncology Providers,” along with a complementary guide for patients. These resources include guidance on: continued on page 59

Explore Cancer Care That Best Supports Patients and Families at the Palliative Care in Oncology Symposium

alliative care is essential to good cancer care, but it is a topic that can raise red flags because of the common misperception that it is reserved for those in the terminal stage of the disease. In truth, palliative care is highly necessary for all patients with cancer, and when it is integrated into a treatment plan, evidence reveals that it results in improved outcomes for patients and their families. The Palliative Care in Oncology Symposium, to be held October 24 to 25 in Boston, highlights the critical need driving the integration of palliative and supportive care into cancer care. Cosponsored by the American Academy of Hospice and Palliative Medicine (AAHPM), the American Society of

Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Multinational Association of Supportive Care in Cancer (MASCC), this inaugural event will bring together the cancer community—

including oncologists, nurses, advanced practice providers, health services researchers, and other interdisciplinary stakeholders—for a focused dialogue on palliative care in oncology and how it can enhance the value of cancer care.

Providing palliative care is a responsibility that all of us share, each and every clinician that interacts with a cancer patient—whether you are an oncologist, infusion nurse, social worker, or specialty palliative care clinician. —Jennifer S. Temel, MD

Increased Focus on Palliative Care “Providing palliative care is a responsibility that all of us share, each and every clinician that interacts with a cancer patient—whether you are an oncologist, infusion nurse, social worker, or specialty palliative care clinician,” said Jennifer S. Temel, MD, Clinical Director of Thoracic Oncology and Associate Director of the Dana-Farber/Partners Cancer Care Hematology/Oncology Fellowship at Massachusetts General Hospital. “This Symposium will specifically present the state-of-the-art science behind providing cancer care that best supports patients and their families.” continued on page 60

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Direct From ASCO Obesity and Cancer continued from page 58

• The impact of obesity on cancer treatment, including its effect on outcomes and treatment complications • Strategies to promote weight loss and/or prevent weight gain in cancer survivors • Ways for physicians and patients to communicate effectively about challenges that patients face when trying to lose or maintain their weight • Guidance on insurance coverage and reimbursement for obesity-related care The obesity and cancer provider guide is available at asco.org/obesity along with additional resources. For patients, “Managing Your Weight After a Diagnosis With Cancer: A Guide for Patients and Families” and other resources on weight management during and after cancer treatment are available on ASCO’s patient website, Cancer.Net, at cancer.net/obesity. Printed versions of both the provider guide and patient booklet may also be ordered in bulk for physicians’ practices via the ASCO University Bookstore, at asco.org/store. The obesity and cancer provider guide is funded through the Conquer Cancer Foundation with the generous support of Roche and Ethicon Endo-Surgery.

develop and create access to effective treatments and interventions that help reduce obesity-related cancers and improve cancer care for obese patients,” said Dr. Hudis. “At the same time, we’ll continue looking for ways to ensure that the oncology community is wellequipped to meet the evolving needs of patients at a time when obesity is a de-

fining health challenge for the nation.” The Society is already working to integrate weight management into the oncology fellowship training curriculum. And later this year, ASCO will issue a policy statement that lays out a range of concrete B:7.875 recommendations in for addressing obesity and cancer, T:7.625 in along with ASCO’s plans to achieve S:6.625 in

these goals. Also this year, ASCO plans to convene a research summit that brings together investigators from a range of obesity-related disciplines to identify the most urgent questions and focus research resources. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCO’s Priorities on Obesity The new educational resources are just one part of ASCO’s stepped-up efforts to address the obesity-cancer connection. “Looking ahead, our focus will expand. For example, we’ll be advocating for policymakers and researchers to

ASCO’s Latest Breast Cancer Guidelines

n Cancer.Net, your patients can find information about ASCO’s new guidelines on the treatment of metastatic breast cancer and the updated guideline on hormone therapy for early-stage breast cancer. Each summary for patients provides an explanation of the recommendations, what they mean for patients, and a list of questions to ask the doctor. Learn more at www .cancer.net/recommendations. n

In mCRPC, is it appropriate to

INHIBIT ANDROGEN PRODUCTION BEFORE BLOCKING THE ANDROGEN RECEPTOR?* THIS APPROACH IS AN OPTION FOR TREATMENT IN ADVANCED PROSTATE CANCER.1,2 Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, prospective clinical study data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Sartor AO, Tangen CM, Hussain MHA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008; 112(11):2393-2400. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 02/14 008088-140106

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Direct From ASCO Palliative Care in Oncology Symposium continued from page 58

Improving outcomes has always been integral to ASCO’s mission, and the Society continues to champion quality in cancer care. While the Society has addressed palliative care–related issues through sessions at the ASCO Annual Meeting and as part of other events and campaigns, this Symposium will bring exclusive focus to palliative care in oncology. ASCO’s fellow cosponsoring organizations also recognize this need and have partnered with the Society to bring palliative care to the forefront, acknowledging that value in cancer care is measured, in part, by the patient experience. “The integration of palliative care into oncology is just the definition of good oncology care. We don’t provide good oncology care if we don’t integrate palliative care,” said Jamie Von Roenn, MD, Senior Director of Education, Science, and Professional Development at ASCO. Palliative care is sometimes used synonymously with end-of-life care, due to its specialized focus on reliev-

ing patient suffering. In fact, when cancer patients hear “palliative care,” they often assume they’re in the ter-

Jamie Von Roenn, MD

driven. Every cancer patient is concerned with how they’re going to live their life and how the treatments will affect them. Palliative care can help them live as well as possible in the face of their illness. Getting palliative care involved as you begin a treatment plan can be beneficial to ensure the least amount of suffering, good symptom control, and the control of distress and disruption in life.” While aspects of good symptom control and pain management are al-

minal stages of the disease. However, palliative care isn’t about simply ensuring comfort at the end of life; it’s key to delivering quality cancer care, starting from diagnosis and continuing through survivorship care.

Symposium Borne Out of Patient Need Michael J. Fisch, MD, MPH, Chair of the Symposium’s Steering Committee and Chair of the Department of General Oncology at The University of Texas MD Anderson Cancer Center, said, “The underlying need for this Symposium is patient-

Conquering

Michael J. Fisch, MD, MPH

ready integrated into oncology care, the Symposium will focus on more than managing the physical effects of cancer treatment. Sessions will focus on the physical—the biology of pain and fatigue, targeted therapy, symptom sci-

ence in preventing and treating acute effects of treatment, risk prediction models for treatment toxicities, biologic mechanisms and the underlying basis of cognitive complaints—and also psychosocial and emotional well-being of cancer patients. In addition, it will highlight the full spectrum of palliative care needed for patients at every stage of the disease—from diagnosis through treatment to survivorship and/or end of life.

Oral Abstract and Poster Sessions In addition to educational sessions, the Symposium will feature scientific abstracts in oral and poster sessions. Abstracts are currently being accepted on a range of topics, including: • Patient-Reported Outcomes: Mechanisms of Symptoms and Treatment Toxicities • Early Integration of Palliative Care in Cancer Care • Psycho-Oncology • End-of-Life Care • Survivorship For submission guidelines and to submit an abstract, visit pallonc.org /abstracts. The submission deadline is

Cancer. Together, anything is possible. The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supportingthe world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

DonATe ToDAY! ConquerCancerFoundation.org

ASCOPost.com | JUNE 10, 2014

PAGE 61

Direct From ASCO July 1, 2014, at 11:59 PM EDT. Each first author will receive a letter of notification via email regarding abstract selection in mid-August.

Spotlight on State-of-the-Art Practices Abstracts and didactic talks will examine the latest research findings and state-of-the-art practices, bringing specialized focus to the science behind palliative care. Session chairs and speakers are among the most recognized leaders in palliative care and oncology—an international panel of experts. Symposium highlights begin with the very first session, which explores the mechanisms, measurement, and management of palliative and supportive care and discusses the entire scope of symptom science.

“It’s all about making sure we understand the science behind what’s occurring, and that we can intercede in a mechanistically based way that has the best chance of reducing the impact of

and Senior Consultant Medical Oncologist at Royal Adelaide Hospital, “The session specifically focuses on what we know about the state-of-the-art bits of cancer care, including the science behind why the patient isn’t well and how we can intervene in that.”

Integrating Palliative Care Into Cancer Care

Dorothy M. K. Keefe, MD, FRACP

toxicities,” said Dorothy M.K. Keefe, MD, FRACP, President of MASCC, Service Director of South Australian Cancer Services, Professor of Cancer Medicine at the University of Adelaide,

Other sessions will explore survivorship issues, end-of-life care, and psycho-oncology. Several sessions will also examine the complexities of integrating palliative care into cancer care. Casting light on differing perspectives and what characterizes palliative and supportive care, the sessions will serve as a catalyst for discussion, and highlight different models of integrated care. Dr. Fisch noted,

“We’ll discuss these palliative care issues from a palliative care (AAHPM), supportive oncology (MASCC), and oncology (ASCO) perspective. We’ll acknowledge that palliative care is provided within all of these perspectives, but exactly how it should be integrated will require exploration, dialogue, and innovation.” “Every session will foster collaboration, present new research, generate novel ideas, and explore how we can move palliative care—and the field of oncology—forward,” added Dr. Temel. For the latest details and to register to attend the Palliative Care in Oncology Symposium, visit pallonc.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCO Immediate Past President Hudis Urges Congress to Invest in Medical Research

n April, ASCO Immediate Past President Clifford A. Hudis, MD, FACP, urged Congress to recognize the need for further investment in medical research to protect this valuable infrastructure in testimony submitted to the U.S. Senate Committee on Appropriations. The testimony provided examples of how federal funding for medical research, specifically through the National Institutes of Health and the National Cancer Institute, are driving medical innovation and resulting in new therapies for people with cancer. In the testimony, Dr. Hudis stated, “Domestically, declining federal funding for clinical trials, coupled with the rising costs of increasingly complex studies, will severely harm the nation’s

clinical research enterprise by limiting opportunities for innovation and demoralizing young clinical investigators. As opportunities to develop and lead trials diminish and institutional pressures to generate research funding and clinical revenue continue to

grow, young investigators may leave the field of research, or choose to pursue research opportunities in other countries. Not only does this threaten our progress against cancer, but it also diminishes the overall scientific workforce in America.”

ICD-10 Adoption Requirements Delayed for 1 Year

he legislation signed into law in early April creating another patch for the fundamentally flawed sustainable growth rate (SGR) formula for reimbursing physicians under Medicare also delays the adoption of International Classification of Diseases, 10th edition (ICD-10) coding system, which will fully replace ICD-9 on October 1,

2015. The October 1, 2014, deadline is no longer in effect. ASCO is encouraging practices to continue preparing for the transition before the new October 1, 2015, deadline. After this date, providers may no longer bill with ICD-9 codes. ASCO is currently updating the ICD-10 transitioning resources available in its on-

line resource center (available at www. asco.org/practice-research/icd-10) to reflect the new deadline. If you have any questions regarding ICD10, please contact ASCO via email at billingandcoding@asco.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

Save the Date Best of ASCO® Boston

Best of ASCO® Chicago

Best of ASCO® Seattle

August 8-9, 2014

August 15-16, 2014

August 22-23, 2014

Renaissance Boston Waterfront Hotel

Hilton Chicago

The Westin Seattle

Boston, Massachusetts

Chicago, Illinois

Seattle Washington

In the research of advanced cancers

What What if if inhibiting inhibiting the the PD-1 PD-1 helped helped restore restore immune immune

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checkpoint checkpoint pathway pathway response response to to tumor tumor cells? cells? Bristol-Myers Bristol-MyersSquibb Squibbisisresearching researchingways waysofofinhibiting inhibitingthe theinteraction interactionbetween betweenthe the PD-1 PD-1receptor receptorand andPD-L1 PD-L1and andPD-L2 PD-L2ligands, ligands,allowing allowingthe theimmune immunesystem systemtotorestore restore 3,10 3,10 T-cell T-cellattack attackon ontumor tumorcells, cells,which whichmay mayplay playaarole roleininhelping helpingthe thebody bodyfight fightcancer cancer Active T cell

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The ThePD-1 PD-1immune immunecheckpoint checkpointpathway: pathway:ananinnovative innovativetarget targetfor forcancer cancerresearch research 1-3,8 1-3,8 • By • By exploiting exploiting the the PD-1 PD-1 immune immune checkpoint checkpoint pathway, pathway, cancer cancer cells cells can can evade evade the the normal normal immune immune response response and and continue continue toto proliferate proliferate • Understanding • Understanding the the PD-1 PD-1 pathway pathway has has the the potential potential toto change change the the way way wewe approach approach certain certain cancers cancers

Learn more at www.pd1pathway.com • Experience the PD-1 checkpoint pathway through an immersive video • Hear a leading oncologist answer questions about the PD-1 checkpoint pathway • Learn more about how Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology

PD-1=programmed PD-1=programmed death death 1; PD-L1=PD-1 1; PD-L1=PD-1 ligand ligand 1; PD-L2=PD-1 1; PD-L2=PD-1 ligand ligand 2. 2. References: References: 1. Pardoll 1. Pardoll D, Drake D, Drake C. Immunotherapy C. Immunotherapy earns earns its spot its spot in the in the ranks ranks of cancer of cancer therapy. therapy. J Exp J Exp Med. Med. 2012;209(2):201-209. 2012;209(2):201-209. 2. Freeman 2. Freeman GJ, GJ, Long Long AJ, AJ, IwaiIwai Y, etY,al. etEngagement al. Engagement of the of the PD-1 PD-1 immunoinhibitory immunoinhibitory receptor receptor by abynovel a novel B7 family B7 family member member leads leads to negative to negative regulation regulation of lymphocyte of lymphocyte activation. activation. J Exp J Exp Med. Med. 2000;192(7):1027-1034. 2000;192(7):1027-1034. 3. Dong 3. Dong H, Strome H, Strome SE, SE, Salomao Salomao DR,DR, et al. etTumor-associated al. Tumor-associated B7-H1 B7-H1 promotes promotes T-cell T-cell apoptosis: apoptosis: a potential a potential mechanism mechanism of immune of immune evasion. evasion. NatNat Med. Med. 2002;8(8):793-800. 2002;8(8):793-800. 4. Hanahan 4. Hanahan D, Weinberg D, Weinberg RA.RA. Hallmarks Hallmarks of cancer: of cancer: thethe next next generation. generation. Cell.Cell. 2011;144(3):646-674. 2011;144(3):646-674. 5. Finn 5. Finn OJ. OJ. Cancer Cancer immunology. immunology. N Engl N Engl J Med. J Med. 2008;358(25):2704-2715. 2008;358(25):2704-2715. 6. Mellman 6. Mellman I, Coukos I, Coukos G, Dranoff G, Dranoff G. Cancer G. Cancer immunotherapy immunotherapy comes comes of age. of age. Nature. Nature. 2011;480(7378):480-489. 2011;480(7378):480-489. 7. Trapani 7. Trapani JA, JA, Smyth Smyth MJ.MJ. Functional Functional signifi signifi cance cance of the of the perforin/granzyme perforin/granzyme cellcell death death pathway. pathway. NatNat RevRev Immunol. Immunol. 2002;2(10):735-747. 2002;2(10):735-747. 8. Azuma 8. Azuma T, Yao T, Yao S, Zhu S, Zhu G, et G,al. etB7-H1 al. B7-H1 is aisubiquitous a ubiquitous antiapoptotic antiapoptotic receptor receptor on cancer on cancer cells. cells. Blood. Blood. 2008;111(7):3635-3643. 2008;111(7):3635-3643. 9. Latchman 9. Latchman Y, Wood Y, Wood CR, CR, Chernova Chernova T, etT,al. etPD-L2 al. PD-L2 is second is second ligand ligand for PD-1 for PD-1 andand inhibits inhibits T cell T cell activation. activation. NatNat Immunol. Immunol. 2001;2(3):261-268. 2001;2(3):261-268. 10.10. IwaiIwai Y, Ishida Y, Ishida M, Tanaka M, Tanaka Y, etY,al. etInvolvement al. Involvement of PD-L1 of PD-L1 on tumor on tumor cellscells in the in the escape escape from from hosthost immune immune system system andand tumor tumor immunotherapy immunotherapy by PD-L1 by PD-L1 blockade. blockade. ProcProc NatlNatl Acad Acad Sci U SciS U A.S2002;99(19):12293-12297. A. 2002;99(19):12293-12297.

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In the Clinic Thoracic Oncology

Ceritinib in ALK-Positive Metastatic NSCLC Patients With Progression on or Intolerance to Crizotinib 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.

n April 29, 2014, ceritinib (Zykadia) was granted accelerated approval for treatment of patients with anaplastic lymphoma kinase (ALK)positive, metastatic non–small cell lung cancer (NSCLC) with disease progression on or intolerance to crizotinib (Xalkori).1-3 Accelerated approval was based on tumor response rate and duration of response. No improvement in survival or disease-related symptoms has yet been established. Continued approval may be contingent on verification of clinical benefit in confirmatory trials.

Pivotal Study Approval was based on findings in a multicenter, single-arm, open-label trial in 163 patients with metastatic ALK-positive NSCLC who had shown

OF NOTE Ceritinib carries warnings/precautions for gastrointestinal toxicity, hepatotoxicity, interstitial lung disease/pneumonitis, QT interval prolongation, hyperglycemia, bradycardia, and embryofetal toxicity.

disease progression on or were intolerant of crizotinib. All patients received ceritinib at a dose of 750 mg once daily. The primary endpoint supporting approval was objective response rate according to RECIST v1.0 criteria as evaluated by both investigator and blinded independent central review committee. Duration of response was also assessed. Patients had a median age of 52 years, 54% were female, 66% were white, 97% were never or former smokers, 87% had Eastern Cooperative Oncology Group performance status of 0 or 1, 93% had adenocarcinoma histology, 91% had disease progression on crizotinib, 84% had received at least two prior therapies for metastatic disease, and sites of extrathoracic metastasis included the brain in 60%, liver in 42%, and bone in 42%. The objective response rate was 44%

(95% confidence interval [CI] = 36%– 52%), and median duration of response was 7.1 months based on independent central review and 55% (95% CI = 47%–62%) and 7.4 months based on investigator assessment. Editor’s note: Data were updated in abstract 8003 presented at the ASCO Annual Meeting, where after a median of 7 months of follow-up, patients treated with ceritinib achieved an overall response rate of 58.5% and median progression-free survival of 8.2 months. See the next issue of The ASCO Post for a full report on the ASCO presentation by Dong-Wan Kim, MD, PhD, of Seoul National University Hospital or visit ASCOPost.com.

How It Works Ceritinib is an inhibitor of ALK, insulin-like growth factor 1 receptor (IGF1R), insulin receptor (InsR), and ROS1 kinases, with greatest activity against ALK. It has been shown to inhibit autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays. The drug inhibits proliferation of cell lines expressing EML4-ALK and NPMALK fusion proteins and exhibits dosedependent inhibition of EML4-ALK– positive NSCLC xenograft growth in mice and rats. It also has exhibited dose-dependent antitumor activity at clinically relevant concentrations in mice with EML4ALK–positive NSCLC xenografts with demonstrated resistance to crizotinib.

How It Is Given The recommended dose of ceritinib is 750 mg once daily until disease progression or unacceptable toxicity. A recommended dose has not been determined for patients with moderate to severe hepatic impairment. Approximately 60% of patients starting treatment at this dose required at least one dose reduction, and the median time to first dose reduction was 7 weeks. Ceritinib should be discontinued in patients unable to tolerate 300 mg daily. Dose interruption or reduction is recommended for alanine transaminase or aspartate transaminase elevation more than five times the upper limit of normal with bilirubin elevation less than or equal to two times the upper limit of normal, QTc interval > 500 msec on two separate measurements, severe or intol-

erable nausea, vomiting, or diarrhea, persistent hyperglycemia > 250 mg/dL, and symptomatic bradycardia. Permanent discontinuation of ceritinib is recommended for alanine transaminase or aspartate transaminase elevation more than three times the upper limit of normal with bilirubin elevation more than two times the upper limit of normal in the absence of cholestasis or hemolysis, QTc interval prolongation with Torsade de pointes or polymorphic ventricular tachycardia or signs/ symptoms of serious arrhythmia, and life-threatening bradycardia in patients not taking medication known to cause bradycardia or hypotension. Concurrent use of strong CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole) should be avoided; if such use is unavoidable, the ceritinib dose should be reduced by approximately one-third (rounding to nearest 150 mg) and can be resumed at the former dose after discontinuation of the CYP3A inhibitor.

Safety Profile The median duration of exposure to ceritinib in the clinical trial was 6 months. The most common clinical adverse events of any grade were diarrhea (86%), nausea (80%), vomiting (60%), abdominal pain (54%), and fatigue (52%); the most common grade 3 or 4 adverse events were diarrhea (6%), fatigue (5%), nausea (4%), and vomiting (4%). The most common grade 3 or 4 laboratory abnormalities were increased alanine transaminase (27%), increased aspartate transaminase (13%), increased glucose (13%), increased lipase (10%), decreased phosphate (7%), and decreased hemoglobin (5%). Additional clinically significant adverse events included neuropathy (17%), vision disorder (9%), interstitial lung disease/ pneumonitis (4%), prolonged QT interval (4%), and bradycardia (3%). Adverse events led to dose reduction in 59% of patients, with the most com-

mon causes of dose reduction or interruption being increased alanine transaminase (29%), nausea (20%), increased aspartate transaminase (16%), diarrhea (16%), and vomiting (16%); overall, gastrointestinal toxicity resulted in dose modification in 38% of patients. Adverse events led to discontinuation of treatment in 10%. Serious adverse events in ≥ 2% consisted of convulsion, pneumonia, interstitial lung disease/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Fatal adverse events occurred in 5% of patients, consisting of pneumonia in four patients and respiratory failure, interstitial lung disease/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis in one patient each. Ceritinib carries warnings/precautions for severe or persistent gastrointestinal toxicity, hepatotoxicity, interstitial lung disease/pneumonitis, QT interval prolongation, hyperglycemia, bradycardia, and embryofetal toxicity. Liver tests should be performed at least monthly. Electrocardiograms and electrolytes should be monitored in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and those who are taking medications that are known to prolong the QTc interval.

Cost The wholesale cost of ceritinib is estimated at $13,500 per month. n References 1. U.S. Food and Drug Administration: Ceritinib. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm395386.htm. 2. ZYKADIA™ (ceritinib) capsules prescribing information, Novartis Pharmaceuticals Corporation, April 2014. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/2014/205755lbl.pdf. 3. Shaw AT, Kim D-W, Mehra R, et al: Ceritinib in ALK-rearranged non–small-cell lung cancer. N Engl J Med 370:1189-1197, 2014.

Role of Ceritinib in Lung Cancer ■■ Ceritinib (Zykadia) was granted accelerated approval for treatment of patients with ALK-positive, metastatic non–small cell lung cancer with disease progression on or intolerance to crizotinib (Xalkori). ■■ The recommended dosage of ceritinib is 750 mg once daily until disease progression or unacceptable toxicity.

As patient needs are changing— Pfizer’s assistance programs are changing too

Introducing Pfizer RxPathways™— our answer to changing patient needs For more than 25 years, Pfizer has offered an array of prescription assistance programs to help eligible patients get access to their Pfizer medicines. To meet the changing needs of today’s patients, we’ve consolidated these services into one comprehensive program. Introducing Pfizer RxPathways, formerly Pfizer Helpful Answers, our remodeled patient assistance program that helps eligible patients get access to their Pfizer medicines by offering a range of support services, including insurance counseling, co-pay help,* providing Pfizer medicines for free or at a savings, and more. Pfizer RxPathways: filling a need for prescription assistance

Visit www.PfizerRxPath.com to learn more. *This is not health insurance. Terms and conditions apply. Pfizer RxPathways™ is a joint program of Pfizer Inc. and the Pfizer Patient Assistance Foundation. Pfizer RxPathways™ is part of Pfizer’s Global Social Investments portfolio. For more information, please visit www.pfizer.com/responsibility. PHA562610

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The ASCO Post | JUNE 10, 2014

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European Multidisciplinary American Roentgen Ray Society Cancer Annual Congress Meeting Thoracic Oncology

Experts Share Keys to a Successful Lung Screening Program By Shalmali Pal

here are currently 172 computed tomography (CT)-based lung screening centers up and running in the United States, according to the Lung Cancer Alliance.1 In a presentation at the American Roentgen Ray Society (ARRS) 2014 Annual Meeting in San Diego, Reginald Munden, MD, DMD, MBA, and Ralph Drosten, MD, discussed their experiences with launching lung screening programs in an academic and community setting, respectively.2 Both physicians agreed that creating guidelines, setting rules for implementation and reporting, and considering the financial implications are keys to a successful program. Dr. Munden is currently Chair and Professor at Houston Methodist Hospital and Research Institute. Dr. Drosten is Associate Professor of Radiology at the University of Arizona, Tucson, and Creighton University, Omaha.

Setting program guidelines includes deciding who to screen. National organizations have developed elgibility criteria for screening including: • U.S. Preventive Services Task Force (USPSTF): Low-dose CT screening for high-risk individuals, ages 55 through 80, who have a 30 pack-year history of smoking or who have quit in the past 15 years. • National Comprehensive Cancer Network: Screening at 50 or with a smoking history of 20 pack-years for those who have one or more additional risk factors, such as occupational exposure to carcinogens.

A lung cancer screening program must be a multidisciplinary effort, with close consultation between radiologists, primary care physicians, thoracic and cancer specialists, and subspecialists.

Role of Collaboration The speakers emphasized that a lung cancer screening program must be a multidisciplinary effort, with close consultation between radiologists, primary care physicians, thoracic and cancer specialists, and subspecialists. Dr. Munden pointed out that this may be easier to achieve in an academic setting because everyone is “under the same roof.” But Dr. Drosten noted that collaboration is still possible even when the interested parties are scattered. The lung screening program at his hospital is done through a partnership with SimonMed, an outpatient imaging corporation with 35 locations in the Phoenix area. Through weekly meetings and semiregular, in-house symposia, the physicians in the lung screening program have overcome geography to “break down barriers. With the weekly interaction with my colleagues, I know more about what what affects their practice and they know more about what affects mine,” he said.

ing. The group at MD Anderson Cancer Center began by accepting selfreferred patients, but found it caused some problems. “If you accept self-referral, you have to be willing to become the physician of record, which means you assume all responsibility for their care. We required that the person have a physician of record … so that when we did the screening study, that results were sent to [that physician]. That can cause a problem because sometimes the physician of record doesn’t know this exam is transpiring. Now we require the patient to have an order [for lung screening] from a

—Reginald Munden, MD, DMD, MBA, and Ralph Drosten, MD

series of questions that will set eligible patients in the right direction. Once the appointment is scheduled, CT technologists need to be trained in how to answer questions the patients have about the screening process or the results. In addition, “you really need a coordinator for the program; someone who is … the face of the program; patients will identify with and communicate with that person,” Dr. Munden said, adding that at MD Anderson, the lung screening coordinator is a full-time position. At St. Joseph’s, the coordinator is full-time, and the position is currently held by a nurse navigator. One role of that coordinator is to help patients enter a smoking cessation program, and this needs to be an integral part of a screening system, the radiologists agreed. In the early days of the Phoenix program, 48% of the patients screened were active smokers, but at 6 months’ follow-up, 46% said they had decreased their smoking and 33% had stopped smoking altogether, Dr. Drosten noted. Achieving those kinds of results means taking the time and resources to lead patients to a stop-smoking program. It’s “not enough to hand out a [smoking cessation] brochure; you need to talk to patients and possibly sign them up for a cessation program,” Dr. Munden advised.

Who Gets the Results? Positive results from the National Lung Screening Trial (NLST) were achieved in current and former smoker, ages 55 to 74, with a smoking history of at least 30-pack years and without signs, symptoms, or history of lung cancer. Dr. Munden and Dr. Drosten were part of the NLST trial.3

Self-Referral Issues Eligible or not, patients will self-refer, usually after seeing advertising or a marketing campaign for lung screen-

Lung Cancer Screening ■■ A lung cancer screening program must be a multidisciplinary effort, requiring close consultation among radiologists, primary care physicians, thoracic and cancer specialists, and subspecialists. ■■ A smoking cessation program needs to be an integral part of a lung screening program. ■■ Initial investments in a lung screening program will be offset by “downstream revenue,” or revenues generated by referring patients for treatment or continued imaging studies.

physician,” Dr. Munden explained. Dr. Drosten noted that patients who self-select tend to be healthier and have better outcomes, which introduces screening bias. Also, overdiagnosis and unnecessary treatment are of concern as screening may detect disease that will never be clinically important. He also emphasized that lung screening is likely to find other diseases—coronary pulmonary disease, hiatal hernias, or other (esophageal, breast) cancers.

Key Elements Two elements are needed to ensure that the right patients are being screened: an algorithm deployed by every program employee who comes into contact with the patient, and a program manager to coordinate care. At both MD Anderson and St. Joseph’s Hospital, the algorithm kicks in with the call center staff, who are trained to ask a

For image interpretation, both programs follow the Lung CT Screening Reporting and Data System (LungRADS) set out by the American College of Radiology.4 In terms of who gets a report, results are mailed to the patients and the primary care physician to ensure that nothing “falls through the cracks,” Dr. Munden stressed. Given their multiple-site setup, the Phoenix program uses a teleradiology program in which images acquired offsite are sent to a central location and interpreted by one of three trained readers. This ensures a homogeneous reporting process, Dr. Drosten said. However, one issue that program managers will have to decide on is how long to keep the images, because they will accumulate as a screening program grows, he warned.

Program Costs Finally, there are money matters. The radiologists agreed that the initial continued on page 68

Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months

Median DR

9.2 months (95% CI: 7.1, 10.8)

All responders (n=74) Patients who achieved a CR/CRu

10.4 months (95% CI: 9.3, 13.6)

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Months

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. 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 myelosuppressionrelated 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 NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥ 15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia. Please see accompanying brief summary of Full Prescribing Information on following pages. Learn more at TREANDAHCP.com. Reference: 1. Data on file. Teva Pharmaceuticals. ©2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40313 December 2013.

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European Multidisciplinary American Roentgen Ray Society Cancer Annual Congress Meeting Successful Lung Screening continued from page 66

investment in a lung screen program will be rewarded down the line. Dr. Drosten noted that as part of his program’s marketing effort, the initial cost of the screening study was reduced over the course of a year, from a high of $199 to a low of $29.

Each price cut spiked patient interest enough that there was a dramatic increase in volume. “We scanned more people in December than we had from January to November,” he said. Dr. Munden pointed out that some patients who self-pay will gain private insurance coverage under the Affordable Care Act (as a result of a grade B

rating from the USPSTF) for screening. However, while the ARRS meeting was being held, an advisory committee for the Centers for Medicare & Medicaid Services (CMS) gave a “no” vote to covering the test.5 A proposed decision from CMS is expected in November, with a final ruling 90 days later (see page 1).6

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin’s Lymphoma That Has Progressed 1 INDICATIONS AND USAGE TREANDA® is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. 2 DOSAGE AND ADMINISTRATION 2.2 Dosing Instructions for NHL Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic 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 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. 2.3 Reconstitution/Preparation for Intravenous Administration Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer 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 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. Use Sterile Water for Injection, USP, for reconstitution and then 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 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 refrigerated (2-8°C or 36-47°F) or for 3 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 for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. 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 (see Table 2). Three patients (2%) died from myelosuppression-related 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 treatmentrelated 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 (2.2)]

What that decision will mean to lung screening programs is unclear, Dr. Munden said. “The government paid us $230 million to prove [that lung screening worked in the NLST], and we did. n Disclosure: Drs. Munden and Drosten reported no potential conflicts of interest.

5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing 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 infusion 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 postmarketing 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); Infusion Reactions and Anaphylaxis (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6). The data described below reflect exposure to TREANDA in 176 patients who participated in two singlearm trials for the treatment of indolent B-cell NHL. 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. 6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥ 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥ 5%) were fatigue

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European Multidisciplinary American Roentgen Ray Society Cancer Annual Congress Meeting References 1. Phend C: Community centers take up lung screening torch. MedPage Today. April 29, 2014. Available at www.medpagetoday.com. 2. Muden R, Drosten R: Lung cancer screening: A practical approach. 2014 ARRS Annual Meeting. Presented May 4, 2014.

3. Aberle DR, DeMello S: Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 369:920-931, 2013. 4. Lung CT Screening Reporting and Data System (Lung-RADS), version 1.0 assessment categories. American College of Radiology, April 28, 2014. Available at www.acr.org.

(11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176) Number (%) of patients* System organ class Preferred term All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) Cardiac disorders 0 Tachycardia 13 (7) Gastrointestinal disorders 7 (4) Nausea 132 (75) 5 (3) Vomiting 71 (40) 6 (3) Diarrhea 65 (37) 1 (<1) Constipation 51 (29) 1 (<1) Stomatitis 27 (15) 2 (1) Abdominal pain 22 (13) 0 Dyspepsia 20 (11) 0 Gastroesophageal reflux disease 18 (10) 1 (<1) Dry mouth 15 (9) 0 Abdominal pain upper 8 (5) 0 Abdominal distension 8 (5) General disorders and administration site conditions 19 (11) Fatigue 101 (57) 3 (2) Pyrexia 59 (34) 0 Chills 24 (14) 1 (<1) Edema peripheral 23 (13) 4 (2) Asthenia 19 (11) 1 (<1) Chest pain 11 (6) 0 Infusion site pain 11 (6) 0 Pain 10 (6) 0 Catheter site pain 8 (5) Infections and infestations 5 (3) Herpes zoster 18 (10) 0 Upper respiratory tract infection 18 (10) 4 (2) Urinary tract infection 17 (10) 0 Sinusitis 15 (9) 9 (5) Pneumonia 14 (8) 11 (6) Febrile neutropenia 11 (6) 2 (1) Oral candidiasis 11 (6) 0 Nasopharyngitis 11 (6) Investigations 3 (2) Weight decreased 31 (18) Metabolism and nutrition disorders 3 (2) Anorexia 40 (23) 8 (5) Dehydration 24 (14) 1 (<1) Decreased appetite 22 (13) 9 (5) Hypokalemia 15 (9) Musculoskeletal and connective tissue disorders 5 (3) Back pain 25 (14) 0 Arthralgia 11 (6) 2 (1) Pain in extremity 8 (5) 0 Bone pain 8 (5) Nervous system disorders 0 Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) Psychiatric disorders 0 Insomnia 23 (13) 1 (<1) Anxiety 14 (8) 0 Depression 10 (6) Respiratory, thoracic and mediastinal disorders Cough 1 (<1) 38 (22) Dyspnea 3 (2) 28 (16) Pharyngolaryngeal pain 1 (<1) 14 (8) Wheezing 0 8 (5) Nasal congestion 0 8 (5) Skin and subcutaneous tissue disorders Rash 1 (<1) 28 (16) Pruritus 0 11 (6) Dry skin 0 9 (5) Night sweats 0 9 (5) Hyperhidrosis 0 8 (5) Vascular disorders Hypotension 2 (1) 10 (6) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

5. Centers for Medicare & Medicaid Services: MEDCAC Meeting 4/30/2014—Lung Cancer Screening With Low Dose Computed Tomography. Available at www.cms.gov. 6. Phend C: Medicare advisers say no to lung cancer screening. MedPage Today. April 30, 2014. Available at www. medpagetoday.com.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology variable All Grades Grades 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. 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. 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 an antineoplastic product. Follow special handling and disposal procedures1. 16.2 How Supplied TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. 16.3 Storage TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd or its affiliates. All rights reserved. 8/2013 (Label Code: 00016287.06) TRE-40155 This brief summary is based on TRE-008 TREANDA full Prescribing Information.

NIH Addiction Science Award

ily Wei Lee, a high school senior at Stuyvesant High School in New York City, was named the recipient of the top Addiction Science Award at the 2014 Intel International Science and Engineering Fair (ISEF) for her project, “Assessment of Third-Hand Exposure to Nicotine from Electronic Cigarettes.” The Intel ISEF Addiction Science Awards were presented at a ceremony held recently at the Los Angeles Convention Center.

Third-Hand Exposure The 18-year-old wondered whether e-cigarette use could pose a risk of thirdhand exposure, where nicotine from vapors sticks to surfaces to affect nonusers even if they aren’t exposed to the e-cigarette use. She took three brands of e-cigarettes and filled them with varying nicotine concentrations. Using a syringe to ensure consistent puffs, e-cigarettes were “vaped,” after which nicotine concentrations were measured from surrounding surfaces—a glass window, vinyl walls, tiled floor, metal, and wood. Ms. Lee found significant increases in the amount of nicotine on all five surfaces; the floor and window had the greatest nicotine levels. The amount of residual nicotine depended on the particular brand used. She hopes to next explore whether ecigarette use is related to increased thirdhand exposure to cancer-causing agents. “This bright, young scientist showed that nonusers can be exposed to nicotine residue from just one e-cigarette, even if the e-cigarette usage occurred some time ago,” said Nora D. Volkow, MD, Director of the National Institute of Drug Addiction (NIDA), part of the National Institutes of Health, which coordinates the Awards. “Chronic e-cigarette use would be expected to produce even higher levels of third-hand nicotine exposure, and it’s unclear how such exposure could impact the health of close family members, friends, and coworkers who are regularly exposed to these environments.” n

First-place winner of 2014 Addiction Science Award (l-r): Judges and NIDA grantees Keith Heinzerling, MD, and Mitchell Wong, MD, PhD, UCLA; winner Lily Wei Lee; Judge and NIDA grantee Bridget Freisthler, PhD, UCLA; and NIDA’s Sheri Grabus, PhD.

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Health-Care Policy MEDCAC and Lung Cancer Screening continued from page 1

Under the Affordable Care Act, private insurers must cover any procedure that receives a grade B recommendation from the USPSTF. However, the Affordable Care Act preventive services coverage clause does not apply to Medicare, the population that screening advocates maintain would most benefit from lung cancer screening. “The MEDCAC decision is surprising and disappointing. Keep in mind, the NLST was one of the largest, cleanest lung cancer screening studies ever performed and established firm evidence that CT screen-

Benjamin P. Levy, MD

ing reduces lung cancer mortality. In this study, the number needed to screen to save a life was 320, which is comparable to other cancer screening modalities,” said Benjamin P. Levy, MD, Director of Thoracic Medical Oncology at Mount Sinai Beth Israel Hospital, New York, and a member of ASCO’s Integrated Media and Technology Committee. Dr. Levy continued, “Not endorsing a modality that saves lives is a missed opportunity. It is estimated that if CT screening were implemented appropriately it would save anywhere from 5,000 to 10,000 patients a year. Clearly, the panelists took issue with some of the well-known shortcomings of the NLST study, such as the high false-positive rate. I don’t want to minimize these concerns, because they are valid. However, I believe that in short time, quality assessment measures will refine and address these limitations.” Dr. Levy emphasized that detecting and treating early-stage lung cancer saves lives and downstream costs. He sensed that the MEDCAC panel was overly concerned about the logistical challenges of conducting highquality screening programs outside of the clinical trial setting. “Again, the concerns voiced by MEDCAC are real, but they can be addressed. Considering the public health benefit at

stake, I think we should take a leap of faith in the system and move forward with screening.

Major Organizations Back Screening More than 40 medical organizations, including the Lung Cancer Alliance, the Society of Thoracic Surgeons, and the American College of Radiology, petitioned CMS to provide national Medicare coverage for lung cancer screening. Moreover, based largely on the results of the NLST, the National Comprehensive Cancer Network (NCCN) recommended lung cancer screening, which is a significant endorsement given that in 2008, CMS recognized the NCCN compendium in its coverage decisions. The MEDCAC meeting, which was conducted on a single working day, featured presentations by Peter Bach, MD, Director of Memorial Sloan Kettering Cancer Center’s Center for Health Policy and Outcomes, Laurie Fenton Ambrose, President and CEO of the Lung Cancer Alliance, and lung cancer experts James L. Mulshine, MD, Associate Provost for Research and Director of the Translational Sciences Consortium at Rush Medical College, Rush University, Claudia I. Henschke, PhD, MD, Head of Lung and Cardiac Screening at Mount Sinai Medical Center and principal investigator for the Early Lung Cancer Action Project (ELCAP) studies, and Ella A. Kazerooni, MD, Professor of Radiology at University of Michigan Health System and Chair of the American College of Radiology (ACR) Lung Cancer Screening Committee.

“Without national Medicare coverage for CT lung cancer screening, seniors face a two-tier coverage system in which those with private insurance will be covered for these exams and many of their lives saved, while Medicare beneficiaries are left with lesser access to these exams and placed at increased risk of dying from lung cancer,” Dr. Kazerooni told The ASCO Post.

Ella A. Kazerooni, MD

Asked about the structure of the meeting, Dr. Kazerooni replied, “We only had 1 day to present our data. The morning session consisted of presentations, which in the end gave us only 90 minutes to debate this issue, which was not nearly enough time to have meaningful dialogue and rebut MEDCAC’s questions on safety, quality, and the ability to generalize screening programs outside the clinical trial setting.” To the panel’s lack of confidence in quality programs conducted outside of the clinical trial setting, Dr. Kazerooni responded, “People have the misconception that the entire NLST study was performed in tertiary care academic centers, when in fact about 25% of the centers involved were not academic medical centers.” She continued, “In NLST, the follow-up testing done on positive

How the MEDCAC Panelists Voted

rading their responses on a 5-point scale, where 5 represented the highest level of confidence, Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) members were asked the following questions: • How confident are you that there is adequate evidence to determine if the benefits outweigh the harms of lung cancer screening with low-dose CT? Mean score = 2.2222. • How confident are you that the harms of lung cancer screening with lowdose CT if implemented in the Medicare population will be minimized? Mean score = 2.3333. • How confident are you that clinically significant evidence gaps remain regarding the use of low-dose CT for lung cancer screening in the Medicare population outside a clinical trial? Mean score = 4.4444.

screens could be performed anywhere. NLST made some general recommendations, but there was no algorithm recommended for followup of positive screens. So if you were part of NLST and had a positive screen and you lived in a big city like Chicago or New York, it’s most likely that your follow-up was done outside of the screening center.”

Standardized Reporting On May 1, the ACR released the first edition of its Lung Imaging Reporting and Data System (LungRADS), a quality assurance tool for the standardized reporting of lungcancer CT screening studies. LungRADS features a number-based rating method similar to the college’s successful Breast Imaging–Reporting and Data System (BI-RADS) for mammography reporting. As Lung-RADS primary author, Dr. Kazerooni commented, “I talked about Lung-RADS in my MEDCAC presentation, and I was also able to briefly touch on the program during the discussion portion of the meeting. However, as I mentioned, there simply was not enough time to fully explain how the program standardizes the quality and reporting.” She added, “The committee that developed Lung-RADS studied the NLST and ELCAP databases to see how we could reduce the falsepositive rates in lung screening. Our preliminary observation showed that using Lung-RADS would reduce the false-positive screen rates from 1 in 4 to about 1 in 10. This is a very good number, and we arrived at this place because of our increased ability to detect malignant from benign nodules.” Dr. Kazerooni commented that along with not having enough time to make their case, the MEDCAC panelists were not conversant in the field of radiology, radiation oncology, and medical imaging, making their task even harder (see sidebar, MEDCAC Roster, on page 71). She also noted that most, if not all, the MEDCAC panelists practice at medical centers with active lung cancer screening programs. Looking forward, Dr. Kazerooni remarked, “CMS will take MEDCAC’s recommendations into consideration when it puts out a draft of its national coverage decision for low-dose CT screening by mid-November, followed by a 30-day public comment period before it’s finalized. So, we need to continue the dialogue with Medicare on issues like radiation exposure, quality reporting and

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Health-Care Policy

accreditation in the community, and all the other issues that I think when combined, will lead to a favorable coverage decision.”

Medicare Population Data Questioned At the end of the day, which by all accounts was at times contentious, the nine member MEDCAC panel voted on a scale of 1 to 5 on whether they were confident that the benefits of low-dose CT lung cancer screening would outweigh the harms in the Medicare population (see sidebar). The mean score was 2, which represents low confidence. During the prevote discussion, the MEDCAC panel members voiced concerns about the potential for overdiagnosis and a high frequency of false-positives, which would result in additional workups, patient anxiety, and far too many unnecessary treatments along with the

attendant side effects. Given the USPSTF’s earlier B recommendation, MEDCAC’s low confidence caught many health-care experts by surprise. Asked to explain the evaluation process, MEDCAC Panel Chair Rita Redberg, MD, of the University of California, San Francisco, told The ASCO Post, “It’s important to note that the USPSTF and MEDCAC were looking for answers to different questions. The MEDCAC conclusions are really not out of line with the USPSTF, but the scope of our work was slightly different in that we focused on the overall harms and benefits in the Medicare population alone; the benefits shown in the NLST were less significant in that population.” She continued, “Surgical mortality increases as one gets older, and the benefits of early detection tend to disappear as you get older because there are more competing causes of death. Moreover, there are no quality-of-life

data available from NLST, but clearly when you have a technique where 96% of the nodules turn out to be benign, it creates a lot of unnecessary anxiety plus additional procedures, which are not insignificant.” Asked about the 20% survival benefit shown in the NLST, Dr. Redberg said, “It’s easy to focus on an overall number, but we drilled into the data and looked at the net benefit in the Medicare population, which did not convince us that the benefits of screening outweighed the substantial harms. Another issue of concern was the ability to conduct standardized widespread screening. From past experience, we know that the ideal conditions of a clinical trial protocol are rarely replicated in actual practice. For instance, Dr. Bach’s presentation showed that many community programs were not using the same rigid criteria used by the NLST. But in the

end, MEDCAC was focused on the benefits vs harms in the Medicare population, and the evidence just wasn’t there to support screening.”

Long and Difficult Debate The vast majority of lung cancer patients are current or former smokers, and while survival rates have vastly improved for most cancers over the past 40 years, lung cancer survival rates have remained dismally low. Advocates are adamant that properly conducted lung cancer screening programs would save thousands of lives per year. Others, such as the ninemember MEDCAC panel, remain unconvinced that the benefits outweigh the potential harms of screening. The next critical phase in this long and difficult debate will unfold before the end of the year. Stay tuned. n Disclosure: Drs. Levy, Kazerooni, and Redberg reported no potential conflicts.

MEDCAC Roster Rita Redberg, MD, MS, Chair Professor of Medicine UCSF School of Medicine Division of Cardiology University of California, San Francisco, Medical Center Art Sedrakyan, MD, PhD, Vice Chair Associate Professor and Director Patient Centered Comparative Outcomes Research Program Weill Cornell Medical School Harry Burke, MD, PhD Associate Professor Biomedical Informatics and Medicine Uniformed Services University of the Health Sciences Clinician, Internal Medicine Service Walter Reed National Military Medical Center Allan M. Fendrick, MD Professor Department of Internal Medicine University of Michigan School of Public Health Mark D. Grant, MD, PhD Director Technology Assessment Technology Evaluation Center Center for Clinical Effectiveness Blue Cross Blue Shield Association

Jo Carol Hiatt, MD, MBA, FACS Chair, Inter-Regional New Technology Committee Kaiser Permanente David Howard, PhD Associate Professor Health Policy and Management Emory University Gail Melkus, EdD, C-NP, FAAN Florence and William Downs Professor in Nursing Research Director, Muriel and Virginia Pless Center for Nursing Research Curtis Mock, MD, MBA Senior Medical Director Vice President, Medicare Advantage UnitedHealthcare Medicare & Retirement Gerald A. White, Jr, MS, AAPM, FACR Medical Physicist Penrose Cancer Center St. Mary Corwin Regional Medical Center

Industry Representative Martin D. Marciniak, MPP, PhD Vice President US Health Outcomes GlaxoSmithKline

Guest Panel Members

Invited Guest Speakers

V. Paul Doria-Rose, DVM, PhD Epidemiologist National Cancer Institute Division of Cancer Conrol and Population Sciences Applied Research Program Health Services and Economics Branch

Laurie Fenton Ambrose President and CEO Lung Cancer Alliance

Michael K. Gould, MD, MS Senior Research Scientist Director for Health Services Research and Implementation Science Kaiser Permanente Southern California Kaiser Permanente Research Department of Research & Evaluation Jeffrey B. Rich, MD CardioThoracic Surgeon Mid-Atlantic Cardiothoracic Surgeons, Ltd Steven H. Woolf, MD, MPH Director Center on Society and Health Professor Department of Family Medicine and Population Health Virginia Commonwealth University

Peter Bach, MD, MAPP Attending Physician & Director Center for Health Policy and Outcomes Memorial Sloan Kettering Cancer Center Doug Campos-Outcalt MD, MPA Chair Department of Family, Community and Preventive Medicine University of Arizona College of Medicine, Phoenix Paul Pinsky, MD Division of Cancer Prevention National Cancer Institute National Institutes of Health

CMS Liaison Tamara Syrek Jensen, JD Acting Director Coverage and Analysis Group

Executive Secretary Maria Ellis Coverage and Analysis Group

The ASCO Post | JUNE 10, 2014

PAGE 72

JCO Spotlight Breast Cancer

ASCO Endorses SSO/ASTRO Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stage I/II Breast Cancer By Matthew Stenger

s reported in the Journal of Clinical Oncology,1 ASCO has endorsed the recently published Society of Surgical Oncology (SSO) and American Society for Radiation Oncology (ASTRO) consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer.2 The endorsement, with minor qualifications, was made after ASCO Clinical Practice

Lisa A. Newman, MD, MPH

Guidelines Committee staff reviewed the SSO/ASTRO guideline for developmental rigor and an ad hoc review panel reviewed the guideline content. The panel was co-chaired by Thomas A. Buchholz, MD, of The University of Texas MD Anderson Cancer Center, Houston, (see commentary by Dr. Buchholz on page 76), and Lisa A. Newman, MD, MPH, of the University of Michigan Comprehensive Cancer Center, Ann Arbor. The primary recommendation of the SSO/ASTRO guideline is that the use of “no ink on tumor” (ie, no cancer cells adjacent to any inked edge/surface of the specimen) is the standard for adequate surgical margin in invasive cancer in the era of multidisciplinary therapy. This margin criterion is associated with low rates of ipsilateral breast tumor recurrence and has the potential to decrease re-excision rates, improve cosmetic outcomes, and reduce healthcare costs. The ASCO review panel agreed “that the recommendations are clear, thorough, and based on the most relevant scientific evidence in the area and that they present options acceptable to patients.” The SSO/ASTRO clinical questions and recommendations and ASCO qualifying comments are summarized below.

SSO/ASTRO Recommendations What is the absolute increase in risk of ipsilateral breast tumor recurrence with a positive margin? Can the use of radia-

tion boost, systemic therapy, or favorable tumor biology mitigate this increased risk? Recommendation: Positive margins, defined as ink on invasive cancer or ductal carcinoma in situ, are associated with at least a twofold increase in ipsilateral breast tumor recurrence. This increased risk is not eliminated by delivery of radiation boost, systemic therapy, or favorable biology. Do margin widths wider than no ink on tumor cells reduce the risk of ipsilateral breast tumor recurrence? Recommendation: Negative margins (no ink on tumor) optimize ipsilateral breast tumor recurrence. Wider margin widths do not significantly lower this risk. What are the effects of endocrine or biologically targeted therapy or systemic chemotherapy on ipsilateral breast tumor recurrence? Should a patient who is not receiving any systemic treatment have wider margin widths? Recommendation: Rates of ipsi-

Recommendation: The choice of whole-breast radiation delivery technique, fractionation, and boost dose should not be dependent on margin width.

ductal carcinoma in situ burden after lumpectomy. There is no evidence of an association between increased risk of ipsilateral breast tumor recurrence when margins are negative.

Is the presence of lobular carcinoma in situ at the margin an indication for re-excision? Do invasive lobular carcinomas require a wider margin (than no ink on tumor)? What is the significance of pleomorphic lobular carcinoma in situ at the margin? Recommendation: Wider negative margins than no ink on tumor are not indicated for invasive lobular cancer. Classic lobular carcinoma in situ at the margin is not an indication for re-excision. The significance of pleomorphic lobular carcinoma in situ at the margin is uncertain.

ASCO Qualifying Statements

Should increased margin widths be considered for patients of young age (≤ 40 years)? Recommendation: Young age (≤ 40 years) is associated with both increased ipsilateral breast tumor recur-

The ASCO ad hoc guideline review panel has reviewed the SSO/ASTRO guideline and endorses the adoption of the guideline, with minor qualifications. lateral breast tumor recurrence are reduced with the use of systemic therapy. There is no evidence suggesting that margins wider than no ink on tumor are needed in the rare case of a patient not receiving adjuvant systemic therapy. Should unfavorable biologic subtypes (such as triple-negative breast cancers) require wider margins (than no ink on tumor)? Recommendation: Margins wider than no ink on tumor are not indicated based on biologic subtype. Should margin width be taken into consideration when determining wholebreast radiation delivery techniques?

rence after breast-conserving therapy and increased local relapse on the chest wall after mastectomy and is also more frequently associated with adverse biologic and pathologic features. There is no evidence that increased margin width removes the increased risk of ipsilateral breast tumor recurrence in young patients. What is the significance of an extensive intraductal component in the tumor specimen, and how does this affect margin width? Recommendation: An extensive intraductal component identifies patients who may have a large residual

Margins for Breast-Conserving Surgery ■■ The primary recommendation of the SSO/ASTRO guideline is that the use of no ink on tumor is the standard for adequate surgical margin in invasive cancer. ■■ The ASCO ad hoc guideline review panel endorses the adoption of the SSO/ASTRO guideline, with minor qualifications.

The ASCO panel stated that it reinforces and amplifies the guideline authors’ call for monitoring of outcomes at the institutional level during the transition to adoption of the SSO/ASTRO recommendations. The panel authors noted, “Margin assessments can be influenced by institutionspecific practices related to specimen handling, imaging, and processing. Outcome monitoring should include frequency of re-excision, rates of local recurrence, and the institutional or program standard for defining a minimal negative margin thickness (ie, distance between cancer cells and inked margin surface on microscopic specimen sections) as being adequate.” The panel noted that use of the guideline will likely result in narrower margins and fewer patients undergoing re-excision. Thus, the panel urges heightened emphasis on the importance of postlumpectomy mammography for cases involving microcalcifications. The authors stated, “If narrower margins become more common as a consequence of the SSO/ ASTRO guideline, post-lumpectomy mammography for cases that involve satellite lesions or microcalcifications will be essential to insure adequate resection of the primary site of disease before proceeding to breast irradiation.” Finally, the panel noted the inherent weaknesses, particularly selection bias, of the retrospective, observational studies that form the basis of many of the SSO/ASTRO recommendations, and thus urged that flexibility be used in application of the guideline. The panel quotes Jagsi and colleagues, in a recent comment on the guideline in International Journal of Radiation Oncology Biology Physics,3 who commended the SSO/ASTRO guideline authors for avoiding the “blanket prescription of behavior,” and thus allowing clinicians to make more individualized treatment decisions. In this regard, it is noted that the continued on page 76

When mCRC tumors

after progression on an oxaliplatin-containing regimen, should you consider an alternative approach? ZALTRAP® (ziv-aflibercept), in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. ZALTRAP inhibits angiogenesis by trapping VEGF-A, VEGF-B, and PLGF as shown in pre-clinical studies1-3,* * The clinical significance is unknown.

Important Safety Information for ZALTRAP® (ziv-aflibercept) WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage. GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation. Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. WARNINGS AND PRECAUTIONS Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. — Bleeding/hemorrhage (all grades) occurred in 38% of ZALTRAP/ FOLFIRI patients vs. 19% of placebo/FOLFIRI patients. Grade 3-4 hemorrhagic events, including GI hemorrhage, hematuria, and post-procedural hemorrhage, occurred in 3% of ZALTRAP/ FOLFIRI patients vs. 1% of placebo/FOLFIRI patients. Severe intracranial hemorrhage and pulmonary hemorrhage/ hemoptysis including fatal events have occurred in patients receiving ZALTRAP. — Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage. GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. — Across three clinical trials (colorectal, pancreatic, and lung cancer), GI perforation (all grades/Grade 3-4) occurred in 0.8%/0.8% of ZALTRAP patients and 0.3%/0.2% for placebo patients. — Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP in patients who experience GI perforation. ZALTRAP impairs wound healing in animal models. Grade 3 compromised wound healing occurred in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI and none of the patients treated with placebo/FOLFIRI. — Discontinue ZALTRAP in patients with compromised wound healing. — Suspend ZALTRAP for at least 4 weeks prior to elective surgery and do not initiate/resume ZALTRAP until at least 4 weeks after major surgery and surgical wound is fully healed. — For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 1.5% (9/611) of ZALTRAP/FOLFIRI treated patients and 0.5% (3/605) of placebo/FOLFIRI patients. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula.

ZALTRAP.com/HCP

increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP. — There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Of patients treated with ZALTRAP/FOLFIRI who developed Grade 3-4 hypertension, 54% had onset during the first two cycles of treatment. — Monitor blood pressure at least every two weeks, treat with appropriate anti-hypertensive therapy, and continue monitoring blood pressure regularly during ZALTRAP treatment. Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy. Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. ATE occurred in 2.6% of ZALTRAP/FOLFIRI patients and 1.7% of placebo/FOLFIRI patients. Grade 3-4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE. Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. — Proteinuria was reported in 62% of ZALTRAP/FOLFIRI patients compared to 41% of placebo/FOLFIRI patients. Grade 3-4 proteinuria occurred in 8% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/ FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. — Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria. Obtain a 24-hour urine collection in patients with a dipstick of ≥2+ for protein or UPCR >1. — Suspend ZALTRAP when proteinuria ≥2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours. — If recurrent, suspend until proteinuria <2 grams/24 hours and then reduce ZALTRAP dose to 2 mg/kg. — Discontinue ZALTRAP if nephrotic syndrome or TMA develops. A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. — Grade 3-4 neutropenia occurred in 37% of ZALTRAP/FOLFIRI patients compared to 30% of placebo/FOLFIRI patients. Grade 3-4 febrile neutropenia occurred in 4% of ZALTRAP/FOLFIRI patients compared to 2% of placebo/FOLFIRI patients. Grade 3-4 neutropenic infection/sepsis occurred in 1.5% of ZALTRAP/FOLFIRI patients compared to 1.2% of placebo/FOLFIRI patients. — Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ≥1.5 x 109/L.

Incidence

of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI. — Grade 3-4 diarrhea was reported in 19% of ZALTRAP/FOLFIRI patients compared to 8% of placebo/FOLFIRI patients. Grade 3-4 dehydration was reported in 4% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients. — The incidence of diarrhea is increased in patients ≥65 years of age compared to patients <65 years of age. Monitor closely. RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Confirm diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death. ADVERSE REACTIONS The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache. The most common Grade 3-4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia. Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/ FOLFIRI and 7% of patients treated with placebo/FOLFIRI. PREGNANCY AND NURSING MOTHERS ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment. It

is not known whether ZALTRAP is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Please see Brief Summary of full Prescribing Information on next page. References: 1. ZALTRAP Prescribing Information. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; October 2013. 2. Tew WP, Gordon M, Murren J, et al. Clin Cancer Res. 2010;16:358-366. 3. Riely GJ, Miller VA. Clin Cancer Res. 2007;13(15 suppl):4623s-4627s.

In the U.S., ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. US.AFL.14.02.002 2/14 Printed in the U.S.A. © 2014 sanofi-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion

Rx Only

Brief Summary of Prescribing Information WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

INDICATIONS AND USAGE

ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) in the full prescribing information]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) in the full prescribing information]. Continue ZALTRAP until disease progression or unacceptable toxicity. 2.2 Dose Modification / Treatment Delay Recommendations Discontinue ZALTRAP for: • Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula formation [see Warnings and Precautions (5.4)] • Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)] • Arterial thromboembolic events [see Warnings and Precautions (5.6)] • Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)] • Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)] Temporarily suspend ZALTRAP: • At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)] • For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)]. • For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)]. For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information. 2.3 Preparation for Administration Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles. Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial. Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags. Store diluted ZALTRAP at 2–8°C (36–46°F) for up to 4 hours. Discard any unused portion left in the infusion bag. 2.4 Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Do not administer as an intravenous (IV) push or bolus. Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line. Administer ZALTRAP using an infusion set made of one of the following materials: • PVC containing DEHP • DEHP free PVC containing trioctyl-trimellitate (TOTM) • polypropylene • polyethylene lined PVC • polyurethane 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) were reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and postprocedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)]. 5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo.

Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)]. 5.3 Compromised Wound Healing ZALTRAP impairs wound healing in animal models [see Nonclinical Toxicology (13.2) in the full prescribing information]. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/ FOLFIRI regimen and in none of the patients treated with placebo/FOLFIRI regimen. Suspend ZALTRAP for at least 4 weeks prior to elective surgery. Do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with compromised wound healing [see Dosage and Administration (2.2)]. 5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2)]. 5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/ FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment. Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled, and permanently reduce ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)]. 5.6 Arterial Thromboembolic Events Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2)]. 5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC, proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/ FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Patients with a dipstick of ≥2+ for protein or a UPCR greater than 1 should undergo a 24-hour urine collection. Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)]. 5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/ FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 109/L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/ FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea. 5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Confirm the diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula Formation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.6)] • Proteinuria [see Warnings and Precautions (5.7)] • Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)] • Diarrhea and Dehydration [see Warnings and Precautions (5.9)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)]

6.1 Clinical Trial Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI. The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1). The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1). The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria. The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modification in 5% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI. The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients treated with ZALTRAP/ FOLFIRI compared to placebo/FOLFIRI are shown in Table 1. Table 1 – Selected Adverse Reactions and Laboratory Findings in Study 1: Placebo/FOLFIRI (N=605) Primary System Organ Class Preferred Term (%)

ZALTRAP/FOLFIRI (N=611)

All grades

Grades 3–4

All grades

Grades 3–4

0.8%

Infections and infestations Urinary Tract Infection Blood and lymphatic system disorders Leukopenia

72%

12%

78%

16%

Neutropenia

57%

30%

67%

37%

Thrombocytopenia

35%

48%

Decreased Appetite

24%

32%

Dehydration

0.3%

22%

11%

1.5%

41%

19%

28%

0.2%

Metabolism and nutrition disorders

Nervous system disorders Headache Vascular disorders Hypertension

Respiratory, thoracic and mediastinal disorders Epistaxis

Dysphonia

25%

0.5%

Dyspnea

0.8%

12%

0.8%

Oropharyngeal Pain

0.2%

Rhinorrhea

Diarrhea

57%

69%

19%

Stomatitis

33%

50%

13%

Abdominal Pain

24%

27%

4% 1%

Gastrointestinal disorders

Abdominal Pain Upper

11%

Hemorrhoids

Rectal Hemorrhage

0.5%

0.7%

Proctalgia

0.3%

0.5%

11%

Proteinuria*

41%

62%

Serum creatinine increased

19%

0.5%

23%

Skin and subcutaneous tissue disorders Palmar-Plantar Erythrodysesthesia Syndrome Skin Hyperpigmentation Renal and urinary disorders

General disorders and administration site conditions Fatigue

39%

48%

13%

Asthenia

13%

18%

AST increased

54%

62%

ALT increased

39%

50%

Weight decreased

14%

0.8%

32%

Investigations

Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 *Compilation of clinical and laboratory data Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4),

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion

including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/ FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%). In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZALTRAP with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with ZALTRAP in pregnant women. ZALTRAP was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose. 8.3 Nursing Mothers It is not known whether ZALTRAP 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 ZALTRAP, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)]. The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. No dose adjustment of ZALTRAP is recommended for patients greater than or equal to 65 years of age. 8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3) in the full prescribing information]. There are no data available for patients with severe hepatic impairment. 8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.8 Females and Males of Reproductive Potential Male and female reproductive function and fertility may be compromised during treatment with ZALTRAP, as suggested by findings in monkeys [see Nonclinical Toxicology (13.1) in the full prescribing information]. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment. 10 OVERDOSAGE There have been no cases of overdose reported with ZALTRAP. There is no information on the safety of ZALTRAP given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2013 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC ZIV-BPLR-SA-OCT13

Revised: October 2013

The ASCO Post | JUNE 10, 2014

PAGE 76

Perspective

Margin Reassessment in Breast-Conservation Therapy By Thomas A. Buchholz, MD, FACR, FASTRO

ignificant progress has been made in local-regional and systemic treatments of breast cancer. Most patients currently diagnosed with breast cancer in the United States are diagnosed with early-stage disease and achieve excellent outcomes with breast-conservation therapy. Indeed, outcomes have significantly improved compared to the first generation of trials investigating breast conservation. For example, patients with stage I to II estrogen receptor– positive, HER2/neu–negative disease treated with breast-conservation surgery, breast irradiation, and adjuvant hormonal therapy have in-breast recurrence rates of only 0.5% per year.

Important Concept An important surgical concept in breast conservation is the resection of gross disease with achievement of negative surgical margins. Over the past 2 decades, there has never been consensus on what represents an optimal negative margin. Some have considered having no tumor present on the inked resection margin to be adequate, whereas others preferred having at least 1 or 2 mm of normal tissue separating the disease and the margin. Unfortunately, while numerous publications have explored the issue Dr. Buchholz is Executive Vice President and Physician-in-Chief, The University of Texas MD Anderson Cancer Center, Houston.

SSO/ASTRO Guideline continued from page 72

guideline states that it is not known whether the recommendations apply to women treated with accelerated partial-breast irradiation. Further, as suggested by Jagsi et al, re-excision might be reasonably considered in patients who are underrepresented in the studies included in the SSO/ASTRO analysis, including, for example, a young patient with “multiple very close mar-

of margin width, there has never been a well-designed prospective trial to investigate this question. Accordingly, individual practitioners have adopted their own standards, resulting in heterogeneous practice patterns across the United States. Many were trained to recommend reexcision for margins within 1 mm or within 2 mm. These recommendations are made with the hope that they minimize the

whole-breast irradiation in stage I and II invasive breast cancer is an excellent attempt to bring some consensus to this topic.1 The authors of the guideline represented a multidisciplinary panel of experts who critically evaluated the available data and provided consensus recommendations to aid practitioners in their decisions regarding the need for reexcision. The guideline was recently en-

It is hoped that the guideline can lead to more selective use of reexcision and thereby improve cosmetic outcomes and reduce costs. —Thomas A. Buchholz, MD, FACR, FASTRO

risk of breast recurrence. However, it is clear that reexcision subjects patients to additional surgery, can affect long-term cosmesis, and increases costs. Management of close margins can also result in more women being treated with mastectomy.

Attempt at Consensus The recently published Society of Surgical Oncology (SSO) and American Society for Radiation Oncology (ASTRO) guideline on margins for breast-conservation surgery with gins of less than 1 mm across a broad front, an extensive intraductal component, and large breasts that would easily accommodate a re-excision.”3 The authors concluded, “The ASCO ad hoc guideline review panel has reviewed the SSO/ASTRO guideline and endorses the adoption of the guideline, with minor qualifications.” n Disclosure: Dr. Newman reported no potential conflicts of interest.

dorsed by ASCO, as reported in Journal of Clinical Oncology2 and reviewed in this issue of The ASCO Post. It is hoped that the guideline can lead to more selective use of reexcision and thereby improve cosmetic outcomes and reduce costs. It is important for practitioners to appreciate that breast cancer is a biologically diverse spectrum of disease. The most common subcategory of breast cancer is driven by estrogen receptor signaling and, as indicated above, the outcomes for References 1. Buchholz TA, Somerfield MR, Griggs JJ, et al: Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/ American Society for Radiation Oncology consensus guideline. J Clin Oncol. April 7, 2014 (early release online). 2. Moran MS, Schnitt SJ, Giuliano AE, et al: Society of Surgical Oncology-American

such patients treated with modernday combined-modality treatment is truly outstanding. For such patients, the costs of routine reexcision of close but negative margins likely outweigh any benefit. However, in less common subsets, such as young patients with triple-negative disease, breast recurrence rates remain at clinically significant levels despite modern multidisciplinary treatment. For situations in which breast recurrence rates remain high, it is still reasonable to consider reexcision of a close margin. n

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

References 1. Moran MS, Schnitt SJ, Giuliano AE, et al: Society of Surgical OncologyAmerican Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole breast irradiation in stage I and II invasive breast cancer. Ann Surg Oncol 21:704716, 2014; Int J Radiat Oncol Biol Phys 88:553-564, 2014; J Clin Oncol 32:15071515, 2014. 2. Buchholz TA, Somerfield MR, Griggs JJ, et al: Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline. J Clin Oncol 32:1502-1506 2014.

Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole breast irradiation in stage I and II invasive breast cancer. Ann Surg Oncol 21:704-716, 2014; Int J Radiat Oncol Biol Phys 88:553-564, 2014; J Clin Oncol. February 10, 2014 (early release online). 3. Jagsi R, Smith BD, Sabel M, et al: Individualized, patient-centered application of consensus guidelines to improve the quality of breast cancer care. Int J Radiat Oncol Biol Phys 88:535-536, 2014.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | JUNE 10, 2014

PAGE 77

Clinical Trials Resource Guide Gastrointestinal Oncology

Ongoing Clinical Trials Actively Recruiting Patients With Pancreatic Cancer Compiled by Jo Cavallo

he information in this Clinical Trials Resource Guide includes details of actively recruiting clinical studies of patients with pancreatic cancer. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov. The studies presented here are nonrandomized, randomized, and interventional and include phase I and phase II clinical trials.

PANCREATIC CANCER Study Type: Phase II/interventional/single-group assignment Study Title: Phase II Study of Modified FOLFIRINOX in Advanced Pancreatic Cancer Study Sponsor and Collaborators: Yale University Purpose: The primary goal of this study is to determine the progression-free survival in patients with metastatic pancreatic cancer and in patients with locally advanced unresectable nonmetastatic pancreatic cancer treated with a dose-attenuated modification of leucovorin, fluorouracil, irinotecan, and oxaliplatin. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Progression-free survival (time frame: 24 weeks) Principal Investigator: Jill Lacy, MD, Associate Professor of Medicine, Yale University. Contact: Jill Lacy, MD, 203-737-1600, jill.lacy@yale.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01523457 Study Type: Phase I/interventional/ randomized Study Title: A Pharmacodynamic Study of Metforim in Patients With Resectable Pancreatic Cancer Study Sponsor and Collaborators: Case Comprehensive Cancer Center; National Cancer Institute Purpose: To study metforim hydrochloride in treating patients with pancre-

atic cancer that can be removed by surgery. Metforim hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Pancreatic tumor cell proliferation and apoptosis as measured by the percentage of cells Ki-67–positive, percentage of cells TUNEL-positive, and mitotic counts in tissue samples (time frame: at time of surgery after 7 days of metformin treatment) Principal Investigator: Neal J. Meropol, MD, Associate Director for Clinical Research, Case Comprehensive Cancer Center. Contact: Neal J. Meropol, MD, 216-844-5220, neal.meropol@uhhospitals.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01954732 Study Type: Phase II/interventional/single-group assignment Study Title: A Phase II Study of Induction Consolidation and Maintenance Approach for Patients With Advanced Pancreatic Cancer Study Sponsor and Collaborators: Pancreatic Cancer Research Team Purpose: The study investigators have developed a therapeutic regimen that attacks both the tumor compartment and the stromal compartment of pancreatic cancer and induces complete responses in a small percentage of patients with advanced stage IV pancreatic cancer. The induction regimen (gemcitabine plus nab-paclitaxel [Abraxane]) collapses the stroma and addresses the use of a non–cross-resistant active regimen (FOLFIRINOX [fluorouracil, leucovorin, irinotecan, oxaliplatin]) as a consolidation regimen. Both should improve the chance of driving tumor markers down dramatically. The investigators think that FOLFIRINOX with the stromal collapse induced by the initial regimen, plus the non–cross-resistant shot against the disease will maximize the change of achieving a complete response with an attendant improvement in survival Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No

Primary Outcome Measures: Complete response rate (time frame: 1 year) Principal Investigator: Ramesh K. Ramanathan, MD, Medical Director of the Virginia G. Piper Cancer Center Clinical Trials Program at Scottsdale Healthcare. Contact: Amy StollD’Astice, MS, CCRP, 602-358-8319, astoll@td2inc.com For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01488552 Study Type: Interventional/nonrandomized/parallel assignment Study Title: The Use of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE MRI) in the Management of Pancreatic Cancer Study Sponsor and Collaborators: OHSU Knight Cancer Institute; National Cancer Institute Purpose: To study an imaging technique known as dynamic contrastenhanced magnetic resonance imaging (DCE-MRI) in identifying the presence of pancreatic cancer. DCE-MRI is a procedure that takes detailed pictures of functional and structural properties inside the body using magnetic field and radio frequency pulses. These pictures may help identify underlying malignancy in patients at high risk or active malignancy in patients who have undergone chemotherapy for pancreatic cancer. Ages Eligible for Study: 18 to 85 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: The presence of pancreatic cancer (time frame: up to 4 years) Principal Investigator: Erin Gilbert, MD, Assistant Professor of Surgery, Oregon Health & Science University. Contact: Erin Gilbert, MD, 503-494-6900, gilberte@ohsu.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02070705 Study Type: Phase II/interventional/nonrandomized/single-group assignment Study Title: A Pilot Study to Test the Feasibility of the Combination of Gemcitabine and Anti-PD1 Monoclonal Antibody (CT-011) in the Treatment of Resected Pancreatic Cancer Study Sponsor and Collaborators:

Georgia Regents University Purpose: To test the safety and effectiveness of chemotherapy drugs gemcitabine and CT-011 as a follow-up treatment for pancreatic cancer that has been surgically removed Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To determine the feasibility and safety of the combination of CT-011 and gemcitabine in patients after primary macroscopic resection of pancreatic adenocarcinoma (time frame: 2 years) Principal Investigator: Samir N. Khleif, MD, Director, Georgia Regents University Cancer Center. Contact: Robin Dobbins, RN, 706-721-2154, rdobbins@gru.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01313416 Study Type: Phase I/interventional/ randomized/parallel assignment Study Title: A Phase I Trial of Dinaciclib (SCH727965) and MK-2206 in Metastatic Pancreatic Cancer With an Expansion Cohort in Advanced Pancreatic Cancer Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and best dose of dinaciclib and Akt inhibitor MK2206 in treating patients with pancreatic cancer that cannot be removed by surgery. Dinaciclib and MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: MTD of dinaciclib in combination with Akt inhibitor MK2206 defined as the highest dose at which 0 or 1 dose-limiting toxicities are observed in six patients (time frame: 28 days) Principal Investigator: Nilofer S. Azad, MD, Assistant Professor of Oncology, Johns Hopkins/Sidney Kimmel Cancer Center. Contact: Nilofer S. Azad 410-614-9169 nazad2@jhmi.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01783171 n

The ASCO Post | JUNE 10, 2014

PAGE 78

News Genitourinary Oncology

17-Gene Assay Is a Significant Predictor of Prostate Cancer Aggressiveness

esults from three studies published recently in European Urology indicate that the 17-gene Oncotype DX Genomic Prostate Score is a significant predictor of disease aggressiveness at the time of diagnosis before intervention with radiation or surgery.1 The test provides precise and individualized risk assessment and may

tor for the original development studies. The two development studies performed at the Cleveland Clinic analyzed gene expression in prostate cancer tissue from both radical prostatectomy samples (441) and very small needle-biopsy specimens (167). Out of more than 700

candidate genes, the final analysis yielded 17 genes from four biologic pathways that had strong analytic performance and predicted outcomes associated with aggressive prostate cancer, including clinical recurrence, biochemical recurrence, prostate cancer death, and adverse pathology.

Validation Study “Experience to date suggests that refining a man’s risk for having adverse pathology using the Genomic Prostate Score, despite information such as biopsy grade and tumor volume that suggest less aggressive disease, helps them make the most appro-

Redefine treatment goals with Eric A. Klein, MD

YERVOY (ipilimumab) is the ONLY metastatic melanoma therapy proven in a phase 3 study to deliver a durable long-term survival benefit1

46% 1-YEAR survival rate*

Peter Carroll, MD, MPH

help physicians identify the most appropriate treatment for their patients. The Genomic Prostate Score, developed and validated by Genomic Health in collaboration with the Cleveland Clinic and University of California, San Francisco, addresses the challenges of local prostate cancer diagnosis and treatment by revealing the underlying tumor biology and using genes from multiple biologic pathways to predict the aggressiveness of prostate cancer at diagnosis. “Our extensive development studies addressed the key challenges inherent to prostate cancer and helped overcome tumor heterogeneity and biopsy undersampling and understaging to develop a prostate cancer test that improves risk assessment at the time of diagnosis,” said Eric A. Klein, MD, Chairman of Glickman Urological and Kidney Institute, Cleveland Clinic, and Principal Investiga-

UCSF CAPRA Score Cancer of the Prostate Risk Assessment for Prediction of Recurrence (CAPRA) after radical prostatectomy scoring system. Score is based on 0 to 10 sum of weighted risk factors, including biopsy Gleason grade, preoperative PSA level, and percentage of positive cores from diagnostic biopsy.2

24% 2-YEAR survival rate*

Some patients were still alive up to 4.5 years2 The overall survival curve shows 2, 1, and 0 patients were still in follow-up in the YERVOY arm at 48, 52, and 56 months at the time of study closure. *Estimate based on Kaplan-Meier analysis.1

Median overall survival was 10 months in the YERVOY arm3

YERVOY + gp100 vs gp100: HR=0.68 (95% CI: 0.55, 0.85, P=0.0004) YERVOY vs gp100: HR=0.66 (95% CI: 0.51, 0.87, P=0.0026)a YERVOY + gp100 vs YERVOY: HR=1.04 (95% CI: 0.83, 1.30, P=0.76) Not adjusted for multiple comparisons.

A phase 3, double-blind, double-dummy study that randomized 676 patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin (IL-2), dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive YERVOY 3 mg/kg in combination with an investigational gp100 peptide vaccine (gp100) (n=403), YERVOY 3 mg/kg (n=137), or gp100 (n=136). The primary endpoint was overall survival in the YERVOY + gp100 arm vs the gp100 arm.1

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

ASCOPost.com | JUNE 10, 2014

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News

priate choice between active surveillance and immediate definitive treatment,” said Peter Carroll, MD, MPH, Professor and Chair, Department of Urology, UCSF, and Principal Investigator of the validation study of the 17-gene Genomic Prostate Score. In the UCSF-led clinical validation study of diagnostic biopsies from 395 men who were candidates for active sur-

veillance, the Genomic Prostate Score predicted the presence of adverse pathology (high-grade and/or high-stage disease) within the entire prostate prior to intervention (P = .002). Importantly, the 17-gene score predicted adverse pathology (P < .005) after controlling for established clinical factors such as prostatespecific antigen, biopsy Gleason Score,

and age in multivariable analysis. Finally, the use of the Genomic Prostate Score in conjunction with National Comprehensive Cancer Network categories or UCSF Cancer of the Prostate Risk Assessment (CAPRA) score2 was shown to significantly improve risk assessment and potentially increase the number of men who should consider active surveillance. n

durable long-term survival in metastatic melanoma

YERVOY is not indicated for patients under 18 years of age.

Indication

YERVOY® (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

See experts discuss redefining treatment goals for metastatic melanoma Find out at www.RedefineTreatmentGoals1.com

To learn more, visit www.YERVOY.com or call Support Services at 1-855-YERVOY1.

Please see detailed Important Safety Information, including Boxed WARNING regarding immune-mediated side effects, and brief summary of Full Prescribing Information on adjacent pages. ©2014 Bristol-Myers Squibb Company. All rights reserved. 731US13BR03586-03-01 01/14

Disclosure: Dr. Klein is a paid consultant for Genomic Health. Drs. Klein and Carroll are corresponding authors for the European Urology article.

References 1. Klein EA, et al: European Urology. May 16, 2014 (early release online). 2. Cooperberg, MR, et al: Cancer 107:2384–2391, 2006.

The ASCO Post | JUNE 10, 2014

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Announcements

Arizona Oncology Announces Retirement of Kenneth Luk, MD

rian Schade, Executive Director of Arizona Oncology, recently announced the retirement of Kenneth Luk, MD, a well-respected radiation oncologist in Phoenix for over 20 years. Dr. Luk is a Fellow of the American College of Radiology and Clinical

Professor at the Midwestern University School of Medicine of Glendale, Arizona. Prior to joining Arizona Oncology, he was the Chairman of Radiation Oncology Division of City of Hope National Medical Center for a decade, followed by a long tenure as Medical

Director of Radiation Oncology and Chairman of Cancer Committee at Banner Thunderbird Medical Center. He also held faculty appointments at the University of California, San Francisco, the University of Washington, and the University of California, Irvine.

‘Top Doctor’ Dr. Luk is a member of the American Society for Radiation Oncology and a member of the American Society of Clinical Oncology. He served as President of the American Endocurietherapy Society and was named “Top Doctor” in

Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY® (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. Recommended Dose Modifications Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following: • Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day • Failure to complete full treatment course within 16 weeks from administration of first dose • Severe or life-threatening adverse reactions, including any of the following: – Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation – AST or ALT >5× the upper limit of normal (ULN) or total bilirubin >3× the ULN – Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations – Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis – Severe immune-mediated reactions involving any organ system – Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy Immune-mediated Enterocolitis: • In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients • Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis • Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids • Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms • Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients • Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent) Important Safety Information continued on following page.

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Announcements

Kenneth Luk, MD

Phoenix Magazine multiple times. With his retirement, Dr. Luk announced that Benjamin G. Slane, MD, MS, would be taking over his practice in Phoenix. Dr. Slane is graduate of The University of Iowa at Roy J. and Lucille A. Carver College of Medicine, served his internship at Iowa Methodist Medical Center and com-

pleted his residency at The University of Arizona in Tucson. “I am glad to have left my patients in his capable hands,” Dr. Luk added. Dr. Luk had a remarkable career as a radiation oncologist and educator. Not only did he help those fighting the battle against cancer, he inspired many physicians including his trainees and

Important Safety Information (cont’d) Immune-mediated Hepatitis: • In the pivotal Phase 3 study in YERVOY (ipilimumab)-treated patients, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3–5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% • 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2) • Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution • Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids • Withhold YERVOY in patients with Grade 2 hepatotoxicity • In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) Immune-mediated Dermatitis: • In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients – 1 (0.2%) patient died as a result of toxic epidermal necrolysis – 1 additional patient required hospitalization for severe dermatitis • There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis • Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated • Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms • Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week Immune-mediated Neuropathies: • In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported • Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported • Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes • Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities) Immune-mediated Endocrinopathies: • In the pivotal Phase 3 study in YERVOY-treated patients, severe to life-threatening immunemediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients Important Safety Information continued on following page.

colleagues to strive for excellence in their academic and clinical endeavors. “We thank Dr. Luk for all of his years of service, friendship and loyalty,” said Mr. Schade. “We hate to see him leave, but we understand that this chapter of his life most close. We wish him all the best as he embarks on his new journey.” n

The ASCO Post | JUNE 10, 2014

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Announcements

U.S. Team to Read Pap Tests in Botswana Campaign Against Cervical Cancer

n a volunteer medical outreach venture organized by the American Society for Clinical Pathology (ASCP), Barbara M. Frain, MS, SCT (ASCP), CM, Clinical Assistant Professor at the Indiana University School of Medicine, Indianapolis, and 10 colleagues from around the country

are helping medical officials in Botswana work through a backlog of Pap smears. “I’m interested in seeing how they do this in another part of the world, and I hope my skills can help someone out,” said Ms. Frain of the upcoming trip to Gaborone, the capital of Botswana.

The Botswana government has initiated a national cervical cancer prevention program, which resulted in a large number of Pap exams but led to a shortage of professionals to read the slides, said Shannon Castle, Director of the Center for Global Health at ASCP. The society previously sent

teams to Botswana to work on a backlog of more than 2,000 histology specimens. “There are seven cytotechnologists in all of Botswana,” Ms. Castle said. “To add 10 more cytotechnologists can really have an impact in improving the delivery of care.” n

Important Important Safety Safety Information Information (cont’d) (cont’d) Immune-mediated Immune-mediated Endocrinopathies Endocrinopathies (cont’d): (cont’d): – All –9 All patients 9 patients had hypopituitarism, had hypopituitarism, and some and some had additional had additional concomitant concomitant endocrinopathies endocrinopathies suchsuch as adrenal as adrenal insufficiency, insufficiency, hypogonadism, hypogonadism, and hypothyroidism and hypothyroidism – 6 of– the 6 of9the patients 9 patients werewere hospitalized hospitalized for severe for severe endocrinopathies endocrinopathies • Moderate • Moderate endocrinopathy endocrinopathy (requiring (requiring hormone hormone replacement replacement or medical or medical intervention; intervention; Grade Grade 2) 2) occurred occurred in 12in(2.3%) 12 (2.3%) YERVOY YERVOY (ipilimumab)-treated (ipilimumab)-treated patients patients and consisted and consisted of hypothyroidism, of hypothyroidism, adrenal adrenal insufficiency, insufficiency, hypopituitarism, hypopituitarism, and 1 and case 1 case eacheach of hyperthyroidism of hyperthyroidism and Cushing’s and Cushing’s syndrome syndrome • Median • Median time time to onset to onset of moderate of moderate to severe to severe immune-mediated immune-mediated endocrinopathy endocrinopathy was 11 wasweeks 11 weeks and and ranged ranged up toup 19.3 to 19.3 weeks weeks after after the initiation the initiation of YERVOY of YERVOY • Monitor • Monitor patients patients for clinical for clinical signssigns and symptoms and symptoms of hypophysitis, of hypophysitis, adrenal adrenal insufficiency insufficiency (including (including adrenal adrenal crisis), crisis), and hyperand hyperor hypothyroidism or hypothyroidism – Patients – Patients may may present present with with fatigue, fatigue, headache, headache, mental mental status status changes, changes, abdominal abdominal pain,pain, unusual unusual bowel bowel habits, habits, and hypotension, and hypotension, or nonspecific or nonspecific symptoms symptoms which which may may resemble resemble otherother causes causes suchsuch as brain as brain metastasis metastasis or underlying or underlying disease. disease. Unless Unless an alternate an alternate etiology etiology has been has been identified, identified, signssigns or symptoms or symptoms should should be considered be considered immune-mediated immune-mediated – Monitor – Monitor thyroid thyroid function function teststests and clinical and clinical chemistries chemistries at theatstart the start of treatment, of treatment, before before eacheach dose,dose, and as andclinically as clinically indicated indicated based based on symptoms. on symptoms. In a limited In a limited number number of patients, of patients, hypophysitis hypophysitis was was diagnosed diagnosed by imaging by imaging studies studies through through enlargement enlargement of theofpituitary the pituitary glandgland • Withhold • Withhold YERVOY YERVOY in symptomatic in symptomatic patients. patients. Initiate Initiate systemic systemic corticosteroids corticosteroids (1-2 (1-2 mg/kg/day mg/kg/day of of prednisone prednisone or equivalent) or equivalent) and initiate and initiate appropriate appropriate hormone hormone replacement replacement therapy. therapy. Long-term Long-term hormone hormone replacement replacement therapy therapy may may be necessary be necessary OtherOther Immune-mediated Immune-mediated Adverse Adverse Reactions, Reactions, Including Including Ocular Ocular Manifestations: Manifestations: • In the • Inpivotal the pivotal Phase Phase 3 study 3 study in YERVOY-treated in YERVOY-treated patients, patients, clinically clinically significant significant immune-mediated immune-mediated adverse adverse reactions reactions seenseen in <1% in <1% were:were: nephritis, nephritis, pneumonitis, pneumonitis, meningitis, meningitis, pericarditis, pericarditis, uveitis, uveitis, iritis,iritis, and hemolytic and hemolytic anemia anemia • Across • Across the clinical the clinical development development program program for YERVOY, for YERVOY, likelylikely immune-mediated immune-mediated adverse adverse reactions reactions also also reported reported with with <1%<1% incidence incidence were:were: myocarditis, myocarditis, angiopathy, angiopathy, temporal temporal arteritis, arteritis, vasculitis, vasculitis, polymyalgia polymyalgia rheumatica, rheumatica, conjunctivitis, conjunctivitis, blepharitis, blepharitis, episcleritis, episcleritis, scleritis, scleritis, leukocytoclastic leukocytoclastic vasculitis, vasculitis, erythema erythema multiforme, multiforme, psoriasis, psoriasis, pancreatitis, pancreatitis, arthritis, arthritis, autoimmune autoimmune thyroiditis, thyroiditis, sarcoidosis, sarcoidosis, neurosensory neurosensory hypoacusis, hypoacusis, autoimmune autoimmune central central neuropathy neuropathy (encephalitis), (encephalitis), myositis, myositis, polymyositis, polymyositis, and ocular and ocular myositis myositis • Permanently • Permanently discontinue discontinue YERVOY YERVOY for clinically for clinically significant significant or severe or severe immune-mediated immune-mediated adverse adverse reactions. reactions. Initiate Initiate systemic systemic corticosteroids corticosteroids (1-2 (1-2 mg/kg/day mg/kg/day of prednisone of prednisone or equivalent) or equivalent) for severe for severe immune-mediated immune-mediated adverse adverse reactions reactions • Administer • Administer corticosteroid corticosteroid eye drops eye drops for uveitis, for uveitis, iritis,iritis, or episcleritis. or episcleritis. Permanently Permanently discontinue discontinue YERVOY YERVOY for immune-mediated for immune-mediated ocular ocular disease disease unresponsive unresponsive to local to local immunosuppressive immunosuppressive therapy therapy Pregnancy Pregnancy & Nursing: & Nursing: • YERVOY • YERVOY is classified is classified as pregnancy as pregnancy category category C. There C. There are no areadequate no adequate and well-controlled and well-controlled studies studies of YERVOY of YERVOY in pregnant in pregnant women. women. Use Use YERVOY YERVOY during during pregnancy pregnancy only only if theifpotential the potential benefit benefit justifies justifies the potential the potential risk to risk thetofetus the fetus • Human • Human IgG1IgG1 is known is known to cross to cross the placental the placental barrier barrier and YERVOY and YERVOY is anisIgG1; an IgG1; therefore, therefore, YERVOY YERVOY has the haspotential the potential to betotransmitted be transmitted fromfrom the mother the mother to thetodeveloping the developing fetusfetus • It is• not It isknown not known whether whether YERVOY YERVOY is secreted is secreted in human in human milk.milk. Because Because manymany drugsdrugs are secreted are secreted in in human human milk milk and because and because of theofpotential the potential for serious for serious adverse adverse reactions reactions in nursing in nursing infants infants fromfrom YERVOY, YERVOY, a decision a decision should should be made be made whether whether to discontinue to discontinue nursing nursing or to or discontinue to discontinue YERVOY YERVOY Common Common Adverse Adverse Reactions: Reactions: • The• most The most common common adverse adverse reactions reactions (≥5%) (≥5%) in patients in patients who who received received YERVOY YERVOY at 3 mg/kg at 3 mg/kg werewere fatigue fatigue (41%), (41%), diarrhea diarrhea (32%), (32%), pruritus pruritus (31%), (31%), rash rash (29%), (29%), and colitis and colitis (8%)(8%) PleasePlease see brief seesummary brief summary of Full of Prescribing Full Prescribing Information, Information, including including Boxed Boxed WARNING WARNING regarding regarding immune-mediated immune-mediated side effects, side effects, on following on following pages.pages. References: References: 1. Hodi 1. FS,Hodi O’Day FS,SJ, O’Day McDermott SJ, McDermott DF, et al.DF,Improved et al. Improved survivalsurvival with ipilimumab with ipilimumab in patients in patients with metastatic with metastatic melanoma. melanoma. N Engl JNMed. Engl2010;363(8):711-723. J Med. 2010;363(8):711-723. 2. YERVOY 2. YERVOY packagepackage insert. Princeton, insert. Princeton, NJ: Bristol-Myers NJ: Bristol-Myers Squibb Company. Squibb Company. 3. Data 3. onData file. YERV on file.008. YERV Bristol-Myers 008. Bristol-Myers Squibb Company. Squibb Company. Princeton, Princeton, NJ. AprilNJ. 2011. April 2011.

ASCOPost.com | JUNE 10, 2014

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Announcements

University of Louisville Receives $5.5 Million Grant From Helmsley Charitable Trust to Support Innovative Cancer Research

oting the significant progress in drug and vaccine development over the past 3 years, the Leona M. and Harry B. Helmsley Charitable Trust, has provided a 3-year, $5.5 mil-

lion grant to the James Graham Brown Cancer Center at the University of Louisville, Kentucky, to develop new treatments and vaccines for various forms of cancer.

YERVOY® (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information.] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions.] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning.] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range: 1.6–13.4) and 6.3 weeks (range: 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information.] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event. Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution. Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information.] Concurrent Administration with Vemurafenib In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Immune-mediated Dermatitis In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous,

Yrv1213pbs731US13BR02790_0101wip3.indd 1

“Seven years ago, we partnered with Owensboro Health to explore the novel idea of plant-based pharmaceuticals and vaccines in the treatment and prevention of cancer,” said James R. Ramsey, PhD,

or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY (ipilimumab)-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis. The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY. Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information.] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week. Immune-mediated Neuropathies In Study 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information.] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information.] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information.] ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-mediated enterocolitis [see Warnings and Precautions]. • Immune-mediated hepatitis [see Warnings and Precautions]. • Immune-mediated dermatitis [see Warnings and Precautions]. • Immune-mediated neuropathies [see Warnings and Precautions]. • Immune-mediated endocrinopathies [see Warnings and Precautions]. • Other immune-mediated adverse reactions, including ocular manifestations [see Warnings and Precautions].

12/13/13 1:32 PM

President of the University of Louisville. “Our team showed enough promise that the Helmsley Charitable Trust provided more than $3 million in research support continued on page 84

The ASCO Post | JUNE 10, 2014

PAGE 84

Announcements Grant to Support Cancer Research continued from page 83

in 2010. [The new] grant, with Donald Miller, MD, PhD, Director of the James Graham Brown Cancer Center, as the principal investigator, demonstrates the confidence the leaders of the trust have in the work that is being accomplished.

We are extremely grateful to the trust for its support and we look forward to further opportunities to partner.” The new funding will help University of Louisville researchers move into clinical trials of vaccines for cervical and colon cancer. Additionally, researchers will further develop plant-based drug delivery systems to allow for higher concentra-

tions of anticancer drugs to be transported directly to human tumors, as well as to increase a tumor’s sensitivity to anticancer treatment. The plants involved in the research range from tobacco to soybeans to colored berries. “Our goal is to cure cancer in people, not in mice,” Dr.

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for 4 doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information.] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range: 1–4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY (ipilimumab) with the incidences of antibodies to other products may be misleading.

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.

DRUG INTERACTIONS

Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.

USE IN SPECIFIC POPULATIONS

Table 1:

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3–5

Any Grade

Grade 3–5

Any Grade

Grade 3–5

32 8

5 5

37 5

4 3

20 2

1 0

0 2

21 25

<1 2

11 8

0 0

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Table 2:

In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition, at exposure levels either 2.6 or 7.2 times higher by AUC than the exposures at the clinical dose of 3 mg/kg of ipilimumab. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, the ipilimumab treated groups experienced higher incidences of severe toxicities including abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner compared to controls. [See Nonclinical Toxicology (13.2) in Full Prescribing Information.] Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Nursing Mothers

31 29

Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

Including fatal outcome. Including intestinal perforation. c Underlying etiology not established. b

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

It is not known whether ipilimumab is secreted in human milk. In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at the recommended dose, ipilimumab was present in milk at concentrations of 0.1 and 0.4 mcg/mL, representing a ratio of up to 0.3% of the serum concentration of the drug. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother. Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients. Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No dose adjustment is needed for patients with renal impairment. [See Clinical Pharmacology (12.3) in Full Prescribing Information.] Hepatic Impairment No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 × to 1.5 × the upper limit of normal [ULN] or AST >ULN). YERVOY has not been studied in patients with moderate (TB >1.5 × to 3.0 × ULN and any AST) or severe (TB >3 × ULN and any AST) hepatic impairment. [See Clinical Pharmacology (12.3) in Full Prescribing Information.] OVERDOSAGE

Miller said. “The Owensboro Cancer Research Program is a tremendous tool for reaching that goal, not just locally or regionally, but worldwide. Through plant-based pharmaceuticals, we will be able to provide lowcost vaccines and anticancer medications that make them accessible to even the poorest of nations. To have an organization like the Helmsley Charitable Trust partner with us will enable us to move toward our goal at a much quicker pace.” n

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Rights & Permissions e-mail: Permissions@harborsidepress.com

There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. •

Inform patients of the potential risk of immune-mediated adverse reactions.

• • •

Advise patients to read the YERVOY Medication Guide before each YERVOY infusion. Advise women that YERVOY may cause fetal harm. Advise nursing mothers not to breastfeed while taking YERVOY.

Advertising

Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321675A0

Donald Miller, MD, PhD

Contact

Pregnancy There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Percentage (%) of Patientsa

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue

No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

James R. Ramsey, PhD

Rev December 2013 731US13BR02790-01-01

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

Yrv1213pbs731US13BR02790_0101wip3.indd 2

12/13/13 1:32 PM

ASCOPost.com | JUNE 10, 2014

PAGE 85

Society of Surgical Oncology Annual Cancer Symposium Randomized Trials vs Meta-analyses: Which Is the Better Bet? By Shalmali Pal

wo surgical oncology experts who squared off in a “Great Debate” at the 2014 Society of Surgical Oncology (SSO) Annual Cancer Symposium in Phoenix. Heidi Nelson, MD, Professor of Surgery at the Mayo Clinic in Rochester, Minnesota, argued for the superiority of randomized controlled trials in providing a “higher level of medical evidence,” while Natalie G. Coburn, MD, MPH, Associate Professor and Division Head of General Surgery at Sunnybrook Health Sciences Centre, University of Toronto, made the case for why meta-analyses have the upper hand.1

The Bias Factor Dr. Nelson outlined what she called “critical design issues” with meta-analyses, many of which have to do with bias. First, all meta-analyses are biased by being retrospective. Then, the studies for inclusion have to be identified and selected, and there will be heterogeneity to those results. “One laproscopic study might not be asking the same question as another laproscopic study,” Dr. Nelson explained by way of example. “They may have differences in terms of the specificity of the studies.” Third, there is the matter of access to the information. This introduced what Dr. Nelson referred to as data availability bias. Dr. Nelson led the Clinical Outcomes of Surgical Therapy (COST) Study Group for a trial that compared laparoscopically assisted and open colectomy for colon cancer.2 “At least once a year, I get a request from someone who is doing a meta-analysis and they want our data from the COST trial,” she said. “It’s a lot of work to try to get that data, get it formatted, explain what it means, and send it out. Then you just cross your fingers and have to trust that [the meta-analysis authors] understand it and that they do the right thing with it.” Dr. Nelson highlighted results of a study published in 2012 that assessed publication bias, selection bias, and unavailable data in meta-analyses. In more than half the cases (16 of 31 meta-analyses), the requested individual participant data could not be obtained, but only 31% of these meta-analyses mentioned this as a potential limitation. Moreover, a mean of 87% of trial data was obtained.3

“The reality is that most of the time, people don’t get the data that they think they are going to get, or they don’t get enough of it,” she said. Another limitation of a meta-analysis is publication bias. Dr. Nelson cited data from a 2008 paper that looked at the selective publication of U.S. Food and Drug Administration–registered antidepressant trials and how that bias influenced efficacy. She explained that 97% of the studies published showed positive results, whereas only 12% of studies with negative results made it to print. The absence of nonpublished data increased the positive effect anywhere from 11% to 69%.4 “If you don’t have that negative data in the literature to examine, you automatically inflate the positive results, and there’s no way you can compensate for that,” she said. Ultimately, a meta-analysis is only as good as the contributing randomized controlled trials that it is evaluating. Dr. Nelson pointed out that “if you have a bunch of poor-quality randomized, controlled trials, it doesn’t make the meta-analysis data any better. Low quality plus low quality doesn’t equal high quality.” The primary difference between a randomized controlled trial and metaanalysis is that the former “provide the highest level of evidence because they contain the least amount of bias. Randomized controlled trials reduce bias, while meta-analyses increase bias,” she stated. If randomized controlled trials are designed well and conducted properly, the results would concur, and there would be no need for meta-analysis, she stated. Finally, Dr. Nelson likened reading and interpreting a meta-analysis to “an insurance policy. You have to be able to get down to the fine print,” adding, “it’s not only some of the fine print; it’s all the fine print. You have to be able to sort it out.”

All About the Methodology “When you think of meta-analyses, you think of the forest plot and the beautiful set of lines and what that means to you,” Dr. Coburn said. “But what most people underestimate is the importance of the systematic review behind it. I think this is where the true power of the methodology comes into play.”

Dr. Coburn pointed out that when the levels for evidence-based care are laid out in the pyramid formation, systematic reviews/meta-analyses are at the top, followed by randomized controlled trials, cohort studies, case-control studies, case series/case reports, and editorials/expert opinion. Dr. Coburn acknowledged that randomized controlled trials deserve a

not fantasy football. You don’t just get to pick your favorite studies. There’s a methodology here,” and that includes producing a CONSORT (CONsolidated Standards Of Reporting Trials) or PRISMA (Preferred Reporting Items of Systematic reviews and Meta-Analyses) diagram that explains which studies were included or excluded and why that was done. The idea is that if future

[Randomized controlled trials] provide the highest level of evidence because they contain the least amount of bias. —Heidi Nelson, MD

Most people underestimate the importance of the systematic review behind [meta-analysis]. I think this is where the true power of the methodology comes into play. —Natalie G. Coburn, MD, MPH

place near the top of the pyramid because of their strengths, such as the ability to minimize patient selection bias and confounding bias, a superior ability to determine the effects of an intervention, and their tendency to encourage professional collaboration. But the idea that a randomized controlled trial is better than a meta-analysis stems from “a misunderstanding and a bit of misinterpretation of how the methodology works for meta-analyses and systematic reviews,” she said. A systematic review has very specific steps, beginning with the establishment of a question. Once that has been set, a search strategy can be designed. It’s during this step that publication bias can be reduced using multiple sources such as trial registries, conference proceedings, published literature, and contacting the primary author. “You can go after these things and you can minimize the chance of missing negative [trial results],” Dr. Coburn explained. Next comes study selection, and Dr. Coburn emphasized that “this is

investigators revisit the meta-analysis, they will be able to reproduce the results, she explained. The subsequent step is to assess the quality of studies using a grading system to evaluate issues such as bias, concealment, and follow-up. The meta-analysis authors will then select and extract variables. Dr. Coburn referred to an editorial by Dr. Nelson in which she wrote, “[small, inadequate randomized clinical trials] … can be combined via a metaanalysis to gain a more precise estimate of potential impact.”5 These combined data allow for subgroup and secondary analysis, which sometimes cannot be done in a randomized controlled trial that was powered for a single primary outcome. “Often, we come across things in post-hoc analysis that were simply not powered for in the original trial,” Dr. Coburn said. “How does this work? What’s the hocus pocus behind this?” she added. “It’s driven by numbers. The more patients you put in, the tighter your confidence interval. The tighter continued on page 86

The ASCO Post | JUNE 10, 2014

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Society of Surgical Oncology Annual Cancer Symposium Randomized Trials vs Meta-analyses continued from page 85

your confidence interval, the lower your P value, which lowers the risk that you got to these results by chance alone.” Inadequate power is a common weakness of a randomized controlled trial. Dr. Coburn cited a 2007 study that looked at the statistical power of negative randomized controlled trials presented at ASCO Annual Meetings from 1995 to 2003.6 According to that research, “more than half of negative randomized controlled trials presented at ASCO Annual Meetings do not have an adequate sample to detect a mediumsize treatment effect,” she explained. But “only 10% of the abstracts stated that they were underpowered. The rest just reported themselves as being negative. And I wonder as I watch some of the presentations [at the SSO meeting] this past week, why we’re so quick to call a trial negative, and why we often don’t admit they are just underpowered.” Finally, meta-analyses are more likely to reflect actual practice vs the strict protocols that guide a randomized controlled trial, Dr. Coburn said. By evaluating results from multiple trials done globally, meta-analyses give clinicians the chance to see if those findings apply outside the trial and in a real-world setting.

Rebuttals Dr. Nelson responded to Dr. Coburn’s argument by emphasizing the strengths of randomized controlled trials, specifically:

• Focused hypothesis • Rigorous inclusion and exclusion criteria • Adequate sample to avoid overestimates or underestimates of effect size • Randomization to eliminate bias • Quality assurance and quality controls “When you do a post-hoc analysis, you can’t tell anything about quality assurance and quality control,” Dr. Nelson said. “But when you do a prospective, randomized trial, you can actually look at [quality]. There’s

analysis, Dr. Coburn described studies done on using corticosteroids to reduce the risk of death in preterm delivery. She explained that the topic had been covered in 2 decades of studies during the 1970s and 1980s, including a dozen randomized controlled trials. Yet the uptake of corticosteroids for this condition among gynecologists was only 20% to 40% by the early 1990s. It was only after a 1991 meta-analysis and a 1994 National Institutes of Health consensus conference that it became standard of care to give a single course of corticosteroids in pre-

Randomized Trials and Meta-analyses ■■ A properly randomized trial provides definitive evidence, answers specific questions, and has a low risk for misinterpretation and selection/publication bias. ■■ The combined data of a meta-analysis allow for subgroup and secondary analysis, which sometimes cannot be done in a randomized control trial powered for a single primary outcome. ■■ Meta-analyses are more likely to reflect real-world practice vs the strict protocols that guide a randomized controlled trial.

nothing about that in a meta-analysis.” She pointed out that a properly randomized trial provides definitive evidence, answers specific questions, has a low risk for misinterpretation, and a low risk for selection/publication bias. “It might be nice to have lots of fireworks [with a meta-analysis]. But one well done randomized trial is going to address the … issue,” she said. To illustrate the influence of meta-

term labor to reduce the risk of death and respiratory distress syndrome in infants.7,8 “I know that’s a bit far off oncology,” she said, “but I think [this illustrates] the power of metaanalysis.” n Disclosure: Drs. Nelson and Coburn reported no potential conflicts of interest.

References 1. Nelson H, Coburn NG: Randomized clinical trials versus meta-analysis:

Which is a higher level of medical evidence? 2014 SSO Annual Cancer Symposium. Presented March 15, 2014. 2. Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:2050-2059, 2004. 3. Ahmed I, Sutton AJ, Riley RD: Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: A database survey. BMJ 3:344, 2012. 4. Turner EH, Matthews AM, Linadartos E, et al: Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 358:252260, 2008. 5. Nelson H, Ballman K: Achieving the right volume of randomized controlled trials. Ann Surg 258:208-209, 2013. 6. Bedard PL, Krzyzanowska MK, et al: Statistical power of negative randomized controlled trials presented at American Society for Clinical Oncology annual meetings. J Clin Oncol 10:3482-3487, 2007. 7. Crowley P, Chalmers I, Keirse MJ: The effects of corticosteroid administration before preterm delivery: An overview of the evidence from controlled trials. Br J Obstet Gynaecol 97:11-25, 1990. 8. National Institutes of Health Consensus Development Conference Statement: The Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. February 28–March 2, 1994. Available at consensus.nih.gov/1994/1994Antenatal SteroidPerinatal095html.htm.

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G N I L ROL STUDY

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Additional inclusion/exclusion criteria apply.

Study Design Randomization (1:1)

Ceritinib

Chemotherapya

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival Investigatorâ&#x20AC;&#x2122;s choice: pemetrexed or docetaxel

ALK, anaplastic lymphoma kinase; ALK+, ALK-positive; RECIST, Response Evaluation Criteria In Solid Tumors.

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The ASCO Post | JUNE 10, 2014

PAGE 88

Integrative Oncology By Jyothirmai Gubili, MS Editor, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center

St. John’s Wort Scientific name: Hypericum perforatum Common names: Saint John’s wort, hypericum, goatweed, God’s wonder plant, witches herb

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidencebased information on integrative and complementary therapies commonly used by patients with cancer. We chose St. John’s wort for this issue because of its popularity among cancer patients. Compiled by Barrie R. Cassileth, PhD, and Jyothi Gubili, MS, Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, Memorial Sloan Kettering Cancer Center.

Overview

A perennial herb indigenous to Europe, West Asia, and North Africa, St. John’s wort has a centuries-long history as a remedy to treat wounds, headaches,

kidney problems, nerve disorders, and melancholia. Brought to the United States by the colonists, it grows in many areas of the country. Today, St. John’s wort is used to alleviate anxiety and depression, as well as for sleep disorders. It is available in health food stores and online in the form of capsules, tablets, liquid extracts, tinctures, and teas. It is also a common ingredient in skin lotions. St. John’s wort is among the more extensively researched herbs. Data from clinical trials strongly support its effectiveness in treating mild to moderate depression. A few studies indicate benefit in controlling vasomotor symptoms in peri- and postmenopausal women. Interactions between St. John’s wort and prescription drugs, including chemotherapeutic agents, are well documented in the literature.

The Science

Among several bioactive compounds discovered, hyperforin and hypericin are thought to be responsible for the beneficial effects of St. John’s wort. In vitro and in vivo experiments with the herb have shown neuroprotective effects1 and the ability to relieve neuropathic pain in a rat model.2 Current evidence indicates that St. John’s wort may be as effective as selective serotonin-reuptake inhibitors in treating mild to moderate depression.3 It is seen as a cost-effective alternative to generic antidepressants.4 Studies have shown that the effects of St. John’s wort are comparable to those of paroxetine5 and other selective serotonin-reuptake

GUEST EDITOR

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 269 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. inhibitors6 in controlling moderate to severe depression. It is well tolerated, with sustained reductions in depression following continued use in those with acute moderate depression.7 However, analyses of all types of depression yielded inconsistent data,8,9 and a random-

ized trial found St. John’s wort ineffective in treating minor depression.10 A few studies support its efficacy in controlling premenstrual syndrome11 and vasomotor symptoms in peri- and postmenopausal women.12

Adverse Effects

Case reports: Mania was reported in three patients with underlying bipolar disorder, which resolved in two patients following discontinuation; the third experienced persistent agitation for several months.13 Serotonin syndrome: Hypertension, diaphoresis, agitation, dizziness, and weakness with acute onset were reported following 10 days of St. John’s wort intake. The syndrome resolved following discontinuation of St. John’s wort.14

Learn More About

Herbs, Botanicals, & Other Products For additional information, visit the free About Herbs website at

http://www.mskcc.org /cancer-care/herb/st-john-wort

ASCOPost.com | JUNE 10, 2014

PAGE 89

Integrative Oncology Skin disease: Erythroderma developed 4 days after initiation of St. John’s wort; resolved after 5 weeks of concomitant treatment with oral steroids.15 Sexual dysfunction: Decreased sexual libido was reported with St. John’s wort; the condition normalized following discontinuation of the herb.16 Withdrawal syndrome: Nausea,

OF NOTE Physicians should be aware of the adverse effects associated with use of St. John’s wort, including its interactions with chemotherapy and other prescription medications.

anorexia, dry retching, dizziness, dry mouth, thirst, cold chills, and extreme fatigue were observed in a patient following intake of St. John’s wort for 32 days.17 Prolonged facial dystonia: A 58-year-old Caucasian woman suffered prolonged facial dystonia following use of bupropion along with St. John’s wort.18 Cardiovascular issues: Long-term use of St. John’s wort was identified as a potential contributor to cardiovascular collapse during anesthesia in a patient.19 Photosensitivity: Photosensitivity reactions occurred in individuals who used topical and/or oral St. John’s wort preparations prior to sun exposure or undergoing phototherapy.20

Herb-Drug Interactions

Cytochrome P450 3A4 substrates: St. John’s wort induces cytochrome P450 isoenzyme 3A4, thereby affecting metabolism of certain medications and reducing serum concentrations.21 Examples of drugs metabolized by 3A4 include: Irinotecan: Due to changes in hepatic metabolism caused by St. John’s wort, levels of SN-38, a metabolite of the chemotherapy agent irinotecan, may be lowered by as much as 40% for up to 3 weeks following discontinuation of St. John’s wort.22

Warfarin: St. John’s wort may increase or decrease warfarin activity when the two agents are administered concomitantly. International normalized ratio (INR) should be monitored routinely.23 Tricyclic antidepressants: An increased serotonergic effect and possible serotonin syndrome is seen when St. John’s wort is combined with nefazodone, amitriptyline, or imipramine. Possible reduction in efficacy of antidepressants may be due to metabolism changes induced by St. John’s wort.13 Alprazolam: St. John’s wort may reduce blood levels of alprazolam, resulting in decreased efficacy.24 Dextromethorphan: St. John’s wort may reduce blood levels of dextromethorphan, resulting in decreased efficacy.24 P-glycoprotein substrates: St. John’s wort induces intestinal P-glycoprotein, resulting in decreased absorption and lowered plasma concentrations of certain drugs including digoxin.25 UGT (Uridine 5’-diphospho-glucuronosyltransferase) substrates: St. John’s wort modulates UGT enzymes in vitro, and can increase the side effects of drugs metabolized by them.26 n Disclosure: Ms. Gubili reported no potential conflicts of interest.

References 1. Griffith TN, Varela-Nallar L, Dinamarca MC, et al: Neurobiological effects of hyperforin and its potential in Alzheimer’s disease therapy. Curr Med Chem 17:391406, 2010. 2. Galeotti N, Vivoli E, Bilia AR, et al: St. John’s wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase Cgamma and epsilon activity. Biochem Pharmacol 79:1327-1336, 2010. 3. Linde K, Knuppel L: Large-scale observational studies of hypericum extracts in patients with depressive disorders—a systematic review. Phytomedicine 12:148157, 2005. 4. Solomon D, Adams J, Graves N: Economic evaluation of St. John’s wort (Hypericum perforatum) for the treatment of mild

to moderate depression. J Affect Disord 148:228-234, 2013. 5. Szegedi A, Kohnen R, Dienel A, et al: Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John’s wort): Randomised controlled double blind non-inferiority trial versus paroxetine. BMJ 330:503, 2005. 6. Rahimi R, Nikfar S, Abdollahi M: Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: A meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 33:118-127, 2009. 7. Kasper S, Volz HP, Moller HJ, et al: Continuation and long-term maintenance treatment with Hypericum extract WS((R)) 5570 after recovery from an acute episode of moderate depression: A doubleblind, randomized, placebo controlled long-term trial. Eur Neuropsychopharmacol 18:803-813, 2008. 8. Linde K, Mulrow CD, Berner M, et al: St John’s wort for depression. Cochrane Database Syst Rev (2):CD000448, 2005. 9. Linde K, Berner MM, Kriston L: St John’s wort for major depression. Cochrane Database Syst Rev (4):CD000448, 2008. 10. Rapaport MH, Nierenberg AA, Howland R, et al: The treatment of minor depression with St. John’s Wort or citalopram: Failure to show benefit over placebo. J Psychiatr Res 45:931-941, 2011. 11. Canning S, Waterman M, Orsi N, et al: The efficacy of Hypericum perforatum (St John’s wort) for the treatment of premenstrual syndrome: A randomized, double-blind, placebo-controlled trial. CNS Drugs 24:207-225, 2010. 12. Abdali K, Khajehei M, Tabatabaee HR: Effect of St John’s wort on severity, frequency, and duration of hot flashes in premenopausal, perimenopausal and postmenopausal women: A randomized, double-blind, placebo-controlled study. Menopause 17:326-331, 2010. 13. Barnes J, Anderson LA, Phillipson JD: St John’s wort (Hypericum perforatum L.): A review of its chemistry, pharmacology and clinical properties. J Pharm Pharmacol 53:583-600, 2001. 14. Parker V, Wong AH, Boon HS, et al: Adverse reactions to St John’s Wort. Can J

Psychiatry 46:77-79, 2001. 15. Holme SA, Roberts DL: Erythroderma associated with St John’s wort. Br J Dermatol 143:1127-1128, 2000. 16. Bhopal JS: St John’s wort-induced sexual dysfunction. Can J Psychiatry 46:456-457, 2001. 17. Dean AJ, Moses GM, Vernon JM: Suspected withdrawal syndrome after cessation of St. John’s wort. Ann Pharmacother 37:150, 2003. 18. Milton JC, Abdulla A: Prolonged oro-facial dystonia in a 58 year old female following therapy with bupropion and St John’s Wort. Br J Clin Pharmacol 64:717718, 2007. 19. Irefin S, Sprung J: A possible cause of cardiovascular collapse during anesthesia: Long-term use of St. John’s Wort. J Clin Anesth 12:498-499, 2000. 20. Lane-Brown MM: Photosensitivity associated with herbal preparations of St John’s wort (Hypericum perforatum). Med J Aust 172:302, 2000. 21. Imai H, Kotegawa T, Tsutsumi K, et al: The recovery time-course of CYP3A after induction by St John’s wort administration. Br J Clin Pharmacol 65:701-707, 2008. 22. Mathijssen RH, Verweij J, de Bruijn P, et al: Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 94:1247-1249, 2002. 23. Jiang X, Williams KM, Liauw WS, et al: Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 57:592-599, 2004. 24. Markowitz JS, Donovan JL, DeVane CL, et al: Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA 290:1500-1504, 2003. 25. Gurley BJ, Swain A, Williams DK, et al: Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: Comparative effects of St. John’s wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol Nutr Food Res 52:772-779, 2008. 26. Mohamed ME, Frye RF: Effects of herbal supplements on drug glucuronidation. Review of clinical, animal, and in vitro studies. Planta Med 77:311-321, 2011.

For Your NPs and PAs A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2nd Loews Royal Pacific Hotel at Universal Orlando, FL apsho.org/jadprolive

Take a bite out of G-CSF acquisition costs*

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

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

The ASCO Post | JUNE 10, 2014

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Palliative Care in Oncology Bringing Palliative Care Services to Local Community Clinical Practices and Health Facilities Throughout the World A Conversation With Jeannine M. Brant, PhD, APRN, AOCN® By Jo Cavallo

n 2007, the Billings Clinic Cancer Center in Billings, Montana, became

one of 15 community-based oncology centers nationwide to receive funding

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

from the National Cancer Institute (NCI) to expand programs for clinical

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

trials, health-care disparities outreach, survivorship and palliative care, multidisciplinary care, and electronic health records to improve patient access to the most effective cancer care. As part of that initiative, in 2010, Jeannine M. Brant, PhD, APRN, AOCN®, Oncology Clinical Nurse Specialist and Nurse Scientist at the Billings Clinic Cancer Center, and her colleagues developed a symptom management clinic that includes an interdisciplinary team of physicians, physician assistants, nurses (including an oncology and psychiatric nurse practitioner, supportive care nurse navigator, and clinical trials coordinator), social workers, dietitians, and physical therapists. The team offers a broad variety of services to improve physical and emotional quality of life for patients with cancer while they are undergoing treatment and throughout their survivorship. A pain and symptom management specialist, Dr. Brant recently completed a study examining pain care quality in 326 U.S. hospitals1 and was appointed to an NCI Executive Committee of the Middle East Cancer Consortium (MECC), which oversees palliative care services in countries in the Middle East, including Cyprus, Egypt, Israel, Palestine, Jordan, Turkey, and parts of Northern Africa. Dr. Brant is Editor of ONS Standards of Oncology Nursing Practice and a new edition of the ONS Core Curriculum, and is Associate Editor of the Journal of the Advanced Practitioner in Oncology. The ASCO Post talked with Dr. Brant about how she is instituting palliative and supportive care services in the Billings Clinic Cancer Center, assessing and managing patient pain in the hospital setting, and bringing palliative care programs to the Middle East.

Multitude of Services Please talk about how you have incorporated palliative care services into your program at the Billings Clinic Cancer Center. We initially implemented distress screening and looked at information from nearly 1,400 patients in our database. We found that 67% of our patients had problems with fatigue—that was number 1 on the list—followed by pain, sleep disturbances, neuropathy, dry and

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Palliative Care in Oncology itchy skin, and memory and concentration problems. Twenty-one percent of patients reported having emotional problems, including depression, anxiety, and fear. As we started analyzing the data, the information became the foundation for the supportive care work we do. Although National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines on distress management say any patient with a score of 4 or higher should be monitored for symptoms of psychosocial distress, we thought following that many patients would overwhelm our staff, so our supportive care nurse navigator started monitoring patients with scores of 6 or higher on the distress thermometer.

We also counsel patients on establishing advanced directives and offer dignity therapy, so patients have a chance to put their story in writing and pass on their legacy. When we first launched the supportive care program in 2010, we saw 80 patients the first year. Today, we see over 100 patients a month.

Pain Care Please talk about the in-hospital survey you codeveloped and disseminated nationwide to examine pain care quality. My research collaborators at the University of Utah and Dartmouth Hitchcock Cancer Center developed pain care quality surveys through a series of psychometric studies. Using the

When we first launched the supportive care program in 2010, we saw 80 patients the first year. Today, we see over 100 patients a month. —Jeannine M. Brant, PhD, APRN, AOCN®

Our cancer center is located in Montana, the fourth largest but one of the least populated states in the country. Many patients have to drive hundreds of miles to get here, and often their symptoms arise between visits. We developed telephone triage protocols to assess and manage physical or emotional symptoms for patients who could not come to the clinic. We also recognized that we needed to establish a regular day and time for patients whose symptoms could not be managed over the phone to come to our supportive care clinic and meet with members of our interdisciplinary team in person. We added interdisciplinary chart rounds on the day we see patients for palliative care services. This provided us with the opportunity to review their records before we met with them and discuss their challenges, such as nausea, vomiting, fatigue, or pain, strategize options, and determine which specialists they may need to see that day. In addition, our clinical trials coordinator looks for available cancer center supportive care trials that match with patients’ care needs.

prototype of 20 questions, we surveyed over 20,000 hospitalized adult patients on 1,611 nursing units throughout the United States, 114 of which were oncology units. The mean pain score of the oncology patients (n = 810) was 5.7 on a scale of 0 to 10, and 25% of patients reported being in frequent or constant severe pain more than 50% of the time. A meta-analysis of randomized controlled studies among adult patients with cancer found that pain is one of the most common symptoms experienced by patients and estimated that its prevalence is 53%.2 The percentage of patients with metastatic disease is 64%, with over one-third of patients rating their pain as moderate to severe. The take-home message is that we have spent 30 years trying to manage pain, and patients are still complaining of poor pain control. We have to do a better job of controlling pain in patients with cancer. Current guidelines, such as those available through the American Pain Society (APS) and the NCCN, exist to guide clinicians in the assessment and management of pain and are very effective when used appropriately.

At tumor board meetings, the question often asked is, “What do the NCCN guidelines say regarding the management of this cancer?” But I wonder how often we ask, “Are we managing pain according to the APS or NCCN guidelines?” Establishing protocols for the management of specific pain syndromes or intractable pain can increase the consistency and quality of pain management. At our clinic, we use both an acute pain PCA [patient-controlled analgesia] titration protocol and an intractable pain titration protocol, both of which expedite the time to comfort and promote patient satisfaction.

Middle East Initiative Please talk about your appointment to the NCI Executive Committee to bring supportive and palliative care services to Middle Eastern countries. MECC is committed to promoting quality palliative care to patients with cancer throughout the Middle East. Because so many doctors and nurses in the Middle East are from war-ridden countries and don’t have access to a lot of opioids and strategies for pain and symptom management, they are in different points of progression in terms of providing supportive and palliative care services to patients. We meet two or three times a year with physicians, nurses, and social workers in over 15 countries across the Middle East and into Northern Africa and conduct educational workshops. In April, ASCO, in collaboration with MECC, held the ASCO International Palliative Care Workshop in Ankara, Turkey. At these meetings we discuss the barriers and cultural challenges that healthcare teams face in bringing palliative care to patients. Palliative care is very much in its infancy in these countries. Physicians and patients in this area of the world commonly think of palliative care as being synonymous with end-oflife care, though there is a movement to integrate palliative care earlier into the disease process. During these workshops, there is a very active exchange of ideas about “truth telling” and whether patients should be told that they have cancer or that they are dying. We facilitate the exchange of ideas and are starting to see good progress. For example, although the use of do-not-resuscitate orders

GUEST EDITOR

Jamie H. Von Roenn, MD

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.

is prohibited in some Middle Eastern countries, physicians in other countries in the region are starting to allow patients to die naturally. Local leaders from each of the Middle Eastern countries provide palliative care progress reports at MECC’s interdisciplinary annual meeting. It is exciting to hear about their success stories in the development of palliative care teams and palliative care units, the dissemination of palliative care education, and the integration of palliative care education into nursing schools and hospital settings. We have seen some very positive changes over the last few years. I feel privileged to be part of this important work, and I’m honored to work with MECC and the health-care providers in the Middle East as they advance palliative care throughout the region. The programs being established in the Middle East could certainly become role models to further palliative care in other parts of the world. n

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

References 1. Pett MA, Beck SL, Guo JW, et al: Confirmatory factor analysis of the pain care quality surveys (PainCQ©). Health Serv Res 48:1018-1038, 2013. 2. Gorin SS, Krebs P, Badr H, et al: Meta-analysis of psychosocial interventions to reduce pain in patients with cancer. J Clin Oncol 30:539-547, 2012.

More on Palliative Care in Oncology Watch futures issues of The ASCO Post for coverage of "Palliative Care: Interventions That Matter," a clinical science symposium at ASCO's Annual Meeting, chaired by Teresa Gilewski, MD, of Memorial Sloan Kettering Cancer Center.

The ASCO Post | JUNE 10, 2014

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FDA Update

FDA Approves Palonosetron Hydrochloride for Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients

he U.S. Food and Drug Administration (FDA) has approved palonosetron hydrochloride (Aloxi) injection for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy, in children aged 1 month to less than 17 years. This is the first approval of a product for acute chemo-

achieved in 59.4% of patients who received palonosetron hydrochloride at 20 µg/kg vs 58.6% of those who received the ondansetron regimen. Treatment-emergent adverse events

CODE: PFZ-14-1

PUB/POST: Island Sp

DESCRIPTION: Palbo MKT Dul Unbranded Spread Ad (2 S

were comparable across both arms, require a higher palonosetron dose Delivery Support: 212.237.7000 FILE: 01A-006293-02C-752483-Island.indd with the most frequently reported ad- than adults to prevent chemotherapyverse event in the palonosetron group induced nausea and vomiting, the being headaches. While this study safety profile is consistent with the esdemonstrated that pediatric patients tablished profile in adults. n

In ER+ breast cancer, therapy-induced nausea and vomiting prevention in patients aged 1 month to 6 months. The age of peak cancer incidence among children occurs within the first year of life, so this approval offers an important option to children, and especially infants, undergoing chemotherapy. Chemotherapy-induced nausea and vomiting is among the most common side effects following therapy in patients with cancer. In clinical trials, chemotherapy-induced nausea and vomiting has been seen in 35% to 80% of pediatric patients.

Clinical Trial Details In response to a written request from the FDA, Helsinn Group conducted four pediatric clinical trials with palonosetron hydrochloride. The approval was based on a randomized, double-blind, noninferiority pivotal trial comparing single-dose intravenous (IV) palonosetron hydrochloride at 20 µg/kg given 30 minutes prior to chemotherapy to a standard of care IV ondansetron regimen of 0.15 mg/kg given 30 minutes prior to chemotherapy followed by infusions 4 and 8 hours after the first dose of ondansetron. The primary endpoint of the study was complete response, defined as no vomiting, no retching, and no antiemesis rescue medication. Within the first 24 hours after chemotherapy, complete response was

Targeting only the estrogen receptor may miss a root cause of proliferation

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

References: 1. Weinberg RA. The Biology of Cancer. New York, NY: Garland Science; 2013. 2. Sotillo E, Grana X. In: Enders GH, ed. Cell Cycle Deregulation in Cancer. New York, NY: Humana Press; 2010:3-22. 3. Finn RS, Dering J, Conklin D, et al. Breast Cancer Res. 2009;11(5):R77. doi:10.1186/bcr2419. 4. Fry DW, Harvey PJ, Keller PR, et al. Mol Cancer Ther. 2004;3(11):1427-1438. CDK642416 March 2014 © 2014 Pfizer Inc. All rights reserved.

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FDA Update

FDA Approves Panitumumab Plus FOLFOX for Wild-Type KRAS Metastatic Colorectal Cancer PRODUCTION: Roseann Panariello

LIVE: 14.5” x 10”

WORKORDER #: 006305

15” x 10.5” he U.S. Food and Drug TRIM: Adminfirst-line treatment in patients with SAP #: S.TEMP.02254 BLEED: 15.5” x 10.75” istration (FDA) has approved wild-type KRAS (exon 2) metastatic panitumumab (Vectibix) for use in colorectal cancer. combination with FOLFOX (fluoThis approval converts the accelrouracil, leucovorin, oxaliplatin) as erated monotherapy approval granted

in 2006 to a full approval. Panitumumab was previously approved by the FDA as a monotherapy for patients with EGFR-expressing metastatic colorectal cancer after disease

progression and prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. The agent is not indicated for the treatment of patients with KRASmutant metastatic colorectal cancer or for whom KRAS mutation status is unknown. The FDA has also approved the therascreen KRAS test as a companion diagnostic to guide use of panitumumab in the treatment of metastatic colorectal cancer.

Phase III Studies The approval is based on results from the phase III PRIME and A SPECCT trials. The PRIME study showed that patients with wild-type KRAS tumors in exon 2 achieved sta-

tistically significant improvement in progression-free survival with panitumumab and FOLFOX vs FOLFOX alone (9.6 vs 8.0 months, P = .02) and a significant 4.4-month improvement in overall survival vs FOLFOX alone (23.8 vs 19.4 months). The ASPECCT study met its primary endpoint of noninferiority for improving overall survival in patients taking panitumumab vs cetuximab (Erbitux) as a single agent for the treatment of metastatic colorectal cancer in patients with wild-type KRAS tumors who have not responded to chemotherapy.

Significant Benfit

Within the nucleus, cyclin-dependent kinases 4 and 6 (CDK4/6) often continue to drive cell proliferation1-3 • CDK4/6 activation triggers a sequence of events that can lead to a loss of proliferative control2-4 • Research is focusing on the dual inhibition of ER and CDK4/6 in breast cancer3 Visit TargetCDK.com to learn more about the role of CDK4/6 in ER+ breast cancer.

“[Panitumumab] is now the first approved biologic to show a significant survival benefit when combined with FOLFOX as a first-line treatment,” said Lee S. Schwartzberg, MD, Medical Director of The West Clinic, Memphis. “[Panitumumab] has shown a significant benefit to patients with wild-type KRAS metastatic colorectal cancer when used with FOLFOX, which gives us a valuable new treatment option as we help patients fight this devastating disease.” Colorectal cancer is the third most common cancer found in both men and women in the United States, and is the second leading cause of cancer deaths. n

The ASCO Post | JUNE 10, 2014

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Opinion Clinical Trials Perspective

A Proposal for Patient-Selected Controlled Trials: Good Science and Good Medicine By Jim Omel, MD, and Karl Schwartz, MFA

he Clinical Trials and Translational Research Advisory Committee (CTAC) of the National Cancer Institute (NCI) met for the 22nd time on March 12, 2014, in their ongoing effort to improve efficiency and effectiveness of cancer clinical trials. A significant portion of the meeting addressed lagging patient accrual numbers. An important slide entitled “Analysis of Accrual for NCI Cooperative Group Phase III Trials Activated 2000-2010” explained that 254 such trials were activated during this period. Of this total, 51 are still open and accruing (with one-fifth of them < 90% accrued), and for 203 trials, accrual has stopped. Among the 203 trials that have stopped accruing patients, 119 met their goal by at least 90%, but 84 did not. Fifty-three trials (50 in adults and 3 in pediatric subjects) described by the committee as “the troublesome trials” were closed solely because of an inadequate accrual rate. A second slide summarized the 254 trials during this period by stating that 24.4% of all adult cancer trials ended with < 90% accrual. There was significant discussion around the table regarding the human and financial costs of these failed trials as well as the reasons for the poor accrual. Trial arms with significantly different interventions (believed by patients and their doctors to lack equipoise) and randomization to very disparate arms were the two main reasons for the 24.4% accrual failure rate.

for patients declining to participate in a study and that the recommendation of an oncologist is the primary reason for considering and participating in a study.2 As expected, the discussion of clinical trials with the patient’s oncologist was associated with the highest consideration (85%) and participation (53%) rates, suggesting a need to increase awareness of study protocols among treating physicians so that this discussion can become more routine and productive. Patient issues and perceptions regarding randomization, study risk, eligibility, and tests and procedures provide opportunities to improve enrollment in clinical

Current System Problems

trials by focusing on these aspects of study design, paying special attention to the rationale of the protocol as a treatment decision. During discussion of the patient accrual problems at the CTAC meeting, there seemed to be a sense of “nothing can be done; that’s just the way it is.” We, however, feel that something can be done. We propose that researchers explore the option of using patient-selected controlled trials.

Many reports have described a crisis in clinical research—ie, the very low enrollment rate in clinical trials—indicating that the system is not working for patients, researchers, or drug sponsors. Indeed, one study found that half of unpublished clinical trials have failed to accrue and reach endpoints, and another found that “of all NCI phase I, II, and III trials opened and closed between 2000 and 2007, only 50% to 60% achieved minimal stated accrual goals.”1 Our online survey of patients showed that randomization is the main reason Dr. Omel, a medical doctor and myeloma survivor, and Mr. Schwartz are patient research advocates. Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO.

lets patients either choose to be randomly assigned or pick the study arm they want to be in. Their arm selection may be based on their own expectations, preference, or unique clinical risk factors. Such decisions will most often be guided by the patient’s physician. One patient, for example, might prefer the study arm that would not put her fertility at risk. Another might prefer the treatment arm that appears to have the greater chance to achieve a cure. A third patient, having no opinion or expectation about which is better, might well choose to let a computer decide. We want to underscore that we are not

The novel type of controlled clinical trial that we are proposing is a hybrid system—one that we hope can help to reliably answer the study question, solve the enrollment problem, and also address the ethical concern of forcing patients to be randomly assigned, particularly for studies that lack equipoise. What good is a statistically perfect, well-designed randomized clinical trial if no one signs up? —Jim Omel, MD, and Karl Schwartz, MFA

A Novel Proposal We are seeking your input on the patient-selected controlled trial as an additional tool to consider when comparing treatments for cancer, such as (but not limited to) when the compared interventions have very different risks, or when both treatment protocols can be used offstudy. The patient-selected controlled trial

advocating for replacement of the randomized controlled trial design when it’s feasible and ethical to use it. We are proposing the patient-selected controlled trial as a way to conduct controlled trials when patients are unlikely to accept randomization— when clinical equipoise is lacking. The novel type of controlled clinical trial that we are proposing is a hybrid system—one that we hope can help to reliably answer the study question, solve the enrollment problem, and also address the ethical concern of forcing patients to be randomly assigned, particularly for studies that lack equipoise.

Study Design Illustration This design will lead to a mix of participants in terms of selection method (by patient-physician or computer) and in the number of patients assigned to each arm. Depending on the appeal of

the study drug and the efficacy and risks of regular care, the study arms may be out of balance. For example: • 15% may choose the traditional treatment arm (patients will choose this if they want what is known and “safe”) • 55% may choose the study drug arm (patients will choose this when the traditional treatment is not very effective or is very toxic) or vice versa (depending on the preliminary evidence for the study drug, and the efficacy of the regular treatment) • 30% may choose to be randomized (these are the patients who truly do not care about which arm they are assigned to; they are also the true measure of equipoise of the trial) In this example, 30% would receive the regular treatment, and 70% would receive the study drug. With this distribution, the statisticians can tell us how many participants are needed to get a reliable answer to the study question. With this approach, distribution to the study arms objectively measures equipoise. It should be noted that clinical trials do not require an equal number of patients in each arm, and there are numerous examples of randomized trials with 2:1 enrollment in respective study arms. We appreciate that there will be a need to provide incentives to participants who choose the established treatment in the study, if extra tests are required beyond standard care. To address this issue, it may be necessary to limit the number of tests required by participants choosing the standard treatment arm to only those needed to compare efficacy and toxicity. This will make their decision to participate in the study similar to choosing standard treatment off study. These extra tests can be optional and also encouraged by modest financial incentives sufficient to offset the burden of study participation. It should be emphasized (to enrolling patients) that such tests are done to help future patients or to more accurately monitor for response and toxicity.

Addressing Concerns As with single-arm trials, the introduction of bias is the main weakness of the patient-selected controlled trial design. We believe that this shortcoming could be mitigated by the following factors: • The patient-selected controlled trial design will be more attractive to pa-

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tients and referring physicians, allowing for larger studies and faster accrual. • Participating physicians have the greatest influence on which arm the patient will choose. This source of bias might be minimized by random selection of study doctors. • Participating physicians can agree to refer consecutive patients to the trial. • Because the patient-selected controlled trial design allows for patient choice, study doctors will likely feel there is less patient coercion compared to trials that force patients to be randomly assigned. • Study doctors can provide or capture the reason for choosing one arm or the other, thereby helping to interpret outcomes and to determine whether a larger study is needed. • When a patient is guided by a physician to choose a safer study arm because of a specific risk factor (such as retaining fertility), this improves the ethics of referring the patient to the trial (good medicine). • Prognostic indexes, biomarkers, and refined eligibility criteria can be used increasingly to counteract imbalances in the study arms (good science). • Statisticians may be able to predefine rules to censor outcomes based on prognostic factors or apply methods to achieve balance in the observational arms—such as by limiting accrual in the rapidly enrolling arms of the study.

Propensity Scoring Methods Propensity scoring is a statistical technique that attempts to estimate the effect of an intervention by accounting for the covariates that predict receiving the treatment. Thus, propensity scoring anticipates and accounts for confounding variables in order to adjust for bias.3,4 Can the type of disease influence the reliability of propensity scoring to ac-

count for bias when comparing interventions? For example, heart disease could have many more variables that might influence the course of the disease, such as diet, quality of sleep, anxiety, and belief in the value of the chosen intervention. For lymphoma, prognostic indexes guide clinical decisions and risk stratification in trials (age, tumor bulk, comorbidities, stage, and so on). For cancer, the variables that may guide a choice of study arms appear less formidable to account for. There is no placebo effect with cancer, and there is no observable influence of lifestyle. The main determinant of treatment resistance is the biology of disease, which is often unknown. In addition, subset analysis—a “trial within a trial”—can evaluate whether attending physician or patient selection bias actually has any effect on treatment results. We invite suggestions or comments as to other influences that may need to be considered in interpreting the results of a patient-selected controlled trial.

Unmet Needs and Imperfect Options Large single-arm studies evaluating approved drugs have helped to guide clinical practice, as have the outcomes of small randomized trials. Regulatory agencies have accepted single-arm studies as the basis for accelerated approval of agents that address an unmet need, and in most cases these approvals have been validated by further controlled study. Here the unmet need is to make the clinical trial system more efficient, inclusive, and sensitive to patient concerns, again, in select cases, where a randomized controlled trial is not feasible or ethical. We should not let the perfect be “the enemy of the good”—that is, insisting on perfection can result in no improvement

at all. The degree of study bias in a patientselected controlled trial will depend in part on the distribution to the study arms, which can be mitigated by the methods described previously or by novel ideas not yet considered. The natural history of the disease in the eligible population is another factor that can influence the need for a randomized control. For some cancers, the outcomes with the control are predictable, such as in the relapsed setting for patients with unfavorable prognostic markers. They will fail to respond and ultimately die from the toxicities of the ineffective treatment or of disease progression. Our understanding is that there is no rule requiring randomization as the sole method of control in a pivotal clinical trial. Indeed, in a study of patients with disease that is refractory to standard treatments, each eligible patient is the control. What is critical is that the findings from the study are judged persuasive by expert consensus, and that the outcomes reasonably guide clinical practice or approval. So, for example, the patient-selected controlled trial might be a used as an alternative to: • large phase II single-arm studies • a single-arm study for accelerated approval • the randomized comparison of two interventions with very different risks and approaches, such as when comparing biomarker-based targeted drugs to regular treatment, or when comparing oral drugs with low toxicity to high-dose myeloablative chemotherapy with stem cell transplantation • the randomized comparison of two interventions that can each be used off study (comparative effectiveness research) • a randomized controlled trial where equipoise is deficient (or controver-

sial) for an otherwise valid study question, as an alternative to terminating a randomized controlled trial due to poor enrollment.

In Conclusion We submit that the patient-selected controlled trial is clearly superior to any randomized clinical trial that is never started because it’s judged to be unfeasible, or to any randomized controlled trial that is terminated because of poor enrollment. What good is a statistically perfect well-designed randomized controlled trial if no one signs up? We hope and expect that the patient-selected controlled trial provides another way to do good science while practicing good medicine. n The authors invite comment and guidance, particularly from statisticians in this field. Write to us at karls@ lymphomation.org or care of editor@ ASCOPost.com. Disclosure: Dr. Omel and Mr. Schwartz reported no potential conflicts of interest.

References 1. Curt GA, Chabner BA: One in five cancer clinical trials is published: A terrible symptom—what’s the diagnosis? Oncologist 13:923-924, 2008. 2. Schwartz K: Interest, attitudes, and participation in clinical trials among lymphoma patients with online access. J Clin Oncol 27(15S):Abstract e19514, 2009. 3. Dahabreh IJ, Sheldrick RC, Paulus JK, et al: Do observational studies using propensity score methods agree with randomized trials? A systematic comparison of studies on acute coronary syndromes. Eur Heart J 33:18931901, 2012. 4. Pattanayak CW, Rubin DB, Zell ER: Propensity score methods for creating covariate balance in observational studies. Rev Esp Cardiol 64:897-903, 2011.

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6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events. Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment. Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment. Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

for the treatment of advanced RCC after failure of one prior systemic therapy

What truly matters to you in 2nd-line mRCC?

EVIDENCE In the phase 3, head-to-head study of exclusively 2nd-line patients with mRCC...

INLYTA was the 1st agent to demonstrate

SUPERIOR EFFICACY to sorafenib

Primary endpoint: PFS HR=0.67 (95% CI: 0.54, 0.81; P<.0001)

6.7

months

4.7

months

median PFS

INLYTA

sorafenib

(n=361) (n=362) 95% CI: 6.3, 8.6 and 4.6, 5.6, respectively

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

Data are from a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokinecontaining regimen). Patients were randomized to either INLYTA (5 mg twice daily ) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety and tolerability.1,2

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be coadministered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions]. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients

AXU606812

(7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment. Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib INLYTA Sorafenib (N=359) (N=355) All Grade All Grade Gradesb 3/4 Gradesb 3/4 % % % % Diarrhea 55 11 53 7 Hypertension 40 16 29 11 Fatigue 39 11 32 5 Decreased appetite 34 5 29 4 Nausea 32 3 22 1 Dysphonia 31 0 14 0 Palmar-plantar erythrodysesthesia syndrome 27 5 51 16 Weight decreased 25 2 21 1 Vomiting 24 3 17 1 Asthenia 21 5 14 3 Constipation 20 1 20 1 Hypothyroidism 19 <1 8 0 Cough 15 1 17 1 Mucosal inflammation 15 1 12 1 Arthralgia 15 2 11 1 Stomatitis 15 1 12 <1 Dyspnea 15 3 12 3 Abdominal pain 14 2 11 1 Headache 14 1 11 0 Pain in extremity 13 1 14 1 Rash 13 <1 32 4 Proteinuria 11 3 7 2 Dysgeusia 11 0 8 0 Dry skin 10 0 11 0 Dyspepsia 10 0 2 0 Pruritus 7 0 12 0 Alopecia 4 0 32 0 Erythema 2 0 10 <1 a Percentages are treatment-emergent, all-causality events b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 Adverse Reactiona

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%). The following table presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

Hematology Hemoglobin decreased 320 35 <1 316 52 4 Lymphocytes (absolute) decreased 317 33 3 309 36 4 Platelets decreased 312 15 <1 310 14 0 White blood cells decreased 320 11 0 315 16 <1 Chemistry Creatinine increased 336 55 0 318 41 <1 Bicarbonate decreased 314 44 <1 291 43 0 Hypocalcemia 336 39 1 319 59 2 ALP increased 336 30 1 319 34 1 Hyperglycemia 336 28 2 319 23 2 Lipase increased 338 27 5 319 46 15 Amylase increased 338 25 2 319 33 2 ALT increased 331 22 <1 313 22 2 AST increased 331 20 <1 311 25 1 Hypernatremia 338 17 1 319 13 1 Hypoalbuminemia 337 15 <1 319 18 1 Hyperkalemia 333 15 3 314 10 3 Hypoglycemia 336 11 <1 319 8 <1 Hyponatremia 338 13 4 319 11 2 Hypophosphatemia 336 13 2 318 49 16 a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib). DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/ kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib 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 INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were ≥65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only September 2013

References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc, New York, NY. mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

November 2013

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Patient’s Corner

Cancer Has Robbed Me of My Physical Beauty but Not My Inner Strength I’ve been through a lot in my life, but nothing prepared me for a diagnosis of breast cancer. By Mandy McCown, as told to Jo Cavallo

’ve been plagued with various ailments all my life. Physically and emotionally abused by my stepfather as a child, over the years I’ve developed severe psychological issues including depression and anxiety disorder. I am also in constant physical pain from cervical degenerative disc disease, osteoarthritis in my back, neck, and wrists, and fibromyalgia. The pain is so intense that I have difficulty sleeping and am unable to work, and at age 40 I had to apply for Social Security disability benefits. Still, none of these experiences adequately prepared me for the words, “You have breast cancer.” An ultrasound of my left breast, the result of an abscess from a too-tight bra, showed two suspicious areas. Biopsies of the tissues confirmed stage 0 and stage I HER2-positive invasive micropapillary carcinoma. The cancer was so aggressive that 1 month later, when I

Cancer may have robbed me of all the things that made me beautiful on the outside, but it has only enhanced the qualities that make me beautiful on the inside. — Mandy McCown

had a bilateral mastectomy, the pathology report showed that the cancer had spread to four additional areas in my breast and five lymph nodes. I was prescribed a chemotherapy regimen of docetaxel, cyclophosphamide, and doxorubicin, followed by paclitaxel and trastuzumab (Herceptin). I was told I would also need radiation therapy, but my insurance copays were so high, I couldn’t afford to pay for that

Visit Cancer.Net for information on: Managing Emotions http://www.cancer.net/coping-and-emotions/managingemotions Managing Pain http://www.cancer.net/navigating-cancer-care/side-effects/pain-causesand-diagnosis Caregiver Support http://www.cancer.net/coping-and-emotions/caregiver-support Managing the Cost of Cancer Care http://www.cancer.net/navigating-cancer-care/financial-considerations

in addition to the 20% copays for my chemotherapy treatments (which cost $5,500 per treatment), so I decided to forego the radiation therapy.

Coping With the Ramifications of Cancer This past year has been very difficult, and I’m still struggling to come to terms with the devastation this disease has left in its wake. The side effects from my treatment have robbed me of all the physical attributes that made me feel attractive. Although I’m undergoing breast reconstruction, I don’t expect the result will restore either the look or feel of my natural breasts. And my hair still has not grown back to its former glory. Perhaps, most debilitating of all is that the pain I experienced before my cancer diagnosis has been exacerbated by the chemotherapy, as have my bouts of depression and anxiety. The combination of my feelings of low self-esteem due to the changes in my body, the constant pain, and the emotional turmoil are also taking a toll on my relationship with my husband. He does what he can to help and com-

The ASCO Post Recognizes

June 1, 2014

fort me—and I attempt to do the same for him—but currently I am not physically or emotionally capable of being the person I was before my diagnosis. I need more time to heal and get distance from my cancer. I’m fortunate to have a loving husband and children who never allow me to give up, as well as an oncology team that has shown me compassion and understanding. And I’m grateful to other breast cancer survivors and their loved ones who have reached out to me with so much kindness. Their support is certainly helping me through this journey.

Facing the Future With Optimism Today, despite the ongoing emotional and physical challenges of having cancer, I am feeling more optimistic about the future. I believe that everything happens for a reason and I’m determined to use this experience to fulfill a lifelong dream of writing a book on abuse and hope to help others going through a similar experience. I make jewelry, blankets, and scarves to raise money to pay for my medical expenses, and I’m hoping that I can eventually raise enough funds to create a foundation to support other survivors of abuse and cancer. Cancer may have robbed me of all the things that made me beautiful on the outside, but it has only enhanced the qualities that make me beautiful on the inside. n Mandy McCown lives in Jeffersonville, Ohio.

The ASCO Post | JUNE 10, 2014

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2014–2015 Oncology Meetings June

July

National Coalition of Oncology Nurse Navigators 5th Annual Conference: Setting the Course for Improved Cancer Care June 12-14 • Atlanta, Georgia For more information: www.nconnconference.com

Best of ASCO in Japan July 5-6 • Kobe, Japan For more information: www.jsmo.or.jp/en/

Targeting VEGF-mediated Tumor Angiogenesis in Cancer Therapy June 19-20 • New York, New York For more information: www.nyas.org/Events The Win 2014 Symposium— Winning Combinations for Precision Cancer Medicines June 23-24 • Paris, France For more information: www.winsymposium.org MASCC/ISOO International Symposium on Supportive Care in Cancer June 26-28 • Miami, Florida For more information: www.mascc.org/symposium European Conference of Oncology Pharmacy 2 June 26-28 • Krakow, Poland For more information: http://ecop2014.wordpress.com 6th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone Disease June 28-July 2 • Oxford, United Kingdom For more information: www.oxfordbonepharm.org/ 16th International Symposium on Pediatric Neuro-Oncology June 28-July 2 • Singapore For more information: www.ispno2014.com

23rd Biennial Congress of the European Association for Cancer Research July 5-8 • Munich, Germany For more information: http://eacr23.eacr.org 8th International Conference on Teenage and Young Adult Cancer Medicine July 7-8 • London, United Kingdom For more information: www.teenagecancertrust.org/whatwe-do/international-conference/ NCCN Policy Summit: The Impact of Health Care Reform on Academic Oncology Practice July 10 • Arlington, Virginia For more information: www.nccn.org/professionals/ meetings/oncology_policy_program/ impact_health_care_reform.aspx

2014-2015 Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org

5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

6th Latin American Conference on Lung Cancer August 21-23 • Lima, Peru For more information: www.lalca2014.org ISEH Society for Hematology and Stem Cells 43rd Annual Scientific Meeting August 21-24 • Montreal, Canada For more information: www.iseh.org Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org

August

6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606

Breast Cancer: New Horizons, Current Controversies July 10-12 • Boston, Massachusetts For more information: www.hms-cme.net/341279/

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org

The 12th Annual Scientific Meeting of Japanese Society of Medical Oncology July 17-19 • Fukuoka, Japan For more information: www.congre.co.jp/jsmo2014/en/

ASH Meeting on Lymphoma Biology August 10-13 • Colorado Springs, Colorado For more information: www.hematology.org/LymphomaBiology/

2014 Pan Pacific Lymphoma Conference July 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/ panpacificlymphoma.htm

16th Annual Scientific Meeting: AGITG Trials in Action August 20-22 • Brisbane, Australia For more information: www.agitg.asnevents.com.au

Hematology and Medical Oncology Best Practices August 14-21 • Arlington, Virginia For more information: smhs.gwu.edu/ cehp/activities/courses/hemonc

September Association of Pediatric Hematology/Oncology Nurses 38th Annual Conference September 4-6 • Portland, Oregon For more information: www.aphon.org Breast Cancer Symposium September 4-6 • San Francisco, California For more information: breastcasym.org continued on page 104

July 21-25, 2014

The Kohala Coast, Hawaii

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The ASCO Post | JUNE 10, 2014

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2014–2015 Oncology Meetings continued from page 102

2014 APAO Annual Conference September 10-14, 2014 • Austin, Texas Sheraton Austin at the Capitol For more information: www.apao.cc/node/9 American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: www.aonnonline.org NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/meetings/ hematological/ Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/ meetings--workshops/specialconferences/advances-in-melanomafrom-biology-to-therapy.aspx European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29-October 2 • Cambridge, Massachusetts For more information: steelelab.mgh.harvard.edu

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org International Cancer Imaging Society Meeting and 14th Annual Teaching Course October 9-11 • Heidelberg, Germany For more information: www.icimagingsociety.org.uk/index. cfm?task=meetings&meetingid=37 11th Meeting of the Eurpean Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php 2nd Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/ breastcancer/pages/index.aspx 18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida

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apsho.org/jadprolive

2014-2015

For more information: www2.kenes.com/sis/Pages/Home. aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org 16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com 14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org 11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org 3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/ CourseDetail.aspx/80028747 CNS Anticancer Drug Discovery/ Development Conference November 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgicalspecialties-2014s306

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com 20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians

19th Annual Meeting of the Society for Neuro-Oncology November 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/ EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org

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Issues in Oncology Workforce

Oncology Advanced Practitioners in the Midst of Growth, Change By Caroline McNeil

he number of nurse practitioners (NPs) and physician assistants (PAs) in community cancer practices is growing, according to ASCO’s annual census of oncology practice, published in March 2014.1 As though to illustrate that finding, a new professional society—the Advanced Practitioner Society for Hematology and Oncology (APSHO)—was launched earlier this year at JADPRO Live. That meeting is sponsored by the Journal of the Advanced Practitioner in Oncology ( JADPRO), itself only 4 years old. And these are just the most recent developments in a field experiencing rapid growth and change. “It’s a really different culture,” said Maura Polansky, MS, MHPE, PA-C, who directs PA education at The University of Texas MD Anderson Cancer Center, Houston, and has been in the field more than 19 years. She was speaking of one issue in particular—physician acceptance—but that observation could well apply to other areas of change, according to interviews with PAs and NPs in a variety of practice settings.

Growing Numbers To begin with, there are the growing numbers of PAs and NPs overall. According to the federal Bureau of Labor Statistics, their numbers will grow by more than 30% between 2012 and 2022, much faster than the average 11% growth rate forecast for all professions.2 ASCO’s annual census suggests that the numbers of oncology PAs and NPs in medium and large community practices grew from 2012 to 2013 and are likely to continue to do so. For instance, 35% of practices responding to the survey, including both community and academic practices, said they planned to hire nurse practitioners in the next 12 months, and 21% planned to hire physician assistants. Each percentage was an increase compared to the 2012 census. Steven H. Wei, MPH, PA-C, a physician assistant in MD Anderson’s Department of Surgery, is witnessing the growth firsthand. “The recruitment of PAs and NPs into surgical oncology is growing exponentially,” he said. Up to 10 new PAs and NPs have been hired annually at MD Anderson for the past few years. At the same time, their roles are expanding. PAs and NPs not only assist in the operating room, he said, but now have major responsibility in areas such as pre- and postoperative care and survivorship clinics.

Expanding Roles Other oncology NPs and PAs interviewed by The ASCO Post agreed. In both academic and community cancer centers, they said, their roles and responsibilities have expanded dramatically. When Susan S. VanBeuge, DNP, APRN, FNP-BC, CNE, FAANP, received her nurse practitioner degree 11 years ago, she was the first advanced practice nurse at University Medical Center in Las Vegas to work in the operating

who coordinates the pediatric bone marrow transplant program at the Children’s Hospital of Alabama in Birmingham. Advanced practitioners now manage entire panels of patients in the hospital, make referrals for home health care, conduct patient education at discharge, and write chemotherapy orders, he said. They also can be closely involved with coordination of care, said Todd Pickard, MMSc, PA-C, who manages

Every physician at MD Anderson now expects to have a PA or NP on his or her team. —Todd Pickard, MMSc, PA-C

room as a first assistant in oncologic sur-

gery. As she learned the role, the partnership between NP and physician also evolved. “We had to teach ourselves about our roles,” she said. “Now, many of the schools for surgical first assistant have specific tracks for nurse practitioners that were not in place 11 years ago.” State laws also help determine what advanced practitioners can do. Steven L. Black, MBA, an oncology practice consultant and Vice President of The Oncology Group in Austin, Texas, who spoke at the annual meeting of the Association for Community Cancer Centers in March, said that some states allow full, independent practice (mostly western and rural states). Others allow “reduced” practice, requiring collaboration with a physician, or “restricted” practice, requiring supervision by a physician. Nevada’s law was amended last year to allow full practice authority, and since then, applications for advanced practice licenses in the state have risen by approximately 19%, said Dr. VanBeuge, who actively advocated for the new law. Another reason for expanding roles in academic centers is the cap now placed on the number of hours medical residents can work and the number of patients they can manage at one time. “That caused tremendous growth in the roles of NPs in inpatient settings,” said Richard D. Brown, MSN, CRNP, JD, FAANP,

the PA program at MD Anderson. PAs and NPs there take part in multidisciplinary case review meetings, where the entire team discusses each case. One reason for expanding collaboration, many said, is that PAs, NPs, and physicians now train side by side in both courses and clinical rotations. As a result, “most modern-day physicians are used to thinking of themselves as part

The purpose of the newly launched Advanced Practitioner Society for Hematology and Oncology is education and support, said the group’s founding Chair, Pamela Hallquist Viale, RN, MS, CNS, ANP, an oncology nurse practitioner and Editor-in-Chief of JADPRO. “We saw the need for more live education—meetings and symposia— geared specifically to advanced practitioners as a group,” she said. The new society is the first to include a range of advanced practitioners in oncology, including clinical nurse specialists, advanced degree nurses, and pharmacists, as well as NPs and PAs. The Association of Physician Assistants in Oncology and the Oncology Nursing Society also offer continuing education at their annual meetings. And ASCO has special sessions at its annual meeting for advanced practitioners as well as online courses (see university. asco.org/acapppage). PAs and NPs get most of their formal training through masters programs, where the emphasis is generally on primary care. In a recent survey of PA programs,3 Ms. Polansky and colleagues found that cancer prevention and initial diagnosis were the primary areas of oncology taught. Programs reported a small percentage of students who participated in a clinical elective rotation in

The new society [APSHO] is the first to include a range of advanced practitioners in oncology, including clinical nurse specialists, advanced degree nurses, and pharmacists, as well as NPs and PAs. —Pamela Hallquist Viale, RN, MS, CNS, ANP

of a multidisciplinary team, starting in medical school,” said Mr. Brown. “Every physician at MD Anderson now expects to have a PA or NP on his or her team,” commented Mr. Pickard. “One reason is just that there are more patients and more demand for care than any single person can provide for.”

Continuing Education As roles expand and cancer care becomes more complex, the need for continuing education—and new avenues to provide it—is also growing.

oncology. The authors concluded that “novel means of enhancing cancer education during PA school and continuing medical education following primary PA education will be essential to expand PAs’ competencies in cancer care.” “We don’t expect PA schools will devote more time to oncology,” Ms. Polansky said in an interview. And although she heads MD Anderson’s postgraduate program for PAs specializing in oncology—the only one in the country—she doesn’t think that more continued on page 106

The ASCO Post | JUNE 10, 2014

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Issues in Oncology Oncology Advanced Practitioners continued from page 105

such programs are the answer. The generalist model is “very effective—it is not broken,” she said. Instead, the MD Anderson group is trying to sort out what opportunities can be developed for more learning. One current project is development of an online continuing education program with lectures, interactive case studies, discussion forums, and assignments,

including modules for major cancers and major complications. In general, she thinks that continuing education is needed in more accessible forms, especially for those in community practice, including mentorships and other learning opportunities. “The big question is how to deliv-

er those,” she said. “New models are needed.” n

Disclosure: Ms. Polansky, Mr. Wei, Ms. VanBeuge, Mr. Pickard, and Ms. Viale, reported no potential conflicts of interest.

References 1. Hanley A, Hagerty K, Towle EL, et S:6.75” al: Results of the 2013 American Society of Clinical Oncology National Oncology

Census. J Oncol Pract 10:143-114, 2014. 2. Bureau of Labor Statistics: Occupational Outlook Handbook, 2014-15 Edition. Washington, DC; U.S. Department of Labor, 2014. 3. Polansky M, Ross AC, Coniglio D, et al: Cancer education in physician assistant programs. J Physician Assist Educ 25:4-11, 2014.

Coming Soon in The ASCO Post Continued coverage from ASCO’s 50th Annual Meeting, including reports on: ■■ First-line bevacizumab plus chemotherapy and cetuximab plus chemotherapy provide similar suvival benefit for patients with metastatic colorectal cancer (plenary) ■■ Second-line treatment with ramucirumab plus standard docetaxel extends survival for patients with advanced NSCLC ■■ Ibrutinib is highly active, significantly delaying disease progression and extending survival for patients with resistant or relapsed chronic lymphocytic leukemia ■■ New targeted drug, lenvatinib, yields high response rates, delays progression in patients with radioiodine-resistant, advanced differentiated thyroid cancer

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Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

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

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

05/14 [COM-0086]

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Journal Spotlight Smoking

Water Pipe Smoking May Increase Risk for Cancer and women had in their urine a 73-fold increase in nicotine; fourfold increase in cotinine; twofold increase in NNAL, a breakdown product of a tobacco-specific nitrosamine, NNK, which can cause lung and pancreatic cancers; and 14% to 91% continued on page 108

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

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

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

PFS

1.0

AE/AS

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo COMETRIQ® (n=219) Placebo (n=111)

0.9 0.8 0.6

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

0.7 0.5 0.4

median

4.0 4.0

0.3

11.2 11.2 months months

months months

0.2

Probability of patients who are progression free

31 3

12 2

2 0

1 0

Months 219 111

121 35

78 11

55 6

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%). Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. Please see accompanying brief summary of Prescribing Information, including Boxed Warnings. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

SIGNOFF

Disk

B:11.25”

S:9.75”

COMETRIQ® Placebo

T:10.25”

No. of patients at risk:

0.0

0.1

PharmaGraphics

T:15”

States,” said Gideon St.Helen, PhD, postdoctoral fellow in the Division of Clinical Pharmacology and the Center for Tobacco Control Research and Education at the University of California, San Francisco. After a single evening of water pipe smoking in a hookah bar, young men

S&H

B:17.5”

Epidemiology, Biomarkers & Prevention.1 “This study reports systemic intake of tobacco-specific nitrosamines and [volatile organic compounds] after a typical water pipe-smoking session in a hookah bar setS:6.75” ting, thus making the findings generalizable to most water pipe users in the United

oung adults who smoked water pipes in hookah bars had elevated levels of nicotine, cotinine, tobacco-related cancer-causing agents, and volatile organic compounds in their urine, and this may increase their risk for cancer and other chronic diseases, according to a study published in Cancer

Cosmos C

COORDINATED ATTACK

The ASCO Post | JUNE 10, 2014

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Journal Spotlight Water Pipe Smoking continued from page 107

increase in the breakdown products of compounds such as benzene and acrolein that are known to cause cancer and cardiovascular and respiratory diseases. “There was also a substantial increase in nicotine levels, which raises concerns about the potential addictiveness of wa-

Gideon St.Helen, PhD

COMETRIQ® COMETRIQ® (cabozantinib) (cabozantinib) capsules capsules BRIEF BRIEF SUMMARY SUMMARY OF PRESCRIBING OF PRESCRIBING INFORMATION INFORMATION Initial Initial U.S.U.S. Approval: Approval: 20122012

ter pipe smoking and possible effects on the developing brains of children and youths who use water pipes,” added Dr. St.Helen. “Water pipe smoking is generally perceived to be a safe alternative to cigarette smoking, even for children and youths. Our study shows that water S:6.75” S:6.75” pipe use, particularly chronic use, is not risk-free.” n

Disclosure: The study was funded by the National Institutes of Health and the California Tobacco-related Disease Research Program. Dr. St.Helen reported no potential conflicts of interest.

Reference 1. St.Helen G, et al: Nicotine and carcinogen exposure after water pipe smoking in hookah bars. Cancer Epidemiol Biomarkers Prev. May 16, 2014 (early release online).

5.4 Wound 5.4 Wound Complications: Complications: Wound Wound complications complications havehave beenbeen reported reported withwith COMETRIQ. COMETRIQ. Table 1. Per-Patient 1. Per-Patient Incidence Incidence of Selected of Selected Adverse Adverse Reactions Reactions in Protocol in Protocol StopStop treatment treatment withwith COMETRIQ COMETRIQ at least at least 28 days 28 days priorprior to scheduled to scheduled surgery. surgery. Resume Resume Table XL184-301 Occurring Occurring at aatHigher a Higher Incidence Incidence in COMETRIQ-Treated in COMETRIQ-Treated Patients Patients COMETRIQ COMETRIQ therapy therapy afterafter surgery surgery based based on clinical on clinical judgment judgment of adequate of adequate wound wound XL184-301 1 healing. healing. Withhold Withhold COMETRIQ COMETRIQ in patients in patients withwith dehiscence dehiscence or or wound wound healing healing [Between-Arm [Between-Arm Difference Difference of ≥5% of ≥5% (All(All Grades) Grades) or 1≥2% or ≥2% (Grades (Grades 3-4)] 3-4)] complications complications requiring requiring medical medical intervention. intervention. Cabozantinib Cabozantinib Placebo Placebo 5.5 5.5Hypertension: Hypertension:COMETRIQ COMETRIQtreatment treatmentresults resultsin inan anincreased increasedincidence incidence (n=214) (n=214) (n=109) (n=109) WARNING: WARNING: PERFORATIONS PERFORATIONS ANDAND FISTULAS, FISTULAS, andand HEMORRHAGE HEMORRHAGE MedDRA System System Organ Organ Class/ Class/ of oftreatment-emergent treatment-emergenthypertension hypertensionwithwithJointJointNational NationalCommittee Committeeon on MedDRA Prevention, Prevention,Detection, Detection,Evaluation, Evaluation,andandTreatment Treatmentof ofHighHighBlood BloodPressure Pressure Preferred Preferred Terms Terms See full Seeprescribing full prescribing information information for complete for complete boxedboxed warning. warning. All All Grades Grades All All Grades Grades (modified (modified JNC JNC criteria) criteria) stage stage 1 or 1 or 2 hypertension 2 hypertension identified identified in in 61% 61% of of Grades Grades 3-4 3-4 Grades Grades 3-4 3-4 Perforations Perforations andand Fistulas: Fistulas: Gastrointestinal Gastrointestinal perforations perforations occurred occurred in 3% in 3% COMETRIQ-treated COMETRIQ-treated patients patients compared compared withwith 30%30% of of placebo-treated placebo-treated patients patients andand fistula fistula formation formation in 1%in of 1%COMETRIQ-treated of COMETRIQ-treated patients. patients. Discontinue Discontinue GASTROINTESTINAL DISORDERS DISORDERS in the in randomized the randomized trial.trial. Monitor Monitor blood blood pressure pressure priorprior to initiation to initiation andand regularly regularly during during GASTROINTESTINAL COMETRIQ COMETRIQ treatment. treatment. Withhold Withhold COMETRIQ COMETRIQ for for hypertension hypertension thatthat is not is not adequately adequately DIARRHEA COMETRIQ COMETRIQ in patients in patients withwith perforation perforation or fistula. or fistula. (5.1)(5.1) DIARRHEA 63 63 16 16 33 33 2 2 controlled controlled withwith medical medical management; management; when when controlled, controlled, resume resume COMETRIQ COMETRIQ at aat a Hemorrhage: Hemorrhage: Severe, Severe, sometimes sometimes fatal,fatal, hemorrhage hemorrhage including including hemoptysis hemoptysis reduced 2 2 reduced dose.dose. Discontinue Discontinue COMETRIQ COMETRIQ for severe for severe hypertension hypertension thatthat cannot cannot be controlled be controlled STOMATITIS STOMATITIS 51 51 5 5 6 6 0 0 withwith anti-hypertensive anti-hypertensive therapy. therapy. andand gastrointestinal gastrointestinal hemorrhage hemorrhage occurred occurred in 3% in of 3%COMETRIQ-treated of COMETRIQ-treated NAUSEA NAUSEA 43 43 1 1 21 21 0 0 5.6 5.6 Osteonecrosis Osteonecrosis of the of the JawJaw (ONJ): (ONJ): Osteonecrosis Osteonecrosis of the of the jaw jaw (ONJ)(ONJ) occurred occurred in 1%in 1% patients. patients. Monitor Monitor patients patients for signs for signs andand symptoms symptoms of bleeding. of bleeding. Do not Do not 3 3 ORALORAL PAINPAIN 36 36 2 2 6 6 0 0 of COMETRIQ-treated of COMETRIQ-treated patients. patients. ONJ ONJ can can manifest manifest as jaw as jaw pain, pain, osteomyelitis, osteomyelitis, osteitis, osteitis, administer administer COMETRIQ COMETRIQ to patients to patients withwith severe severe hemorrhage. hemorrhage. (5.2)(5.2) bonebone erosion, erosion, toothtooth or periodontal or periodontal infection, infection, toothache, toothache, gingival gingival ulceration ulceration or erosion, or erosion, CONSTIPATION CONSTIPATION 27 27 0 0 6 6 0 0 persistent persistent jaw jaw painpain or slow or slow healing healing of the of the mouth mouth or jaw or jaw afterafter dental dental surgery. surgery. Perform Perform 4 4 ABDOMINAL PAINPAIN 27 27 3 3 13 13 1 1 an oral an oral examination examination priorprior to initiation to initiation of COMETRIQ of COMETRIQ andand periodically periodically during during COMETRIQ COMETRIQ ABDOMINAL therapy. therapy. Advise Advise patients patients regarding regarding goodgood oraloral hygiene hygiene practices. practices. For For invasive invasive dental dental VOMITING VOMITING 24 24 2 2 2 2 1 1 1. INDICATIONS 1. INDICATIONS ANDAND USAGE USAGE procedures, procedures, withhold withhold COMETRIQ COMETRIQ treatment treatment for for at least at least 28 days 28 days priorprior to scheduled to scheduled DYSPHAGIA DYSPHAGIA 13 13 4 4 6 6 1 1 surgery, surgery, if possible. if possible. COMETRIQ COMETRIQ is indicated is indicated for the for the treatment treatment of patients of patients withwith progressive, progressive, metastatic metastatic medullary medullary thyroid thyroid cancer cancer (MTC). (MTC). 5.7 Palmar-Plantar 5.7 Palmar-Plantar Erythrodysesthesia Erythrodysesthesia Syndrome: Syndrome: Palmar-plantar Palmar-plantar erythrodysesthesia erythrodysesthesia DYSPEPSIA DYSPEPSIA 11 11 0 0 0 0 0 0 syndrome syndrome (PPES) (PPES) occurred occurred in 50% in 50% of patients of patients treated treated withwith cabozantinib cabozantinib andand waswas HEMORRHOIDS 9 9 0 0 3 3 0 0 2. DOSAGE 2. DOSAGE ANDAND ADMINISTRATION ADMINISTRATION severe severe (≥Grade (≥Grade 3) in3)13% in 13% of patients. of patients. Withhold Withhold COMETRIQ COMETRIQ in patients in patients whowho develop develop HEMORRHOIDS 2.1 2.1Recommended RecommendedDose: Dose:The Therecommended recommendeddailydailydosedoseof ofCOMETRIQ COMETRIQis is intolerable intolerable Grade Grade 2 PPES 2 PPES or Grade or Grade 3-4 3-4 PPESPPES untiluntil improvement improvement to Grade to Grade 1; resume 1; resume GENERAL GENERAL DISORDERS DISORDERS ANDAND ADMINISTRATION ADMINISTRATION SITESITE CONDITIONS CONDITIONS 140 140 mg mg (one(one 80-mg 80-mg andand threethree 20-mg 20-mg capsules). capsules). Do not Do not administer administer COMETRIQ COMETRIQ withwith COMETRIQ COMETRIQ at a atreduced a reduced dose.dose. FATIGUE FATIGUE 41 41 9 9 28 28 3 3 food.food. Instruct Instruct patients patients not not to eat to eat for atforleast at least 2 hours 2 hours before before andand at least at least 1 hour 1 hour afterafter Proteinuria: Proteinuria: Proteinuria Proteinuria waswas observed observed in 4in(2%) 4 (2%) patients patients receiving receiving COMETRIQ, COMETRIQ, taking taking COMETRIQ. COMETRIQ. Continue Continue treatment treatment untiluntil disease disease progression progression or unacceptable or unacceptable 5.8 5.8 ASTHENIA ASTHENIA 21 21 6 6 15 15 1 1 including including one one with with nephrotic nephrotic syndrome, syndrome, as compared as compared to none to none of the of patients the patients receiving receiving toxicity toxicity occurs. occurs. Swallow Swallow COMETRIQ COMETRIQ capsules capsules whole. whole. Do not Do not openopen COMETRIQ COMETRIQ capsules. capsules. placebo. Monitor Monitor urineurine protein protein regularly regularly during during COMETRIQ COMETRIQ treatment. treatment. Discontinue Discontinue INVESTIGATIONS INVESTIGATIONS Do not Do not taketake a missed a missed dosedose within within 12 hours 12 hours of the of the nextnext dose.dose. Do not Do not ingest ingest foodsfoods (e.g.,(e.g., placebo. COMETRIQ COMETRIQ in patients in patients who who develop develop nephrotic nephrotic syndrome. syndrome. grapefruit, grapefruit, grapefruit grapefruit juice)juice) or nutritional or nutritional supplements supplements thatthat are are known known to inhibit to inhibit DECREASED WEIGHT WEIGHT 48 48 5 5 10 10 0 0 5.9 5.9Reversible ReversiblePosterior PosteriorLeukoencephalopathy LeukoencephalopathySyndrome: Syndrome: Reversible Reversible DECREASED cytochrome cytochrome P450P450 during during COMETRIQ. COMETRIQ. Posterior Leukoencephalopathy Leukoencephalopathy Syndrome Syndrome (RPLS), (RPLS), a syndrome a syndrome of of subcortical subcortical METABOLISM METABOLISM ANDAND NUTRITION NUTRITION DISORDERS DISORDERS 2.2 2.2 Dosage Dosage Adjustments: Adjustments: For For Adverse Adverse Reactions Reactions : Withhold : Withhold COMETRIQ COMETRIQ Posterior vasogenic edema edema diagnosed diagnosed by by characteristic characteristic finding finding on on MRI,MRI, occurred occurred in one in one for for NCI NCI CTCAE CTCAE Grade Grade 4 hematologic 4 hematologic adverse adverse reactions, reactions, Grade Grade 3 or3 or greater greater vasogenic DECREASED APPETITE APPETITE 46 46 5 5 16 16 1 1 (<1%) patient. patient. Perform Perform an evaluation an evaluation for RPLS for RPLS in any in any patient patient presenting presenting withwith seizures, seizures, DECREASED non-hematologic non-hematologic adverse adverse reactions reactions or intolerable or intolerable Grade Grade 2 adverse 2 adverse reactions. reactions. (<1%) headache, visual visual disturbances, disturbances, confusion confusion or altered or altered mental mental function. function. Discontinue Discontinue DEHYDRATION DEHYDRATION 7 7 2 2 2 2 1 1 UponUpon resolution/improvement resolution/improvement of the of the adverse adverse reaction reaction (i.e.,(i.e., return return to baseline to baseline or or headache, COMETRIQ COMETRIQ in patients in patients whowho develop develop RPLS.RPLS. resolution resolution to Grade to Grade 1), reduce 1), reduce the the dosedose as follows: as follows: MUSCULOSKELETAL MUSCULOSKELETAL ANDAND CONNECTIVE CONNECTIVE TISSUE TISSUE DISORDERS DISORDERS DrugDrug Interactions: Interactions: Avoid Avoid administration administration of COMETRIQ of COMETRIQ withwith agents agents thatthat are strong are strong • If• previously If previously receiving receiving 140-mg 140-mg dailydaily dose,dose, resume resume treatment treatment at 100 at 100 mg mg 5.105.10 ARTHRALGIA ARTHRALGIA 14 14 1 1 7 7 0 0 CYP3A4 CYP3A4 inducers inducers or inhibitors. or inhibitors. dailydaily (one(one 80-mg 80-mg andand oneone 20-mg 20-mg capsule) capsule) Hepatic Hepatic Impairment: Impairment: COMETRIQ COMETRIQ is not is not recommended recommended for for use use in patients in patients withwith MUSCLE MUSCLE SPASMS SPASMS 12 12 0 0 5 5 0 0 • If• previously If previously receiving receiving 100-mg 100-mg dailydaily dose,dose, resume resume treatment treatment at 60 at mg 60 mg dailydaily 5.11 5.11 moderate moderate or severe or severe hepatic hepatic impairment. impairment. (three (three 20-mg 20-mg capsules) capsules) MUSCULOSKELETAL MUSCULOSKELETAL CHEST CHEST PAINPAIN 9 9 1 1 4 4 0 0 Embryo-Fetal Embryo-Fetal Toxicity: Toxicity: COMETRIQ COMETRIQ can can cause cause fetalfetal harmharm when when administered administered • If• previously If previously receiving receiving 60-mg 60-mg dailydaily dose,dose, resume resume at 60 at 60 mg mg if tolerated, if tolerated, 5.12 5.12 NERVOUS SYSTEM SYSTEM DISORDERS DISORDERS to atopregnant a pregnant woman. woman. Cabozantinib Cabozantinib waswas embryolethal embryolethal in rats in rats at exposures at exposures below below the the NERVOUS otherwise, otherwise, discontinue discontinue COMETRIQ COMETRIQ recommended recommended human human dose,dose, withwith increased increased incidences incidences of skeletal of skeletal variations variations in rats in rats andand DYSGEUSIA DYSGEUSIA 34 34 0 0 6 6 0 0 Permanently Permanently discontinue discontinue COMETRIQ COMETRIQ for any for any of the of the following: following: development development of visceral of visceral visceral visceral variations variations andand malformations malformations in rabbits. in rabbits. If thisIf this drugdrug is used is used during during pregnancy, pregnancy, perforation perforation or fistula or fistula formation; formation; severe severe hemorrhage; hemorrhage; serious serious arterial arterial thromboembolic thromboembolic or iforthe HEADACHE 18 18 0 0 8 8 0 0 if the patient patient becomes becomes pregnant pregnant whilewhile taking taking this this drug,drug, the the patient patient should should be be HEADACHE eventevent (e.g.,(e.g., myocardial myocardial infarction, infarction, cerebral cerebral infarction); infarction); nephrotic nephrotic syndrome; syndrome; malignant malignant apprised apprised of the of the potential potential hazard hazard to the to the fetus.fetus. DIZZINESS DIZZINESS 14 14 0 0 7 7 0 0 hypertension, hypertension, hypertensive hypertensive crisis,crisis, persistent persistent uncontrolled uncontrolled hypertension hypertension despite despite optimal optimal medical medical management; management; osteonecrosis osteonecrosis of the of the jaw;jaw; or reversible or reversible posterior posterior 6. ADVERSE 6. ADVERSE REACTIONS REACTIONS PARESTHESIA PARESTHESIA 7 7 0 0 2 2 0 0 In Patients In Patients WithWith Hepatic Hepatic Impairment Impairment : COMETRIQ : COMETRIQ is is 6.1 Clinical leukoencephalopathy leukoencephalopathy syndrome. syndrome. 6.1 Clinical TrialTrial Experience: Experience: Because Because clinical clinical trialstrials are conducted are conducted under under widely widely varying varying PERIPHERAL SENSORY SENSORY 7 7 0 0 0 0 0 0 not not recommended recommended for use for use in patients in patients withwith moderate moderate andand severe severe hepatic hepatic impairment. impairment. conditions, conditions, adverse adverse reaction reaction ratesrates observed observed in the in the clinical clinical trialstrials of aofdrug a drug cannot cannot be be PERIPHERAL NEUROPATHY In Patients In Patients Taking Taking CYP3A4 CYP3A4 Inhibitors Inhibitors : Avoid : Avoid the the use use of concomitant of concomitant strong strong CYP3A4 CYP3A4 directly directly compared compared to rates to rates in the in the clinical clinical trialstrials of another of another drugdrug andand maymay not not reflect reflect NEUROPATHY inhibitors inhibitors (e.g.,(e.g., ketoconazole, ketoconazole, itraconazole, itraconazole, clarithromycin, clarithromycin, atazanavir, atazanavir, nefazodone, nefazodone, the the ratesrates observed observed in practice. in practice. The The safety safety of COMETRIQ of COMETRIQ waswas evaluated evaluated in 330 in 330 patients patients PERIPHERAL PERIPHERAL NEUROPATHY NEUROPATHY 5 5 0 0 0 0 0 0 saquinavir, saquinavir, telithromycin, telithromycin, ritonavir, ritonavir, indinavir, indinavir, nelfinavir, nelfinavir, voriconazole) voriconazole) in patients in patients withwith progressive, progressive, metastatic metastatic medullary medullary thyroid thyroid cancer cancer randomized randomized to receive to receive receiving receiving COMETRIQ. COMETRIQ. For For patients patients whowho require require treatment treatment withwith a strong a strong CYP3A4 CYP3A4 140 140 mg mg of COMETRIQ of COMETRIQ (n=214) (n=214) or placebo or placebo (n=109) (n=109) administered administered dailydaily untiluntil disease disease PSYCHIATRIC PSYCHIATRIC DISORDERS DISORDERS inhibitor, inhibitor, reduce reduce the the dailydaily COMETRIQ COMETRIQ dosedose by 40 by mg 40 mg (for (for example, example, fromfrom 140 140 mg mg to to progression progression or intolerable or intolerable toxicity toxicity occurred occurred in a inrandomized, a randomized, double-blind, double-blind, controlled controlled ANXIETY 9 9 0 0 2 2 0 0 100 100 mg mg dailydaily or from or from 100 100 mg mg to 60tomg 60 mg daily). daily). Resume Resume the the dosedose thatthat waswas usedused priorprior to to trial.trial. The The datadata described described below below reflect reflect a median a median exposure exposure to COMETRIQ to COMETRIQ for 204 for 204 days.days. ANXIETY initiating initiating the the CYP3A4 CYP3A4 inhibitor inhibitor 2 to 23 todays 3 days afterafter discontinuation discontinuation of the of the strong strong inhibitor. inhibitor. The The population population exposed exposed to COMETRIQ to COMETRIQ waswas 70%70% male,male, 90%90% white, white, andand hadhad a median a median age age RESPIRATORY, RESPIRATORY, THORACIC, THORACIC, ANDAND MEDIASTINAL MEDIASTINAL DISORDERS DISORDERS In Patients In Patients Taking Taking Strong Strong CYP3A4 CYP3A4 Inducers Inducers : Avoid : Avoid the the chronic chronic use use of concomitant of concomitant of 55ofyears. 55 years. Adverse Adverse reactions reactions which which occurred occurred in ≥25% in ≥25% of COMETRIQ-treated of COMETRIQ-treated patients patients DYSPHONIA 20 20 0 0 9 9 0 0 strong strong CYP3A4 CYP3A4 inducers inducers (e.g.,(e.g., phenytoin, phenytoin, carbamazepine, carbamazepine, rifampin, rifampin, rifabutin, rifabutin, occurring occurring moremore frequently frequently in the in the COMETRIQ COMETRIQ armarm withwith a between-arm a between-arm difference difference of of DYSPHONIA rifapentine, rifapentine, phenobarbital) phenobarbital) if alternative if alternative therapy therapy is available. is available. Do not Do not ingest ingest foodsfoods ≥5%≥5% included, included, in order in order of decreasing of decreasing frequency: frequency: diarrhea, diarrhea, stomatitis, stomatitis, palmar-plantar palmar-plantar SKINSKIN ANDAND SUBCUTANEOUS SUBCUTANEOUS TISSUE TISSUE DISORDERS DISORDERS or nutritional or nutritional supplements supplements (e.g.,(e.g., St. John’s St. John’s WortWort [Hypericum [Hypericum perforatum perforatum ]) that ]) that are are erythrodysesthesia erythrodysesthesia syndrome syndrome (PPES), (PPES), decreased decreased weight, weight, decreased decreased appetite, appetite, nausea, nausea, 5 5 50 50 13 13 2 2 0 0 known known to induce to induce cytochrome cytochrome P450P450 activity. activity. For patients For patients whowho require require treatment treatment withwith a a fatigue, fatigue, oraloral pain,pain, hairhair colorcolor changes, changes, dysgeusia, dysgeusia, hypertension, hypertension, abdominal abdominal pain,pain, andand PPESPPES strong strong CYP3A4 CYP3A4 inducer, inducer, increase increase the daily the daily COMETRIQ COMETRIQ dosedose by 40bymg 40 (for mg (for example, example, fromfrom constipation. constipation. The The mostmost common common laboratory laboratory abnormalities abnormalities (>25%) (>25%) werewere increased increased HAIRHAIR COLOR COLOR CHANGES/ CHANGES/ 34 34 0 0 1 1 0 0 140 mg 140 mg to 180 to mg 180 mg dailydaily or from or from 100 100 mg mg to 140 to mg 140 mg daily) daily) as tolerated. as tolerated. Resume Resume the dose the dose AST,AST, increased increased ALT,ALT, lymphopenia, lymphopenia, increased increased alkaline alkaline phosphatase, phosphatase, hypocalcemia, hypocalcemia, DEPIGMENTATION, DEPIGMENTATION, GRAYING GRAYING thatthat waswas usedused priorprior to initiating to initiating the CYP3A4 the CYP3A4 inducer inducer 2 to 23 to days 3 days afterafter discontinuation discontinuation of of neutropenia, neutropenia,thrombocytopenia, thrombocytopenia,hypophosphatemia, hypophosphatemia,andandhyperbilirubinemia. hyperbilirubinemia. the the strong strong inducer. inducer. The The dailydaily dosedose of COMETRIQ of COMETRIQ should should not not exceed exceed 180 mg. 180 mg. RASH 19 19 1 1 10 10 0 0 Grade Grade 3-4 3-4 adverse adverse reactions reactions andand laboratory laboratory abnormalities abnormalities which which occurred occurred in ≥5% in ≥5% RASH of COMETRIQ-treated of COMETRIQ-treated patients patients occurring occurring moremore frequently frequently in the in the COMETRIQ COMETRIQ armarm withwith a a SKINSKIN 19 19 0 0 3 3 0 0 4. CONTRAINDICATIONS 4. CONTRAINDICATIONS between-arm between-arm difference difference of ≥2% of ≥2% included, included, in order in order of decreasing of decreasing frequency: frequency: diarrhea, diarrhea, DRYDRY None. None. PPES,PPES, lymphopenia, lymphopenia, hypocalcemia, hypocalcemia, fatigue, fatigue, hypertension, hypertension, asthenia, asthenia, increased increased ALT,ALT, ALOPECIA ALOPECIA 16 16 0 0 2 2 0 0 decreased decreased weight, weight, stomatitis, stomatitis, andand decreased decreased appetite appetite (see(see TableTable 1, Table 1, Table 2). Fatal 2). Fatal 5. WARNINGS 5. WARNINGS ANDAND PRECAUTIONS PRECAUTIONS ERYTHEMA ERYTHEMA 11 11 1 1 2 2 0 0 adverse adverse reactions reactions occurred occurred in 6% in 6% of patients of patients receiving receiving COMETRIQ COMETRIQ and and resulted resulted from from 5.1 5.1 Perforations Perforations andand Fistulas: Fistulas: Gastrointestinal Gastrointestinal (GI) (GI) perforations perforations andand fistulas fistulas hemorrhage, pneumonia, pneumonia, septicemia, septicemia, fistulas, fistulas, cardiac cardiac arrest, arrest, respiratory respiratory failure, failure, HYPERKERATOSIS HYPERKERATOSIS 7 7 0 0 0 0 0 0 werewerereported reportedin in3% 3%andand1% 1%of ofCOMETRIQ-treated COMETRIQ-treatedpatients, patients,respectively. respectively. hemorrhage, unspecified unspecified death. death. FatalFatal adverse adverse reactions reactions occurred occurred in 5% in of 5%patients of patients receiving receiving All All werewere serious serious andand oneone GI fistula GI fistula waswas fatalfatal (<1%). (<1%). Non-GI Non-GI fistulas fistulas including including andand VASCULAR DISORDERS DISORDERS placebo andand resulted resulted fromfrom septicemia, septicemia, pneumonia, pneumonia, andand general general deterioration. deterioration. The The VASCULAR tracheal/esophageal tracheal/esophagealwerewerereported reportedin in4% 4%of ofCOMETRIQ-treated COMETRIQ-treatedpatients. patients. placebo waswas reduced reduced in 79% in 79% of patients of patients receiving receiving COMETRIQ COMETRIQ compared compared to 9% to of 9%patients of patients HYPERTENSION HYPERTENSION 33 33 8 8 4 4 0 0 TwoTwo (1%)(1%) of these of these werewere fatal.fatal. Monitor Monitor patients patients for symptoms for symptoms of perforations of perforations andand dosedose receiving receiving placebo. placebo. The The median median number number of dosing of dosing delays delays was was one one in patients in patients receiving receiving fistulas. fistulas. Discontinue Discontinue COMETRIQ COMETRIQ in patients in patients whowho experience experience a perforation a perforation or aorfistula. a fistula. HYPOTENSION 7 7 1 1 0 0 0 0 COMETRIQ COMETRIQ compared compared to none to none in patients in patients receiving receiving placebo. placebo. Adverse Adverse reactions reactions led led to to HYPOTENSION 5.2 Hemorrhage: 5.2 Hemorrhage: Serious Serious andand sometimes sometimes fatalfatal hemorrhage hemorrhage occurred occurred withwith COMETRIQ. COMETRIQ. studystudy treatment treatment discontinuation discontinuation in 16% in 16% of patients of patients receiving receiving COMETRIQ COMETRIQ andand in 8% in of 8% of 1 1 National National Cancer Cancer Institute Institute Common Common Terminology Terminology Criteria Criteria for Adverse for Adverse Events Events Version Version 3.0. 3.0. The The incidence incidence of Grade of Grade ≥3 ≥3 hemorrhagic hemorrhagic events events waswas higher higher in COMETRIQ-treated in COMETRIQ-treated patients patients receiving receiving placebo. placebo. The The mostmost frequent frequent adverse adverse reactions reactions leading leading to permanent to permanent 2 2 Includes the the following following terms: terms: stomatitis, stomatitis, aphthous aphthous stomatitis, stomatitis, mouth mouth ulceration, ulceration, patients patients compared compared withwith placebo placebo (3%(3% vs. 1%). vs. 1%). Do not Do not administer administer COMETRIQ COMETRIQ to patients to patients discontinuation discontinuation in patients in patients treated treated withwith COMETRIQ COMETRIQ were:were: hypocalcemia, hypocalcemia, increased increased lipase, lipase, Includes mucosal inflammation. inflammation. withwith a recent a recent history history of hemorrhage of hemorrhage or hemoptysis. or hemoptysis. PPES,PPES, diarrhea, diarrhea, fatigue, fatigue, hypertension, hypertension, nausea, nausea, pancreatitis, pancreatitis, tracheal tracheal fistula fistula formation, formation, 3mucosal 3 Includes the the following following terms: terms: oraloral pain,pain, oropharyngeal oropharyngeal pain,pain, glossitis, glossitis, burning burning mouth mouth vomiting. vomiting. Increased Increased levels levels of thyroid of thyroid stimulating stimulating hormone hormone (TSH)(TSH) werewere observed observed in in Includes 5.3 5.3 Thrombotic Thrombotic Events: Events: COMETRIQ COMETRIQ treatment treatment results results in an in an increased increased incidence incidence andand syndrome, syndrome, glossodynia. glossodynia. of patients of patients receiving receiving COMETRIQ COMETRIQ afterafter the the firstfirst dosedose compared compared to 19% to 19% of of 4 4 of of thrombotic thrombotic events events (venous (venous thromboembolism: thromboembolism: 6% 6% vs. vs. 3% 3% andand arterial arterial 57%57% Includes the the following following terms: terms: abdominal abdominal pain,pain, abdominal abdominal painpain lower, lower, abdominal abdominal patients receiving receiving placebo placebo (regardless (regardless of baseline of baseline value). value). Ninety-two Ninety-two percent percent Includes thromboembolism: thromboembolism: 2% 2% vs. vs. 0% 0% in COMETRIQ-treated in COMETRIQ-treated andand placebo-treated placebo-treated patients, patients, patients upper, upper, abdominal abdominal rigidity, rigidity, abdominal abdominal tenderness, tenderness, esophageal esophageal pain.pain. (92%) of patients of patients on on the the COMETRIQ COMETRIQ armarm hadhad a prior a prior thyroidectomy, thyroidectomy, andand 89%89% 5pain5pain respectively). respectively). Discontinue Discontinue COMETRIQ COMETRIQ in patients in patients whowho develop develop an acute an acute myocardial myocardial (92%) Palmar-plantar Palmar-plantar erythrodysesthesia erythrodysesthesia syndrome. syndrome. taking taking thyroid thyroid hormone hormone replacement replacement priorprior to the to the firstfirst dose.dose. infarction infarction or any or any otherother clinically clinically significant significant arterial arterial thromboembolic thromboembolic complication. complication. werewere

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Ongoing Molecular Research in the Science of Oncology

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MTH1 Inhibition Blocks Sanitation of Deoxyribonucleotide Triphosphate Pool and Causes Cancer Cell Death CD CD

Dysfunctional redox regulation in cancer results in production of reactive oxygen species, damaging DNA and free deoxyribonucleotide triphosphates (dNTPs). The MTH1 protein, which is nonessential in normal cells, sanitizes oxidized dNTP pools, preventing incorporation of damaged bases during DNA replication in cancer cells. As reported in Nature, Gad and colleagues found that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, which would result in DNA damage and cell death. First-in-class nudix hydrolase family small-molecule inhibitors (TH287 and TH588) were shown to potently and selectively engage and inhibit the MTH1 protein in vitro, with protein co-crystal structures showing that the agents bind in the active site of MTH1. The inhibitors caused incorporation of oxidized dNTPs in cancer cells, resulting in DNA damage, cytotoxicity, and antitumor response in patient-derived mouse xenografts. The investigators concluded, “This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.” Gad H, et al: Nature 508:215-221, 2014.

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Malignant: Malignant: Diastolic Diastolic 0 0 0 0 ≥120≥120 mmHg mmHg 1 1 JointJoint National National Committee Committee on Prevention, on Prevention, Detection, Detection, Evaluation, Evaluation, andand Treatment Treatment of High of High Blood Blood Pressure, Pressure, JAMAJAMA 2003:289:2560. 2003:289:2560. Criteria Criteria applied applied werewere modified, modified, as as multiple multiple readings readings werewere not not available available per per timepoint, timepoint, andand therefore therefore not not averaged. averaged. 2 2 Subjects Subjects classified classified by highest by highest category category based based on allonrecorded all recorded blood blood pressure pressure readings readings beginning beginning afterafter the the firstfirst dosedose through through 30 days 30 days afterafter last last dose.dose. 3 3 Subjects Subjects withwith at least at least twotwo blood blood pressure pressure measurements measurements afterafter the the firstfirst dose.dose.

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of therapy. of therapy. Infertility Infertility : There : There are no aredata no data on the on the effect effect of COMETRIQ of COMETRIQ on human on human fertility. fertility. Cabozantinib Cabozantinib impaired impaired malemale andand female female fertility fertility in animal in animal studies. studies. 8.6 8.6 Hepatic Hepatic Impairment: Impairment: Cabozantinib Cabozantinib pharmacokinetics pharmacokinetics has has not not beenbeen studied studied in patients in patients withwith hepatic hepatic impairment. impairment. ThereThere are are limited limited datadata in patients in patients withwith liverliver impairment impairment (serum (serum bilirubin bilirubin greater greater thanthan 1.5 times 1.5 times the the upper upper limitlimit of normal). of normal). COMETRIQ COMETRIQ is not is not recommended recommended for use for use in patients in patients withwith moderate moderate or severe or severe hepatic hepatic impairment, impairment, as safety as safety andand efficacy efficacy havehave not not beenbeen established. established. 8.7 8.7 Renal Renal Impairment: Impairment: No dose No dose adjustment adjustment is recommended is recommended for patients for patients withwith mildmild or moderate or moderate renalrenal impairment. impairment. ThereThere is noisexperience no experience withwith COMETRIQ COMETRIQ in patients in patients withwith severe severe renalrenal impairment. impairment. 7. DRUG INTERACTIONS 7. DRUG INTERACTIONS OneOne casecase of overdosage of overdosage waswas reported reported in a inpatient a patient whowho inadvertently inadvertently 10. OVERDOSAGE 10. OVERDOSAGE Effect of CYP3A4 Inhibitors: Administration a strong CYP3A4 inhibitor, tooktook 7.1 7.1 Effect of CYP3A4 Inhibitors: Administration of aof strong CYP3A4 inhibitor, twicetwice the the intended intended dosedose (200(200 mg mg daily) daily) for nine for nine days.days. The The patient patient suffered suffered ketoconazole for days) 27 days) to healthy subjects increased single-dose Grade ketoconazole (400(400 mg mg dailydaily for 27 to healthy subjects increased single-dose Grade 3 memory 3 memory impairment, impairment, Grade Grade 3 mental 3 mental status status changes, changes, Grade Grade 3 cognitive 3 cognitive by)38%. by 38%. Avoid Avoid taking taking a strong a strong CYP3A4 CYP3A4 inhibitor inhibitor disturbance, plasma cabozantinib exposure plasma cabozantinib exposure (AUC(AUC 0-inf) 0-inf disturbance, Grade Grade 2 weight 2 weight loss,loss, andand Grade Grade 1 increase 1 increase in BUN. in BUN. The The extent extent of recovery of recovery (e.g.,(e.g., ketoconazole, ketoconazole, itraconazole, itraconazole, clarithromycin, clarithromycin, atazanavir, atazanavir, indinavir, indinavir, nefazodone, nefazodone, waswas not not documented. documented. nelfinavir, nelfinavir, ritonavir, ritonavir, saquinavir, saquinavir, telithromycin, telithromycin, voriconazole) voriconazole) when when taking taking COMETRIQ. COMETRIQ. 17. PATIENT 17. PATIENT COUNSELING COUNSELING INFORMATION INFORMATION 7.2 Effect 7.2 Effect of CYP3A4 of CYP3A4 Inducers: Inducers: Administration Administration of aofstrong a strong CYP3A4 CYP3A4 inducer, inducer, rifampin rifampin FDA-approved FDA-approved patient patient labeling labeling (Patient (Patient Information Information andand Instructions Instructions for Use). for Use). (600(600 mg mg dailydaily for for 31 days) 31 days) to healthy to healthy subjects subjects decreased decreased single-dose single-dose plasma plasma See See by) 77%. by 77%. Avoid Avoid chronic chronic coadministration coadministration of strong of strong Inform cabozantinib cabozantinib exposure exposure (AUC(AUC Inform patients patients of the of the following: following: 0-inf) 0-inf CYP3A4 CYP3A4 inducers inducers (e.g.,(e.g., dexamethasone, dexamethasone, phenytoin, phenytoin, carbamazepine, carbamazepine, rifampin, rifampin, • COMETRIQ oftenoften causes causes diarrhea diarrhea which which maymay be severe be severe in some in some cases. cases. Inform Inform patients patients • COMETRIQ rifabutine, rifabutine, rifapentine, rifapentine, phenobarbital, phenobarbital, St. John’s St. John’s Wort) Wort) withwith COMETRIQ. COMETRIQ. of the of the needneed to contact to contact theirtheir healthcare healthcare provider provider if severe if severe diarrhea diarrhea occurs occurs during during treatment treatment withwith COMETRIQ. COMETRIQ. 8. USE 8. USE IN SPECIFIC IN SPECIFIC POPULATIONS POPULATIONS • COMETRIQ • COMETRIQ oftenoften causes causes palmar-plantar palmar-plantar erythrodysesthesia erythrodysesthesia syndrome. syndrome. Advise Advise 8.1 Pregnancy: 8.1 Pregnancy: Pregnancy Pregnancy Category Category D. D. patients to contact to contact theirtheir healthcare healthcare provider provider for progressive for progressive or intolerable or intolerable rash.rash. RiskRisk Summary Summary : Based : Based on on its its mechanism mechanism of of action, action, COMETRIQ COMETRIQ can can cause cause patients • COMETRIQ • COMETRIQ often often causes causes sores sores in the in the mouth, mouth, oral oral pain, pain, changes changes in taste, in taste, nausea nausea fetalfetalharmharmwhen whenadministered administeredto toa pregnant a pregnantwoman. woman.Cabozantinib Cabozantinibwaswas or vomiting. Advise Advise patients patients to contact to contact theirtheir healthcare healthcare provider provider if any if any of these of these embryolethal embryolethal in rats in rats at at exposures exposures below below the the recommended recommended human human dose,dose, or vomiting. symptoms are severe are severe or prevent or prevent patients patients fromfrom eating eating andand drinking. drinking. withwith increased increased incidences incidences of skeletal of skeletal variations variations in rats in rats andand visceral visceral variations variations symptoms • COMETRIQ oftenoften causes causes weight weight lossloss which which maymay be significant be significant in some in some cases. cases. Advise Advise andand malformations malformations in rabbits. in rabbits. If this If this drugdrug is used is used during during pregnancy pregnancy or iforthe if the • COMETRIQ patients to report to report significant significant weight weight loss.loss. patient patient becomes becomes pregnant pregnant whilewhile taking taking this this drug,drug, the the patient patient should should be apprised be apprised patients of the of the potential potential hazard hazard to the to the fetus. fetus. Animal Animal Data Data : In : an In embryo-fetal an embryo-fetal development development • To • contact To contact their their healthcare healthcare provider provider before before any any planned planned surgeries, surgeries, including including Nearly Nearly all COMETRIQ-treated all COMETRIQ-treated patients patients (96%(96% vs. 84% vs. 84% placebo) placebo) experienced experienced elevated elevated in which in which pregnant pregnant rats rats werewere administered administered dailydaily doses doses of cabozantinib of cabozantinib during during dental dental procedures. procedures. blood blood pressure pressure andand therethere waswas a doubling a doubling in the in the incidence incidence of overt of overt hypertension hypertension in in studystudy organogenesis, increased increased lossloss of pregnancy of pregnancy compared compared to controls to controls waswas observed observed • COMETRIQ COMETRIQ-treated COMETRIQ-treated patients patients overover placebo-treated placebo-treated patients patients (61%(61% vs. 30%) vs. 30%) according according organogenesis, maymay interact interact withwith otherother drugs; drugs; advise advise patients patients to inform to inform theirtheir healthcare healthcare • COMETRIQ at doses as low as low as 0.03 as 0.03 mg/kg mg/kg (less(less thanthan 1% of 1% the of the human human exposure exposure by AUC by AUC at at provider to modified to modified JointJoint National National Committee Committee on Prevention, on Prevention, Detection, Detection, Evaluation, Evaluation, andand at doses provider of allof prescription all prescription or nonprescription or nonprescription medication medication or herbal or herbal products products thatthat recommended recommended dose). dose). Findings Findings included included delayed delayed ossifications ossifications andand skeletal skeletal theythey Treatment Treatment of High of High Blood Blood Pressure Pressure (JNC)(JNC) staging staging criteria. criteria. No No patients patients developed developed the the are taking. are taking. variations variations at doses at doses equal equal to or to greater or greater than than 0.01 0.01 mg/kg/day mg/kg/day (approximately (approximately 0.03% 0.03% malignant malignant hypertension. hypertension. • Patients of childbearing of childbearing potential potential mustmust use use effective effective contraception contraception during during therapy therapy of the of the human human exposure exposure by AUC by AUC at the at the recommended recommended dose). dose). In pregnant In pregnant rabbits rabbits • Patients for atforleast at least fourfour months months following following theirtheir last last dosedose of COMETRIQ. of COMETRIQ. administered administered cabozantinib cabozantinib dailydaily during during organogenesis, organogenesis, therethere werewere findings findings of visceral of visceral andand TableTable 3. 3. • Breast-feeding mothers mothers mustmust discontinue discontinue nursing nursing whilewhile receiving receiving COMETRIQ COMETRIQ therapy. therapy. malformations malformations andand variations variations including including reduced reduced splenic splenic size size andand missing missing lunglung lobelobe at at • Breast-feeding Per-Patient Per-Patient Incidence Incidence of Hypertension of Hypertension in Protocol in Protocol XL184-301 XL184-301 3 mg/kg 3 mg/kg (approximately (approximately 11% of 11%the of human the human exposure exposure by AUC by AUC at the at recommended the recommended dose). dose). • COMETRIQ • COMETRIQ should should not not be taken be taken withwith food.food. Instruct Instruct patients patients not not to eat to eat for at forleast at least Placebo Placebo COMETRIQ COMETRIQ 1 1 2 hours 2 hours before before and and at least at least 1 hour 1 hour after after taking taking COMETRIQ. COMETRIQ. COMETRIQ COMETRIQ capsules capsules should should 8.2 8.2 Nursing Nursing Mothers: Mothers: It isItunknown is unknown whether whether cabozantinib cabozantinib or itsor metabolites its metabolites are are HYPERTENSION, HYPERTENSION, JNC JNC STAGE STAGE 3 3 (%)3 (%) N=107 N=107 (%)3 (%) N=211N=211 be opened be opened or crushed or crushed but but should should be taken be taken withwith a fulla full glassglass (at least (at least 8 ounces) 8 ounces) excreted excreted in human in human milk.milk. Because Because many many drugs drugs are excreted are excreted in human in human milkmilk andand because because not not of water. of water. of the of the potential potential for serious for serious adverse adverse reactions reactions in nursing in nursing infants infants fromfrom COMETRIQ, COMETRIQ, a a Normal: Normal: Grade Grade 0: Systolic 0: Systolic 4 4 15 15 decision decision should should be made be made whether whether to discontinue to discontinue nursing nursing or toordiscontinue to discontinue the the drug,drug, • Patients • Patients should should not not consume consume grapefruits grapefruits or or grapefruit grapefruit juicejuice whilewhile taking taking <120<120 mmHg mmHg andand Diastolic Diastolic taking taking intointo account account the the importance importance of the of the drugdrug to the to the mother. mother. COMETRIQ COMETRIQ treatment. treatment. <80 <80 mmHg mmHg 8.3 Pediatric 8.3 Pediatric Use:Use: The The safety safety andand effectiveness effectiveness of COMETRIQ of COMETRIQ in pediatric in pediatric patients patients havehave Reference Pre-hypertension: Pre-hypertension: Systolic Systolic 34 34 54 54 Reference ID: 3223542 ID: 3223542 not not beenbeen studied. studied. ≥120≥120 mmHg mmHg or Diastolic or Diastolic ≥80≥80 mmHg mmHg Distributed Distributed by Exelixis, by Exelixis, Inc. Inc. 8.4 8.4 Geriatric Geriatric Use:Use: Clinical Clinical studies studies of COMETRIQ of COMETRIQ did did not not include include sufficient sufficient numbers numbers of of 11/2012 Stage Stage 1: Systolic 1: Systolic ≥140≥140 mmHg mmHg or or 46 46 25 25 11/2012 patients patients agedaged 65 years 65 years andand overover to determine to determine whether whether theythey respond respond differently differently fromfrom Diastolic Diastolic ≥90≥90 mmHg mmHg younger younger patients. patients. 15 15 5 5 Stage Stage 2: Systolic 2: Systolic ≥160≥160 mmHg mmHg or or Contraception Contraception : Use: Use effective effective © 2012 8.5 8.5 Females Females andand Males Males of Reproductive of Reproductive Potential: Potential: © 2012 Exelixis, Exelixis, Inc. Inc. 210 East 210 East Grand Grand Avenue, Avenue, So. San So. San Francisco, Francisco, CA 94080 CA 94080 ≥100≥100 mmHg mmHg Diastolic Diastolic contraception contraception during during treatment treatment withwith COMETRIQ COMETRIQ andand up toup4tomonths 4 months afterafter completion completion Printed Printed in USA in USA 11/1211/12 [24523] [24523] 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring TableTable 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at aat a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [BetweenDifference of ≥5% Grades) or ≥2% (Grades 3-4)] [BetweenArmArm Difference of ≥5% (All (All Grades) or ≥2% (Grades 3-4)] COMETRIQ (n=214) Placebo Placebo (n=109) COMETRIQ (n=214) (n=109) ADVERSE EVENT ADVERSE EVENT Grade All GradesGrade Grade All All Grade 3-4 3-4All Grades 3-4 3-4 Grades Grades CHEMISTRIES CHEMISTRIES INCREASED INCREASED AST AST 86 86 3 3 35 35 2 2 INCREASED INCREASED ALT ALT 86 86 6 6 41 41 2 2 INCREASED INCREASED ALP ALP 52 52 3 3 35 35 3 3 HYPOCALCEMIA HYPOCALCEMIA 52 52 12 12 27 27 3 3 HYPOPHOSPHATEMIA HYPOPHOSPHATEMIA 28 28 3 3 10 10 1 1 HYPERBILIRUBINEMIA HYPERBILIRUBINEMIA 25 25 2 2 14 14 5 5 HYPOMAGNESEMIA HYPOMAGNESEMIA 19 19 1 1 4 4 0 0 HYPOKALEMIA HYPOKALEMIA 18 18 4 4 9 9 3 3 HYPONATREMIA HYPONATREMIA 10 10 2 2 5 5 0 0 HEMATOLOGIC HEMATOLOGIC LYMPHOPENIA LYMPHOPENIA 53 53 16 16 51 51 11 11 NEUTROPENIA NEUTROPENIA 35 35 3 3 15 15 2 2 THROMBOCYTOPENIA THROMBOCYTOPENIA 35 35 0 0 4 4 3 3 alanine aminotransferase; alkaline phosphatase; ALT,ALT, alanine aminotransferase; ALP,ALP, alkaline phosphatase; aspartate aminotransferase AST,AST, aspartate aminotransferase

reported in Nature that both reduction of levels of copper transporter 1 (CTR1) and presence of MEK1 mutations that disrupt copper binding result in inhibition of BRAF V600E–driven signaling and tumorigenesis in mice and in human cells. Further, a MEK1-MEK5 chimera that phosphorylates ERK1/2 independently of copper and an active ERK2 both restored tumor growth of Ctr1-negative mouse cells. Treatment with copper chelators resulted in reduced tumor growth of human and mouse cells transformed by BRAF V600E or engineered to be resistant to BRAF inhibition. The investigators concluded, “[T]hese results suggest that [copper]-chelation therapy could be repurposed to treat cancers containing the BRAF V600E mutation.” Brady DC, et al: Nature. April 9, 2014 (early release online).

TC TC

The V600E mutation in BRAF kinase is associated with oncogenesis in melanoma

to a MEK1/2 inhibitor increases survival benefit in metastatic melanoma. After previously finding that copper influx enhances MEK1 phosphorylation of ERK1/2 through a copper-MEK1 interaction, Brady and colleagues recently

QC QC

Copper Chelation for BRAF-Mutated Disease?

and other cancers. BRAF V600E phosphorylates and activates MEK1 and MEK2 kinases, which phosphorylate and activate ERK1S:6.75” and S:6.75”ERK2 kinases, resulting in activation of the MAPK pathway. The addition of a BRAF V600E inhibitor

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Lab Notes Ongoing Molecular Research continued from page 109

TARGETED THERAPY Druggable Oncogene Fusions Found in KRAS Wild-Type Lung Invasive Mucinous Adenocarcinoma

As reported in Clinical Cancer Research, Nakaoku and colleagues identified oncogene fusions that function as driver mutations in KRAS wild-type invasive mucinous adenocarcinoma of the lung. Whole-transcriptome sequencing of 32 invasive mucinous adenocarcinomas, including 27 without KRAS mutations, identified several oncogenic fusions that

Now available at

occurred only in the absence of KRAS mutations, including CD74-NRG1, EZR-ERBB4, and TRIM24-BRAF fusions. NRG1 fusions were present in 18% of KRAS-negative adenocarcinomas. Functional analyses of the fusion gene products showed that the CD74-NRG1 fusion activated HER2:HER3 signaling and that EZR-ERBB4 and TRIM24-BRAF fu-

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Breast Cancer · Treatment of Metastatic Breast Cancer Supported by educational grants from AstraZeneca, Eisai Inc., Genentech, and Novartis Oncology.

Skin Malignancies · Melanoma Guideline Update: New Agents and Opportunities for Treatment · Optimal Treatment of Unresectable Non-Melanoma Skin Cancers · Targeted Agents: Management of Dermatologic Toxicities Supported by educational grants from Genentech and Prometheus Laboratories Inc.

sions constitutively activated the ERBB4 and BRAF kinases, respectively. Signaling pathway activation and fusion-induced anchorage-independent growth and tumorigenicity of NIH3T3 cells expressing these fusions were reduced by treatment with tyrosine kinase inhibitors. The investigators concluded, “Oncogenic fusions act as driver mutations in [invasive mucinous adenocarcinomas] without KRAS mutations, and thus represent promising therapeutic targets for the treatment of such [disease].” Nakaoku T, et al: Clin Cancer Res. April 11, 2014 (early release online).

High Macrophage Inhibitory Cytokine-1 Levels and Colorectal Cancer Risk

Hematologic Malignancies · Developments in the Treatment of Multiple Myeloma · Guidelines for NHL: Updates to the Management of DLBCL and New Guidelines for T-Cell Lymphoproliferative Disorders · Monitoring Molecular Response to TKI Therapy in Chronic Myelogenous Leukemia · Therapeutic Advances in the Treatment of CLL: Focus on Inhibitors of the BCR Signaling Pathways Supported by educational grants from Bristol-Myers Squibb; Millennium: The Takeda Oncology Company; Novartis Oncology; Onyx Pharmaceuticals; and Spectrum Pharmaceuticals, Inc.

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Chronic inflammation is implicated in the development of colorectal cancer, and the plasma inflammatory biomarker macrophage inhibitory cytokine-1 (MIC-1, GDF15) may have a direct role in tumorigenesis. As reported in Journal of the National Cancer Institute, Mehta and colleagues found that subjects in the highest (5th) quintile of plasma MIC-1 as measured by enzyme-linked immunosorbent assay had significantly increased risk of colorectal cancer (relative risk [RR] = 1.93, P = .004 for trend) compared with the lowest quintile on multivariate analysis in a nested case-control study. Further, for patients in the four highest MIC-1 quintiles, regular use vs nonuse of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with significantly reduced risk of prostaglandinendoperoxide synthase 2 (PTGS2)/ cyclooxygenase-2 (COX-2)–positive colorectal cancer (RR = 0.60, 95% confidence interval [CI] = 0.41– 0.88) but not PTGS2-negative colorectal cancer (RR = 1.21, 95% CI = 0.71–2.07). Aspirin and NSAID use was not associated with a significantly altered risk of PTGS2-positive colorectal cancer (RR = 0.57, 95% CI = 0.21–1.54) or PTGS2negative colorectal cancer (RR = 1.41, 95% CI = 0.47–4.23) in patients in the lowest MIC-1 quintile. The investigators concluded, “Our results support an association between higher levels of circulating MIC-1 (GDF15) and [colorectal cancer]. Aspirin/NSAID use appeared to lower risk of PTGS2-positive cancers, particularly among individuals with high levels of circulating MIC-1.” n

Mehta RS, et al: J Natl Cancer Inst 106(4):dju016, 2014.

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In the News Cost of Care

Speaking Up Against High Cancer Drug Prices By Charlotte Bath In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

ate the value in oncology regimens.4,5 A follow-up article in Bloomberg News quoted ASCO Immediate Past President Clifford A. Hudis, MD, FACP, as calling the need to address the rising cost of cancer care as “a moral imperative.”6 “When we wrote the Blood article, there was not much information on how many patients do not take treatment

“P

hysicians have a duty to speak up against high cancer drug prices,” Hagop M. Kantarjian, MD, resolutely stated in an interview with The ASCO Post. “We should speak up because high drug prices are harming patients.” A leader in the effort to drive down the cost of drugs needed to treat patients with cancer, Dr. Kantarjian is Chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. Last year, Dr. Kantarjian led a group of more than 100 chronic myeloid leukemia (CML) experts in writing a well-documented opinion article for Blood to call attention to the high prices of cancer drugs—in particular, tyrosine kinase inhibitors for the treatment of CML—and the need to lower prices of cancer drugs so more patients could afford these drugs.1 More recently, Dr. Kantarjian

Currently there is zero correlation between the efficacy of the drug in terms of survival prolongation and the price of a drug. —Hagop M. Kantarjian, MD

and how many modify the treatment due to high costs,” Dr. Kantarjian said. “Drug companies were saying, ‘We have the free drug program, so no patients should go without the treatment.’ And then there were at least two articles that showed that patients were in fact forgoing treatment or skipping medications.” One of those articles, published earlier this year in the Journal of Clinical Oncology,7 was cited by Dr. Kantarjian and his JOP coauthors in stating that an estimated 10% to 20% of patients may decide not to take treatment or to compromise significantly on the treatment plan because of high drug costs.

Assigning Value

Clifford A. Hudis, MD, FACP

was lead author of an article published by the Journal of Oncology Practice (JOP) online, which proposed solutions to problems related to the high cost of cancer drugs.2

Patients Forgoing Treatment Efforts by other physicians, insurers, and elected officials to raise attention to the escalating cost of cancer treatment have been in the news recently. A Washington Post blog reported that over the past decade, “the average cost of a brandname cancer drug jumped from about $5,000 per month to $10,000 per month in 2013.”3 Articles in The New York Times and Bloomberg have focused on the ASCO Value in Cancer Care Task Force and its initiative to develop a framework to evalu-

on a drug,” Dr. Kantarjian said. “If a drug does not prolong life, why are we paying $100,000 for it?” In other countries, such as New Zealand, Australia, European nations, and Canada, Dr. Kantarjian noted, after a drug is approved, the government, which in many cases is paying for patients to get certain drugs, assigns value to drugs. “Let the drug value reflect its efficacy.

Dr. Kantarjian and others have proposed basing drug prices on how much they help patients. For example, a cancer drug that improves life expectancy for more than 1 year might be priced at $40,000 to $50,000 vs $20,000 to $30,000 for a drug that lengthened survival by 3 to 5 months. “At some point, you have to put a value

Currently there is zero correlation between the efficacy of the drug in terms of survival prolongation and the price of a drug. Some drugs prolong life by years and others prolong life by days, yet both are priced the same per year,” Dr. Kantarjian said. “We have to assign some value to the drug, and this is where the societies like the American Society of Clinical Oncology, the American Society of Hematology, and others could develop pathways that include what would be referred to as treatment value or drug value,” Dr. Kantarjian said. Among factors that would be considered in determining the value of a given regimen would be its objective efficacy, side effects, and cost, Dr. Kantarjian noted.

Reducing the Hype “Professional societies representing cancer specialists and advocating for cancer patients should be involved in reducing the hype around new cancer drugs that do not have a major impact on patient outcomes,” Dr. Kantarjian and coauthors advised in the JOP article. “Right

now, the doctors say, ‘I am going to give the best treatment to my patients, regardless of the price.’ And I agree with that position,” Dr. Kantarjian said. “But the reality is that oncologists are influenced by advertisements and by societies promoting minor improvements as major breakthroughs. This pushes oncologists into a corner, and patients come to their office saying, ‘I want this drug. How can you say it is not a good drug if it was highlighted at ASCO as a breakthrough?’” What is needed, according to Dr. Kantarjian, is for professional societies “to highlight new discoveries for what they truly are, rather than how pharmaceutical companies want them highlighted. And professional societies have to develop pathways that incorporate drug value,” he added. “Once we have this, a practicing oncologist could say to patients, ‘This is what the American Society of Clinical Oncology says.’ Oncologists would not be under pressure to prescribe the most expensive drug because it was advertised at a national meeting and by drug companies as being the best.”

Importation of Foreign Drugs Proposals to allow importation of drugs from foreign countries have met “strong pushback from the pharmaceutical companies, stating that allowing the importation is dangerous because it could put the lives of American citizens at risk,” Dr. Kantarjian said. But those “scare tactics” are preventing U.S. patients from getting safe medication at lower prices. He cited a New York Times op-ed piece contending that drugs currently considered by the U.S. Food and Drug Administration to be “foreign unapproved drugs” do not pose the same risk as counterfeit drugs sold online.8 Those foreign unapproved drugs “are often the exact same ones sold here. Or they’re different brands, or generic versions continued on page 114

Encourage Questions and Actions About the High Cost of Cancer Drugs

hysicians are now more likely to discuss cancer drug prices, “which was a rarity in the past,” Hagop M. Kantarjian, MD, told The ASCO Post. “Oncologists are starting to incorporate the price as a side effect, because if the price is too high, that is a financial side effect to patients, who can go bankrupt, or their families can go bankrupt, if they cannot

afford the drug. Physicians are negotiating or discussing with their patients different treatment options and how much these options might cost patients out of pocket.” A leader in the effort to drive down the cost of drugs needed to treat patients with cancer, Dr. Kantarjian is Chair of the Department of Leukemia at The University of Texas MD Anderson Can-

cer Center in Houston. If patients don’t ask about costs, should physicians bring it up? “I think they should,” Dr. Kantarjian said, “because part of our oath as physicians is to protect patients from harm and injustice. If the drug price will harm patients because it is too high and does not have added benefits, then it our duty to discuss it.” n

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

Jakafi®

JAK1

JAK2

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

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary

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

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

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

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

Patients (%)

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

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

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

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

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

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

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

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

The ASCO Post | JUNE 10, 2014

PAGE 114

In the News Hagop M. Kantarjian, MD continued from page 111

of domestically sold drugs. Thus, many foreign unapproved drugs—specifically those ordered from licensed pharmacies—are almost always going to be safe and effective, like their United States counterparts, whereas a counterfeit drug will almost always be dangerous,” wrote Gabriel Levitt,

Vice President of PharmacyChecker.com. The company “helps Americans find information on obtaining lower-cost medications from Canada and other countries, so I have a financial stake in making sure the public is informed,” he noted. “Brand-name drugs that are still on patent in the U.S. are often 80% less expensive at reputable international online pharma-

cies,” he added. “Without online access, more Americans will go without prescribed medicines.”

Other Potential Solutions Other potential solutions proposed to bring about more reasonable drug prices are allowing Medicare to negotiate drug prices and eliminating pay-for-delay strate-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transAdministration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pre- with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. Active serious infections should have resolved before starting therapy with Jakafi. Tuberculosis has been reported in patients receiving Jakafi for myelofibrosis. Attention should be given to the possibility of latent or DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib active tuberculosis. Observe patients receiving Jakafi for signs and symptoms of infection and initiate increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminif suspected [see Adverse Reactions]. istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under There was an 8% and 27% increase in the C and AUC of ruxolitinib, respectively, with Jakafi administration max widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacomost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses however, it has not been established whether discontinuation of therapy contributed to the clinical course in of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratothese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanStudy During Randomized Treatment tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for Jakafi Placebo fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest (N=155) (N=151) dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of d myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differUrinary Tract Infections 9.0 0 0 5.3 0.7 0.7 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Weight Gaine 7.1 0.6 0 1.3 0.7 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2013 Incyte Corporation. All rights reserved. Issued: November 2013 RUX-1326 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

gies. As noted in the Blood article, “Arrangements by pharmaceutical companies that pay generic companies to delay entering the market with a generic version profit both companies, but financially hurt the national healthcare system and patients.”1 “Drug companies should not be allowed to use pay-for-delay strategies in order to delay availability of generics,” Dr. Kantarjian told The ASCO Post. “When President Obama was negotiating the Affordable Care Act, the plan was to allow Medicare to negotiate drug prices, but because he needed the drug companies to be on board and support the Affordable Care Act, he had to forgo this,” Dr. Kantarjian remarked. But now, he added, “we should encourage legislation to allow Medicare to negotiate drug prices.”

Risks and Responsibilities “We should encourage lobbying and legislation to allow Medicare to negotiate drug prices. We should allow importation of drugs. We should forbid drug companies from implementing pay-for-delay strategies and delaying generics. All these are important additive solutions that will weaken the oligopoly of cancer drug pricing that exists today,” Dr. Kantarjian said. “It would be nice to quote George Merck,” he suggested. The quote from the late George Merck, who took over the family pharmaceutical business from his father in 1929, comes from a 1952 Time magazine cover story: “Medicine is for the people. It is not for the profits.” n

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

References 1. Abboud C, Berman E, Cohen A, et al: The price of drugs for chronic myeloid leukemia is a reflection of the unsustainable prices of cancer drugs. Blood 121:4439-4442, 2013. 2. Kantarjian H, Steensma D, Sanjuan JR, et al: High cancer prices in the United States: Reasons and proposed solutions. J Oncol Pract. May 6, 2014 (early release online). 3. Millman J: Expensive cancer drugs are all the rage in pharma these days. Washington Post Wonkblog, May 6, 2014. 4. Pollack A: Cost of treatment may influence doctors. New York Times, April 17, 2014. 5. Damouni S, Langreth R: Cancer doctors plan to compare value of expensive drugs. Bloomberg. April 17, 2014. 6. Langreth R: Cancer doctors join insurers in U.S. drug-cost revolt. Bloomberg. May 7, 2014. 7. Dusetzina SB, Winn AN, Abel GA, et al: Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 32:304-311, 2014. 8. Levitt G: Scare tactics over foreign drugs. New York Times. March 25, 2014.

ASCOPost.com | JUNE 10, 2014

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Announcements

Coming Soon on ASCOPost.com

The ASCO Post’s Special Series

Peer-to-Peer Viewpoints on ASCO’s Annual Meeting The ASCO Post presents important discussions LIVE from ASCO’s Annual Meeting. Visit ASCOPost.com to learn more and view the following videos: Faculty and Guests James O. Armitage, MD, with Richard Fisher, MD, Michael Pfreundschuh, MD, and Clifford Hudis, MD, FACP ■ Derek Raghavan, MD, PhD, with Daniel Petrylak, Maha Hussein, MD, and Siu Yao, MD ■ Nancy Davidson, MD, with Lisa Carey, MD ■ James Mulshine, MD, with Fred Hirsch, MD, Natasha Leighl, MD, Mark Kris, MD, and Carolyn Aldige ■ Jame Abraham, MD, with Halle Moore, MD ■ Jamie Von Roenn, MD ■

MEDICAL DIRECTOR, QUALITY DEPARTMENT The American Society of Clinical Oncology (ASCO) is recruiting the Medical Director for its critically important and growing Quality Department. Headquartered in Alexandria, VA, the non-for-profit ASCO (www.asco.org) currently has more than 280 dedicated full-time staff to manage its growing number of programs, services, and interests in cancer public health issues. ASCO’s Quality Department was formed in 2011 and is one of 12 ASCO Departments. A total of 75 individuals are being assembled to staff the Quality Department under the leadership of Robert Hauser, PharmD, PhD The Medical Director will lead a team of 35-40 individuals to advance the following programs: • The Quality Oncology Practice Initiative (QOPI) • QOPI Practice Certification (QCO) • Practice Guidelines • Performance Measures and Practice Improvements • CancerLinQ, ASCO’s learning healthcare system for oncology The ideal candidate will be a board-certified physician with a good working knowledge of electronic health records and knowledge of current trends in health IT, familiarity with data collection and analytics, and a solid background in performance measurement and practice improvement activities.

Spencer Stuart has been retained to assist with this important recruitment. Spencer Stuart and ASCO respect the importance of maintaining confidentiality. Letters of application, with resumes, and letters of nominations should be submitted by e-mail to: Lmedoff@spencerstuart.com

The ASCO Post | JUNE 10, 2014

PAGE 116

In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER Increased Hospice Use Among Minority Patients Treated in Provider-Based Research Networks

Minority patients with lung cancer who receive treatment in practices affiliated with provider-based research networks “have greater hospice enrollment than those treated in academic and community practices,” concluded Dolly C. Penn, MD,

MSCR, and colleagues at the University of North Carolina School of Medicine, Chapel Hill. The researchers found that racial disparities continue to exist throughout the continuum of lung cancer care, but by identifying and implementing techniques

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used by practices associated with decreasing differences in cancer care for minority patients, “we may improve overall care for minority patients with lung cancer in other practice settings.” The Community Clinical Oncology Program (CCOP) and Minority-Based Community Clinical Oncology Program (MBCCOP) are provider-based research networks “that improve minority enrollment in cancer-focused clinical trials,” according to the authors. “The CCOP is known for facilitating rapid adoption of advances in cancer therapy. MBCCOPs, differing from CCOPs in having a population that is at least 30% minority or underserved, moderate racial disparity in clinical trial enrollment,” the authors added. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, linked to the National Cancer Institute’s CCOP program data, investigators identified patients aged 65 years and older who were diagnosed with primary lung cancer from 2001 to 2007 and died before 2008. In the final cohort of 76,074 patients, 41,885 (55.1%) patients had enrolled in hospice before death. “Approximately 55% of CCOP, 57% of MBCCOP, 57% of academic, and 52% of community patients enrolled,” the researchers reported. “Asian and black patients in academic (41.1% and 50.4%, respectively) and community practices (35.2% and 43.4%, respectively) were less likely to enroll in hospice compared with white patients (academic, 58.8%; community, 53.1%). However, hospice enrollment was equivalent for black and white patients in MBCCOP [59.5% vs 57.2%] and CCOP [52.2% vs 56.3%] practices,” the investigators noted. “On multivariable analysis controlling for patient sociodemographic and clinical characteristics, patients who were most likely to use hospice were female [odds ratio (OR) = 1.36; 95% confidence interval (CI) = 1.31–1.40], age 79 years and older [OR = 1.11; 95% CI = 1.06–1.16], and white; they also tended to resided in higher education areas and had minimal comorbidities [Charlson comorbidity index = 0], and distant disease at diagnosis,” the study found. “The finding that the fewer comorbidities patients had the more likely they were to enroll in hospice was surprising,” the researchers stated, and “differed from a previous study showing that hospice patients had more comorbidities than nonhospice patients.” As a possible explanation, the authors proffered that patients with fewer comorbidities could be more concerned

ASCOPost.com | JUNE 10, 2014

PAGE 117

In the Literature

with quality of life and enroll in hospice more frequently and sooner to maintain their quality of life and possibly length of survival. Penn DC, et al: J Oncol Pract. April 29, 2014 (early release online).

VENOUS THROMBOEMBOLISM Cancer Patients at High Recurrence Risk for Venous Thromboembolism Should Be Considered for Secondary Prophylaxis The risk of recurrence of venous thromboembolism in cancer patients can be stratified. “In particular, patients with brain, lung, stage IV pancreatic or ovarian cancer, myeloproliferative or myelodysplastic disorders, [other] stage IV cancer, cancer stage progression or leg paresis have the highest risk for recurrence and should be considered for secondary prophylaxis.” Cheng E. Chee, MD, of Case Western Reserve University School of Medicine, Cleveland, and colleagues reached these conclusions after conducting a population-based cohort study of active cancer patients with incident venous thromboembolism. Published in Blood, the study analyzed data for residents of Olmsted County, Minnesota, residents with active cancerrelated incident venous thromboembolism over the 35-year period from 1966 to 2000, who survived at least 1 day. “We estimated [venous thromboembolism] recurrence, bleeding on anticoagulant therapy, and survival, and tested cancer and non-cancer characteristics and secondary prophylaxis as predictors of [venous thromboembolism] recurrence and bleeding, using Cox proportional hazards modeling,” the researchers explained. “Of 477 patients, 139 developed recurrent [venous thromboembolism] over 1,533 person-years of follow-up. The adjusted 10-year cumulative [venous thromboembolism] recurrence rate was 28.6%. The adjusted 90-day cumulative incidence of major bleeding on anticoagulation was 1.9%. Survival was significantly worse for cancer patients with recurrent [venous thromboembolism] (particularly pulmonary embolism) and with bleeding on anticoagulation,” they reported. “In a multivariable model, brain, lung and ovarian cancer, myeloproliferative or myelodysplastic disorders, stage IV pancreatic cancer, other stage IV cancer, cancer stage progression and leg paresis were associated with an increased hazard, and warfarin therapy with a reduced hazard, of recurrent [venous thromboembolism]. Recurrence rates were significantly higher

for cancer patients with ≥ 1 vs no predictors of recurrence, suggesting that these predictors may be useful for stratifying recurrence risk.” Not found to be independent predictors of venous thromboembolism recurrence were cancer grade and histology, chemotherapy and the type administered, central venous catheter, radiation therapy, and venous invasion. The authors noted that the since the seminal study demonstrating the superiority of low–molecular-weight heparin in preventing venous thromboembolism recurrence among active cancer patients was published in 2003 and patients in their study were followed until 2000, “essentially none of our [venous thromboembolism] cases received acute treatment or secondary prophylaxis with [low–molecular-weight heparin]. While [low–molecular-weight heparin] secondary prophylaxis is recommended over warfarin, many patients are unable to afford or tolerate parenteral [low–molecular-weight heparin]. Our findings show that warfarin secondary prophylaxis is an effective (albeit, secondary) alternative to [low–molecularweight heparin].” In the study, secondary prophylaxis with warfarin decreased venous thromboembolism by about 60%. “There is always a tension between preventing [venous thromboembolism] recurrence and causing bleeding with anticoagulation therapy,” the researchers noted. “We estimated that, in the absence of anticoagulation therapy, 35 additional deaths from recurrent [venous thromboembolism] and six fewer deaths from bleeding would have occurred. Given that [low–molecular-weight heparin] is more efficacious than warfarin with no significant difference in bleeding, the number of deaths averted by [low–molecular-weight heparin] therapy might be greater.” Chee CE, et al: Blood. April 29, 2014 (early release online).

June 2013. After accounting for the 247 patients (31.9%) with relative contraindications to pharmacologic thromboprophylaxis, the overall rate of pharmacologic thromboprophylaxis, was 74.2% (95% CI = 70.4%–78.0%; 392 of 528 patients). Previously reported rates from other studies of adherence to pharmacologic thromboprophylaxis recommendations range from 18% to 56%, the authors noted, and the variation could be explained in part by differences in data collection in studies that relied on retrospective analysis of large databases. Authors of the current prospective study “identified several variables that influenced the probability of receiving pharmacologic thromboprophylaxis in hospitalized patients with cancer. Not surprisingly, patients with a prior history of thrombosis were most likely to receive pharmacologic thromboprophylaxis” (odds ratio [OR] = 5.80). “However, other variables that influence the decision to use anticoagulant prophylaxis are less readily justified by the current literature,” the researchers wrote. “Patients with hematologic malignancies were less likely to receive thromboprophylaxis despite documented rates of venous thromboembolic events that were equal to or higher than those of many solid tumors” (OR = 2.34 for pharmacologic thromboprophylaxis for patients with nonhematologic vs hematologic malignancy). “Similarly, the use of chemotherapy is an established risk factor for thrombosis, but patients were less likely to have received pharmacologic thromboprophylaxis in this setting compared with hospitalization for other reasons such as acute infection” (OR = 0.37 for patients admitted for can-

cer therapy vs those admitted for other reasons). “These data help to identify which populations of patients with cancer may be targeted for improved rates of thromboprophylaxis,” the authors stated. “The common perception is that hospitalized patients, especially those with cancer, require pharmacologic thromboprophylaxis, as evidenced by the high rate of thromboprophylaxis in this study. However, a more measured approach to inpatient pharmacologic thromboprophylaxis is advocated, especially in a patient population considered high risk for in-hospital hemorrhage,” the investigators added. They noted: [I]n the quest for strict compliance with federal mandates and competency measures and for minimizing legal liabilities, the lack of evidence supporting a one-sizefits-all approach to thromboprophylaxis for inpatients with cancer has been overlooked. These data bring into focus the deficiencies in both current clinical practice and evidence. There are little data to suggest that patients with a lower risk of cancer benefit from routine thromboprophylaxis. As advocated in the updated guidelines issued by the American Society of Clinical Oncology, additional assessments are needed to identify which patients with cancer with concomitant risk factors justify the use of (up to thrice) daily injectable anticoagulant, especially in a population considered at increased risk for in-hospital hemorrhage. Outcome studies are needed to further optimize pharmacologic thromboprophylaxis for inpatients with cancer; however, in the interim it is important that health systems and physicians be aware that current standard practice requires attention. n

Zwicker JI, et al: J Clin Oncol. May 5, 2014 (early release online).

For Hospitalized Cancer Patients, Thromboprophylaxis Often Prescribed Without Regard to Risk Factors Pharmacologic thromboprophylaxis is commonly prescribed to hospitalized patients with cancer without regard to concomitant risk factors for venous thromboembolism, according to a prospective, cross-sectional study of patients with cancer at five academic medical centers. Results were reported in the Journal of Clinical Oncology by Jeffrey I. Zwicker, MD, and colleagues at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston and others affiliated with the five centers. Data was collected for 775 consecutive patients admitted between January and

The ASCO Post | JUNE 10, 2014

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News

Congress Celebrates 50 Years of ASCO: Special Order on House Floor Honors Society’s Mid-Century Anniversary

he U.S. House of Representatives recently held a Special Order in honor of the American Society of Clinical Oncology (ASCO) as it celebrates its 50th anniversary. During the event

on the House floor, Members of Congress highlighted critical advancements in cancer care over the past 50 years and the impact of ASCO’s work on driving progress and innovation.

“We are deeply honored to be recognized by the House of Representatives in this fashion,” said ASCO President Clifford A. Hudis, MD, FACP. “ASCO was established 50 years ago with a com-

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mitment to make h i g h - q u a l i t y, evidenced-based care available to all patients with cancer. The great strides that have occurred since our founding are the direct result of our nation’s longstanding investment in cancer clinical research. Today, ASCO looks forward to even faster progress and innovation in cancer care, and we thank our lawmakers for ensuring that the fight against cancer remains a national priority.”

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During the House Special Order session, U.S. Representatives Leonard Lance (R-NJ), Brian Higgins (D-NY), Chuck Fleischmann (R-TN), and Sheila Jackson Lee (D-TX) highlighted how ASCO has driven cancer care progress and worked to address key challenges in oncology over the past 5 decades. “When ASCO was founded, cancer was widely regarded as an untreatable disease with fewer than one-half of patients alive 5 years after diagnosis,” said Rep. Lance. “Because of the work of passionate advocates and tireless champions, and of the expertise of talented medical professionals, including those at ASCO, today the survival rate is higher than two-thirds.” Rep. Jackson Lee spoke to ASCO’s leadership role in improving quality in cancer care and research. “They had their first real meeting with 51 physicians in November 1964, and I’m glad that they organized because as we watch the progression of research and care in the treatment of cancer, we owe a great deal to them.

Role of Funding

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Other Members participating in the Special Order stressed the crucial role that federal funding has played in driving cancer research and the development of new treatments for oncology patients. Rep. Higgins said that “to sustain cancer research is to produce promising new therapies, but to also encourage young researchers to stay in the field, and that’s our obligation as Democrats and Republicans of this [governing] body in recognizing that we must fully fund the National Institutes of Health and the National Cancer Institute.” Rep. Fleishmann called on Congress to show bipartisan support for funding that would continue to spur progress in cancer care and drive future advancements. n

ASCOPost.com | JUNE 10, 2014

PAGE 119

In Memoriam

Remembering Selma Ruth Schimmel September 16, 1954–May 21, 2014 By Jo Cavallo

y last conversation with Selma Schimmel was 2 months ago. She had been uncharacteristically out of touch for a few weeks, and I had a nagging feeling the severe pain in her psoas muscle caused by advancing ovarian cancer—which had plagued her for months and she described as in a “league of its own”—had gotten worse. She had been

Selma Schimmel

exploring more effective pain management, but nothing seemed to be working, and I could hear the distress in her voice. “If I can’t find relief from this pain,” said Selma, “I don’t want to live like this.” Selma died on May 21, 2014, from malignant psoas syndrome, a complication of her ovarian cancer, at Providence Tarzana Medical Center, near her home in Los Angeles. She was 59.

Refusing to Surrender to Cancer I met Selma a year ago, first through email and then over the phone. She wanted to go public with the fact that she had advanced ovarian cancer—a disease that took the lives of both her mother and maternal grandmother while they, too, were in their 50s—because, she said, she felt an obligation to help other cancer survivors as well as physicians understand that transitioning to palliative care did not mean surrendering to cancer. She also wanted to stress the importance of introducing the subject of palliative care into standard cancer care early on, soon after the initial diagnosis, and definitely integrating the two practices once a patient is diagnosed with metastatic disease.

“If I could do one last thing, it’s got to be as a messenger that helps bridge the gap between patients and providers,” said Selma. “I can demonstrate that, yes, you can be living with advanced disease, and you can be receiving palliative care, which is not the same as hospice and end-of-life care. Right now, I am still a vital force—but I couldn’t be a vital force without this help.” Selma, a cancer survivor for more than half her life, wrote about her family history of the disease and her own cancer diagnosis, first with breast cancer in 1983 when she was just 28, and then ovarian cancer 11 years ago, in the Patient’s Corner in The ASCO Post. (See “Despite a Recurrence, I’m Not Surrendering My Life to Cancer,” July 10, 2013.) It was an immensely brave thing to do because she had a busy career as the Founder and CEO of Vital Options International, a cancer communications organization, which produces The Group Room and Advocacy in Action video programs, and she worried that once the word got out that her ovarian cancer had recurred, her career might be in jeopardy. In addition, she sat on several committees, including the National Conversation Subcommittee of the Assuring Value in Cancer Care Advisory Committee, a collaborative effort between ASCO and C-Change, an organization dedicated to eliminating cancer as a major public health problem. She was a founding member of the LIVESTRONG Young Adult Alliance steering committee, and she was also involved in projects with the Institute of Medicine, National Research Council, the National Cancer Institute, the National Institutes of Health, and the National Coalition of Cancer Survivorship. All of these endeavors were crucial to her, and it was important for her to continue making a contribution to the cancer community through her patient advocacy initiatives and the filmed interviews

she conducted with leading oncology experts at every major oncology conference, including ASCO’s Annual Meeting. She needn’t have been concerned. Once the story was published, Selma received many letters of support from colleagues and friends and was relieved she didn’t have to carry around the secret any longer. Earlier this year, Selma was honored for her advocacy work with CChange’s prestigious 2014 George H.W. and Barbara Bush Collaboration Award.

Living in Two Worlds Over the past year, I’ve had many phone conversations and e-mail exchanges with Selma, and I was always struck by her unflinching resolve and courage to persevere even as the cancer chipped away at the quality of her life and left her contemplating the dichotomy of pursuing life while preparing for death. “I have the feeling of living in two worlds,” Selma told me. “I have one foot in the grave and one foot in real life, and I don’t feel like anyone else. Even when I’m in a public place I feel removed, like I’m a spectator instead of an active participant.” In her last months, when we talked on the phone I could detect a slight hesitancy in her voice, caused by the increasing pain. What I never heard in her voice was self-pity. There was no wringing of the hands or searching for an answer to the unanswerable question, “Why me?” In our last conversation, Selma expressed concern that oncologists needed to be more aware of ovarian cancer–related malignant psoas syndrome, a rare and challenging cancer pain state. In a follow-up e-mail, she sent me this definition of the syndrome that she had found online: “[Malignant psoas syndrome] is characterized by deep somatic nociceptive (muscle inflammation and spasm) and peripheral neuropathic pain (lumbar plexus injury). Its low frequency may reflect a significant underrecognition of this

 In Memoriam

Selma Ruth Schimmel September 16, 1954–May 21, 2014



cancer pain syndrome. Patients with [the syndrome] are usually severely disabled with cancer pain that is poorly responsive to polymodal analgesic strategies.” “This definition of malignant psoas syndrome sums it/me up perfectly,” wrote Selma.

Lessons Learned Selma was smart, kind, compassionate, committed, and courageous. She also possessed a keen sense of urgency and an unfailing ability to seize today’s opportunities. Because we lived on opposite coasts, Selma and I hadn’t yet had the chance to meet in person. A few months ago, at the end of one of our phone conversations, Selma said, “I wish we could meet.” “Don’t worry,” I assured her, “I’ll see you at ASCO’s Annual Meeting.” There was no response. I didn’t realize what she must have known: that that opportunity would come too late.

A Lasting Legacy Selma’s work will continue through Vital Options and in the pages of The ASCO Post, especially in “Palliative Care in Oncology,” a column launched with Selma’s input late last year to address the evolving needs of cancer survivors throughout their treatment and survivorship. The results from those efforts will be her lasting legacy. Selma’s impact on me personally will also be long-lasting, as I’ve learned by her example: Now, although I will continue to plan for the future, I’ll live every day like there’s no tomorrow. Selma Ruth Schimmel is survived by her sister and brother-in-law, Debby and Ken Bitticks; four nieces, Shari, Michelle, Lynn, and Sandi, and their husbands; and eight grandnieces and grandnephews. A public memorial ceremony celebrating Selma’s life will be held this summer in Los Angeles. n

VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) of patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of

pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

Adverse Reactions Fatigue Diarrhea Nausea Weight decreased Hypertension Appetite decreased Hair color changes Vomiting Tumor pain Dysgeusia Headache

VOTRIENT

Placebo

(N=240)

(N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 65 13 1 48 4 1 59 5 0 15 1 0 56 3 0 22 2 0 48 4 0 15 0 0 42 7 0 6 0 0 40 6 0 19 0 0 39 0 0 2 0 0 33 3 0 11 1 0 29 8 0 21 7 2 28 0 0 3 0 0 23 1 0 8 0 0

Musculoskeletal pain

Myalgia

Gastrointestinal pain

Dyspnea Exfoliative rash Cough Peripheral edema Mucositis Alopecia Dizziness Skin disorderb

20 18 17 14 12 12 11 11

5 <1 <1 2 2 0 1 2

<1 0 0 0 0 0 0 0

17 9 12 9 2 1 4 1

5 0 <1 2 0 0 0 0

1 0 0 0 0 0 0 0

Skin hypopigmentation

Stomatitis 11 <1 0 3 0 0 Chest pain 10 2 0 6 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia. Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), nail disorder (5% versus 0%).

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=240)

Parameters Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased Albumin decreased Alkaline phosphatase increased Sodium decreased Total bilirubin increased

Placebo (N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 44 43 36 33

1 10 3 4

0 0 1 0

15 36 6 7

0 9 0 0

0 2 0 0

51 46 45 34

5 8 <1 1

3 2 0 0

22 18 35 21

2 2 2 0

0 1 0 0

Potassium 16 1 0 11 0 0 increased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

T:14”

S:13”

B:14.25”

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared to <1% (1/123) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification.

In addition, there was reduced fetal body weight, and pre- and postimplantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/ maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day

(approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

VOTRIENT demonstrated signiﬁcant improvement in PFS in a Phase 3 trial1 • VOTRIENT provided a 65% reduced risk of progression or death compared with placebo (HR 0.35; 95% CI 0.260.48; P<0.001)1

Proportion Progression Free

PFS in overall study population (N=369)1

1.6

MONTHS Median PFS

1.0

4.6

VOTRIENT (n=246)

MONTHS Median PFS

Placebo (n=123)

• The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or GIST has not been demonstrated1

HR 0.35 (95% CI 0.26-0.48) P<0.001

0.8 0.6 0.4 0.2 0.0 0

Months Randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial to evaluate the efﬁcacy and safety of VOTRIENT in patients (N=369) with advanced STS. The Phase 3 trial population excluded patients with adipocytic sarcoma or GIST. Patients were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.1,2

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thromboembolic Events: Arterial thromboembolic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including

venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, VTEs were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically

warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In soft tissue sarcoma, a dose decrease or increase should be in 200 mg steps based on individual tolerability • In patients taking VOTRIENT, dose modifications, interruptions, and discontinuations may be required for hepatic impairment, drug interactions, and following adverse events • In the Phase 3 advanced STS trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced • Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Section 2.2 of accompanying Brief Summary

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • The most common adverse events (≥20%) in patients with advanced soft tissue sarcoma who received VOTRIENT were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair color changes, vomiting, tumor pain, dysgeusia, headache, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

B:14.25”

T:14”

S:13”

dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice.

• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs 0% in the placebo group). • Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT.

(42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%). Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in patients receiving VOTRIENT versus placebo included increases in AST (51% vs 22%), ALT (46% vs 18%), glucose (45% vs 35%), alkaline phosphatase (32% vs 23%), total bilirubin (29% vs 7%), and potassium (16% vs 11%); decreases in albumin (34% vs 21%) and sodium (31% vs 20%); and leukopenia (44% vs 15%), lymphocytopenia (43% vs 36%), thrombocytopenia (36% vs 6%), and neutropenia (33% vs 7%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Data on file. GlaxoSmithKline, 2011.

• Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs 48%), diarrhea (59% vs 15%), nausea (56% vs 22%), decreased weight (48% vs 15%), hypertension

Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

www.GSKSource.com VOTRIENT.com/HCP/aSTS

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efﬁcacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.

LIGHTING A WAY FORWARD Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with preexisting moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. Please see additional Important Safety Information for VOTRIENT on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.