TAP Vol 6 Issue 18 by Harborside Press LLC

Issues in DCIS: Is It Cancer? 1, 90 | Adolescent and Young Adult Oncology

28, 29

| Global Cancer Burden

66, 67, 112

VOLUME 6, ISSUE 18

OCTOBER 10, 2015

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

World Conference on Lung Cancer

NCCN Turns 20: Value-Based Care Has Arrived

EGFR Gene Copy Number as Biomarker for Antibody Treatment in Squamous Cell NSCLC By Caroline Helwick

By Charles L. Bennett, MD, PhD, MPP (left), and William S. Shimp, MD

wo studies presented at the 16th World Conference on Lung Cancer suggest that high expression of the epidermal growth factor receptor (EGFR), or gene copy number, may indicate potential benefit from EGFR antibodies in squamous cell non–small cell lung cancer (NSCLC). The studies were presented by Roy Herbst, MD, PhD, Ensign Professor of Medicine, Professor of Pharmacology, Chief of Medical Oncology, and Director of the Thoracic Oncology Research Program at Yale School of Medicine, New Haven, and Fred R. Hirsch, MD, PhD, Professor of Medicine and Pathology and Pia and Fred R. Hirsch Chair in Lung Cancer at the University of Colorado, Denver. Dr. Hirsch provided some context at a press briefing, noting that squamous tumors comprise about 25% of all NSCLCs, tend to be smoking-related, and are characterized by a lack of therapeutic benefits. “In nonsquamous, we have seen lots of progress. In squa-

T Roy Herbst, MD, PhD

Fred R. Hirsch, MD, PhD

continued on page 113

mous, we have seen practically nothing that is therapeutically implementable,” he said. Dr. Herbst reported results from the phase III SWOG 0819 trial, which demonstrated some benefit for cetuximab (Erbitux) plus chemotherapy in patients with tumors positive for EGFR by fluorescent in situ immunohistochemistry, especially among pacontinued on page 4

Perspective

Ductal Carcinoma in Situ: Where We Have Been and Where We Can Be By Laura Esserman, MD, MBA, Jasmine M. Wong, MD, Cheryl Ewing, MD, and Michael Alvarado, MD

uctal carcinoma in situ has been a recent topic of debate in the news because of a recent article by Narod et al1 and an accompanying editorial2 about the study in JAMA Oncology. This study, summarized in this issue of The ASCO Post, chronicled the long-term outcomes for women diagnosed with ductal carcinoma in situ. The article reinforces what we have come to

Laura Esserman, MD, MBA

understand about ductal carcinoma in situ—that by itself, it is not lethal but rather a risk factor for developing breast cancer. Ductal carcinoma in situ, like invasive breast cancer, comes in many forms, so treatment on a one-size-fits-all basis does not work. A very small fraction of ductal carcinoma in situ cases carry more risk than we thought, including the chance of metastatic disease without a recurrence in the breast. Those cases are rare, Ductal carcinoma in situ should however, and relatively not be called cancer. We need to easy to identify. The vast majority of cases appear acknowledge the uncertainty in to have less risk than we the benefit of intervention when we thought, which is good news for women with discuss all the options of treatment this type of breast cancer with our patients. and opens the door to —Laura Esserman, MD, MBA, Jasmine M. Wong, MD, new approaches. Cheryl Ewing, MD, and Michael Alvarado, MD

October is Breast Cancer Awareness month.

wenty years ago, the National Comprehensive Cancer Network (NCCN) began as a cooperative effort of 12 prestigious cancer centers, working to define and promote national guidelines for the care of patients with cancer. A major goal was to encourage uniformity in the management of malignant diseases, such that U.S. cancer patients could be assured of receiving up-to-date, science-based, standard-of-

Dr. Bennett is the SmartStarte Center Chair and Frank P. and Josie M. Fletcher Professor of Medication Safety and Efficacy at the South Carolina College of Pharmacy and the Hollings Cancer Center, Charleston, South Carolina, and Dr. Shimp is a medical oncologist and former Chief Medical Officer of Park Nicollet Health Services in Minneapolis, Minnesota. Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage World Conference on Lung Cancer ��9–12 Best of ASCO �� 14 NIH: Preventing Overdiagnosis ��27 New Data in Early Breast Cancer ��33 Male Breast Cancer ��36 Metastatic Prostate Cancer �� 37, 41 ASCO Statement: Treating Older Adults With Cancer ��42 Direct From ASCO �� 53–56 Advanced Melanoma �� 61 Cancer-Related Pain ��72 In Memoriam �� 110

continued on page 47

A Harborside Press® Publication

The ASCO Post | OCTOBER 10, 2015

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World Conference on Lung Cancer Thoracic Cancer

AZD9291 Updates Encouraging for Treatment-Resistant NSCLC By Caroline Helwick

t the 16th World Conference on Lung Cancer, several studies showed consistent activity with the investigational third-generation inhibitor AZD9291 in patients with advanced non–small cell lung cancer (NSCLC) that is resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Confirmed objective response rates ranged from 61% to 75% in three AURA trials. AZD9291 is a potent oral, irreversible EGFR tyrosine kinase inhibitor that is selective for EGFR-activating mutations and the T790M resistance mutation. The T790M mutation confers resistance to treatment with first-generation EGFR inhibitors, such as erlotinib and gefitinib (Iressa) and the second-generation tyrosine kinase inhibitor afatinib (Gilotrif). Studies are assessing AZD9291 for use in the first-line setting and beyond. The question is whether to use agents sequentially, as patients develop resistance, or perhaps start with a stronger drug— one that seems less likely to cause resistance, like this one—upfront, researchers indicated. AZD9291 also appears to provoke less skin toxicity than current agents, which suggests its potential for combining with other agents.

First-Line, High Response Rate Pasi Jänne, MD, PhD, Director of the Lower Center for Thoracic Oncology at Dana-Farber Cancer Institute, Boston, presented an update of the phase I first-line AURA trial,1 noting that in treatment-naive patients, AZD9291 “demonstrated encouraging clinical activity and a manageable tolerability profile.” Suresh S. Ramalingam, MD, of Emory University School of Medicine in Atlanta, was the study’s first author.

Pasi Jänne, MD, PhD

reached, “if you look at the curves, the lower limit of the 95% confidence interval for progression-free survival was about 12 to 13 months, which is higher than we normally see the medians for EGFR inhibitors…”. He added, “That part is incredibly exciting because, as you move an effective therapy that works in patients that have developed resistance and give it early on in treatment, it may in fact work even better.”

Phase II Studies

Suresh S. Ramalingam, MD

The patients were found to have several EGFR-mutation subtypes, including L858R (40%), exon 19 deletion (37%), other EGFR-sensitizing mutations (3%), and T790M (8%). Patients received 80 mg or 160 mg of AZD9291. After 12.3 months of follow-up, the confirmed objective response rate was 75%, with some responses ongoing at 18 months. The disease-control rate was 97%. A total of 72% of patients remained alive and progression-free at 12 months. “This has prompted the initiation of the phase III FLAURA study, comparing AZD9291 at the 80-mg dose vs the current standard-of-care EGFR tyrosine kinase inhibitors for treatmentnaive patients,” Dr. Jänne said. The data in the first-line setting are still relatively immature, Dr. Jänne said. “For progression-free survival, it is only at 35% maturity.” Although the median progression-free survival has not yet been

Two phase II studies that are part of the AURA clinical program were also presented: the AURA extension and AURA2 cohorts. They evaluated AZD9291 in patients with EGFR-mutated, T790M-mutation–positive advanced NSCLC who progressed after EGFR tyrosine kinase inhibitor treatment. The AURA extension trial is a continuation of a phase I dose-escalation study of 201 patients receiving AZD9291 80 mg once daily.2 The findings were reported by James Chih-Hsin Yang, MD, Director of the Departments of Oncology and Medical Research, National Taiwan University Hospital in Taipei City. The overall response rate was 61% (all partial responses), and the disease-control rate was 91%, with “only a few patients having progressive disease as their best response,” he said. Although the median duration of response and median progression-free survival have not yet reached maturity, Dr. Yang indicated, “The curve shows there is a very long progression-free survival in up to 12 months of follow-up.” Findings were similar in AURA2, a global, open-label, single-arm phase II trial of 210 patients with T790M mutations.3 The response rate was 71%, including two complete responses. The

EXPERT POINT OF VIEW

artin Reck, MD, PhD, of the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf in Germany, discussed the studies. In pretreated patients, he said, “We have seen confirmed efficacy” [for AZD9291] and “impressive activity.” In the first-line setting, its efficacy is still being evaluated, “but that question will be answered by the firstline FLAURA trial,” he said. More also needs to be learned, he added, about the drug’s activity in T790M-negative patients. “We do

disease-control rate was 92%, and median progression-free survival was 8.6 months, but the follow-up is not ma itsudomi, MD, PhD, ture, Tetsuya M

Martin Reck, MD, PhD

see responses in about 20% to 30% of these patients,” noted Dr. Reck. “As far as tolerability, due to the mechanism of these drugs, these com-

pounds seem to be very well tolerated, so we typically do not see the side effects of the first-generation tyrosine kinase inhibitors,” he indicated. Dr. Reck concluded: “I would say that these drugs should become available as soon as possible.” The U.S. Food and Drug Administration has been granted priority review to AZD9291. n Disclosure: Dr. Reck has been a member of advisory boards for Hoffmann-La Roche, Lilly, BMS, AstraZeneca, MSD, BoehringerIngelheim, Pfizer, and Novartis and has received honoraria from all of the above but Novartis.

James Chih-Hsin Yang, MD

Tetsuya Mitsudomi, MD, PhD

Professor, Division of Thoracic Surgery, Kinki University, Japan, said. “AZD9291 has demonstrated a positive clinical benefit across two phase II studies, with encouraging duration of response and progression-free survival. A longer followup is needed…,” Dr. Mitsudomi said. The ongoing phase III AURA3 trial is evaluating AZD9291 vs a platinum-based doublet in patients with T790M-positive advanced NSCLC who progress after tyrosine kinase inhibitor treatment. The planned enrollment is 410 patients. n

Disclosure: Dr. Jänne has been a consultant for AstraZeneca, Roche Genentech, Pfizer, and Merrimack, owns stock in Gatekeeper Pharmaceuticals, and has received postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations licensed to Lab Corp. Dr. Ramalingam serves on advisory boards for AstraZeneca, Genentech, Boehringer Ingelheim, and Clovis. Dr. Yang serves on advisory boards for Boehringer Ingelheim, Lilly, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Merck, Bayer, and Clovis Oncology and has received research support from Boehringer Ingelheim. Dr. Mitsudomi has received grants/research support from AstraZeneca, Pfizer, Chugai, Taiho, and Boehringer Ingelheim, has been a consultant for AstraZeneca, Pfizer, Chugai, Novartis, Boehringer Ingelheim, Kyowa Hakko-Kirin, MSD, and Clovis, and has received honoraria from AstraZeneca, Pfizer, Chugai, Taiho, and Boehringer Ingelheim.

References 1. Ramalingam S, et al: World Conf on Lung Cancer. Abst MINI16.07. Sept 8, 2015. 2. Yang J C-H, et al: World Conf on Lung Cancer. Abst MINI16.06. Sept 8, 2015. 3. Mitsudomi T, et al: World Conf on Lung Cancer. Abst MINI16.08. Sept 8, 2015.

The ASCO Post | OCTOBER 10, 2015

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World Conference on Lung Cancer Biomarker in NSCLC continued from page 1

tients with squamous histology and patients who did not receive bevacizumab (Avastin).1 “The addition of cetuximab had minimal effect on unselected advanced NSCLC patients, but in fluorescent in situ immunohistochemistry–positive patients, there was a suggestion of benefit, predominantly in squamous cell lung cancer and bevacizumab-inappropriate patients,” Dr. Herbst explained. Dr. Hirsch reported on a correlative analysis of the SQUIRE trial, showing that gain in EGFR gene copy number was associated with a trend for more favorable hazard ratios for overall survival among patients receiving necitumumab plus chemotherapy.2 “Pooling these two studies together, evaluating antibodies in the same family, we find that gene copy number detected by fluorescent in situ immunohistochemistry seems to predict a better outcome and could, in the future, be used for selecting patients for treatment with EGFR antibodies,” Dr. Hirsch said at a press briefing.

SWOG 0819 Details Dr. Herbst and colleagues assessed the addition of cetuximab to chemotherapy (carboplatin/paclitaxel, plus or minus bevacizumab) in 1,333 newly diagnosed patients with stage IV NSCLC. The study’s co-primary endpoints were progression-free survival in fluorescent in situ immunohistochemistry–positive patients (n = 400) and overall survival in the whole study population. Patients were stratified not only by EGFR status but also according to their receipt of

bevacizumab (bevacizumab appropriate vs inappropriate). They found no benefit in overall survival for the entire population (hazard ratio [HR] = 0.94, P = .34) and no benefit in progression-free survival in the fluorescent in situ immunohistochemistry–positive population (HR = 0.91, P = .37). As a secondary endpoint, Dr. Herbst and colleagues did find a suggestion of a survival benefit in the entire EGFR fluorescent in situ immunohistochemistry–positive population, but it was not statistically significant (HR = 0.83, P = .10). A statistically significant overall survival benefit, however, was seen among the 759 bevacizumab-inappropriate, fluorescent in situ immunohistochemistry–positive patients (HR = 0.75, P = .048). In this group, median overall survival was 8.7 months with chemotherapy alone vs 11.2 months in the cetuximab-containing arm.

EGFR Antibodies in Squamous Cell NSCLC ■ EGFR gene copy number or fluorescent in situ immunohistochemistry positivity could be a potential biomarker for benefit from anti-EGFR antibodies in the treatment of squamous cell NSCLC. ■ In SWOG 0819, cetuximab plus chemotherapy conveyed a statistically significant overall survival benefit among the 759 fluorescent in situ immunohistochemistry–positive patients not receiving bevacizumab. In an exploratory analysis, squamous cell patients had a significant overall survival benefit with cetuximab. ■ In SQUIRE, median overall survival for fluorescent in situ immunohisto chemistry–positive squamous cell patients was 12.6 months with necitumumab, vs 9.2 months with chemotherapy alone.

have tumors positive for EGFR gene copy number have a survival benefit, whereas those with nonsquamous histology and those with fluorescent in situ immunohistochemistry–negative tumors derive no survival advantage, concluded Dr. Herbst. “These data, along with the recent

These data, along with the recent SQUIRE results [which evaluated necitumumab], suggest a role for EGFR fluorescent in situ immunohistochemistry in selecting patients [with squamous histology] for therapy with EGFR antibodies, especially when bevacizumab is not used. —Fred R. Hirsch, MD, PhD

In addition, in an exploratory analysis, the study showed a statistically significant overall survival benefit in patients with squamous cell NSCLC receiving cetuximab (11.8 months vs 6.4 months), with a strong hazard ratio (HR = 0.56, P = .006). The findings suggest that patients with squamous cell lung cancer who

SQUIRE results [which evaluated necitumumab], suggest a role for EGFR fluorescent in situ immunohistochemistry in selecting patients [with squamous histology] for therapy with EGFR antibodies, especially when bevacizumab is not used,” Dr. Herbst said. “Analysis of EGFR H Score and KRAS mutation is ongoing, to be presented at ASCO 2016.”

Similar Findings From SQUIRE The potential for EGFR gene copy number to serve as a biomarker for EGFR antibodies was supported by correlative analysis of the ongoing SQUIRE trial. SQUIRE evaluated the addition of necitumumab to gemcitabine/cisplatin in 1,093 patients with stage IV squamous NSCLC. Median overall survival was significantly longer in the necitumumab arm than in the chemotherapy-alone arm: 11.5 months vs 9.9 months (HR = 0.84, P = .01).3 As a result of these findings, an advisory board to the U.S. Food and Drug Administration has recommended approval of necitumumab, Dr. Hirsch indicated. Among the 51% of patients with archived tumor tissue, 37.3% had an increased EGFR gene copy number or were fluorescent in situ immunohistochemistry–positive. Dr. Hirsch presented data regarding the relationship between EGFR protein and EGFR gene copy number and outcomes. The analysis showed no consistent trends or clear thresholds for a relationcontinued on page 5

EXPERT POINT OF VIEW

obert Pirker, MD, Professor of Medicine and Program Director for Lung Cancer at the Medical University of Vienna, Austria, discussed the findings at the “Top Abstracts” session of the 16th World Conference on Lung Cancer. Based on these results and the findings of similar studies, Dr. Pirker believes that epidermal growth factor receptor (EGFR) fluorescent in situ immunohistochemistry or H score (which includes the percentage of cells and staining intensity by immunohistochemistry) may serve as a useful biomarker for anti-EGFR antibody treatment. “The consistency of sites

lent example of a predictive biomarker,” although he emphasized the need for them to be validated, for pathologists to be trained in interpretation, and for quality controls to be in place. n

warrants their clinical implementation,” he said.

Favorable Trends Multiple studies have documented favorable trends related to gene copy number or fluorescent in situ immunohistochemistry positivity. For cetuximab, besides SWOG 0819, they include the FLEX trial (hazard ratio [HR] = 0.87, P = .04) and a meta-analysis (HRs = 0.88 for intention to treat and 0.77 for squamous, P = .009). Another recent study of chemoradiotherapy plus or minus cetuximab (RTOG 0617) also showed that in patients with an H score ≥ 200, median

Disclosure: Dr. Pirker reported financial relationships with AstraZeneca, Merck Sharp & Dohme, Synta Pharmaceuticals, Boehringer Ingelheim, Pfizer, and Pierre Fabre. Robert Pirker, MD

overall survival was 42 months with cetuximab, vs 21 months in the control arm (HR = 0.58, P = .03).1 The reproducibility at multiple sites and in multiple datasets, he suggested, makes EGFR fluorescent in situ immunohistochemistry or H score “an excel-

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

ASCOPost.com | OCTOBER 10, 2015

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World Conference on Lung Cancer Thoracic Cancer

Lung Cancer Rates Doubling Among Nonsmokers By Caroline Helwick

ung cancer is becoming an equalopportunity malignancy—with rates rising among never-smokers, especially females, according to studies presented at the 16th World Conference on Lung Cancer in Denver.

Since both the percentage and absolute number of NSCLC cases involving nonsmokers have increased, Dr. Lim believes the rise is real and not an artifact associated with an overall reduction in smoking. “We found that the

What we are seeing is an increase in the incidence of nonsmoking-related lung cancer. We have seen more than double the amount of [nonsmoking] patients coming to us. —Eric Lim, MD

British investigators reported that in one large tertiary medical center, the proportion of patients with lung cancer who never smoked more than doubled between 2008 and 2014.1 In 2008, never-smokers accounted for 13% of non–small cell lung cancer (NSCLC) cases; this rate is now 28%. Women comprise two-thirds of this group, and their cancer is often associated with nonspecific symptoms or no symptoms at all, according to Eric Lim, MD, of Royal Brompton Hospital in London. “When we think of lung cancer, we think of smoking,” Dr. Lim said at a press briefing. Antismoking strategies implemented in the early 1980s, however, have led to a decrease in smokingrelated lung cancer. Instead, he explained, “What we are seeing is an increase in the incidence of non–smoking-related lung cancer. We have seen more than double the amount of [nonsmoking] patients coming to us.”

absolute numbers are increasing in real time,” reported Dr. Lim. A U.S. study involving three medical centers reached a similar conclusion.2 Since 1990, one center has noticed a twofold increase in NSCLC, according to Lorraine Pelosof, MD, PhD, of the University of Texas Southwestern Medical Center (UT Southwestern), Dallas. The investigators noted that a similar increase has not been observed in small cell lung cancer.

Biomarker in NSCLC

histochemistry–positive patients was 12.6 vs 9.2 months (interaction P value = .066), for the necitumumab vs control arms, respectively. For progression-free survival, the hazard ratio was 0.71 for fluorescent in situ immunohistochemistry–positive patients, reflecting 6.1 vs 5.1 months (interaction P value = .066), respectively. The hazard ratio for the fluorescent in situ immunohistochemistry–negative group was 1.04. These were favorable trends observed with necitumumab among the fluorescent in situ immunohistochemistry–positive cohort that were of

continued from page 4

ship between overall or progressionfree survival and the EGFR protein over a range of immunohistochemistry values. However, gain in EGFR gene copy number was associated with a trend for more favorable hazard ratios for overall survival, Dr. Hirsch reported. For overall survival, hazard ratios related to necitumumab were 0.70 for fluorescent in situ immunohistochemistry–positive patients and 1.02 for fluorescent in situ immunohistochemistry–negative patients. Median overall survival for fluorescent in situ immuno-

UK Study Details Dr. Lim and colleagues retrospectively reviewed records of 2,170 newly diagnosed patients who underwent surgery for lung cancer at the Royal Brompton Hospital between 2008 and 2014. They compared the incidence of cancer among the 20% of subjects who had never smoked with that of current and ex-smokers. Over the past 8 years, the incidence of lung cancer in nonsmokers increased steadily, with the greatest jump observed from 2013 (20%) to 2014 (28%). The total number of cases increased from 60 in 2010 to almost 100 in 2014, Dr. Lim reported. Women accounted for 295 (67%) of the never-smokers, with a mean age of 60 years. The most common histology was adenocarcinoma (54%), followed by carcinoid (27%). The potential of having cancer is often dismissed in never-smokers. This issue in diagnosis is often further compounded by the unusual presentation of these cancers. In Dr. Lim’s study, 52% of the never-smokers had nonspecific symptoms at diagnosis (cough in 34%, chest infections in 18%, he-

NSCLC Among Nonsmokers ■ Registries from the United Kingdom and the United States are showing that rates of NSCLC are rising among nonsmokers. ■ A study from the United Kingdom found that rates more than doubled between 2008 and 2014 (13% vs 28%). ■■ Three U.S. centers also documented an increase in lung cancer among nonsmokers, with the largest rise observed in the UT Southwestern cohort—from 8.9% for the period 1990 to 1995 to 19.5% during 2011 to 2013. The proportion of never smokers with NSCLC is increasing but not necessarily the incidence. ■ Rates appear highest among female nonsmokers.

moptysis in 11%), and 36% had no symptoms. Among the one-third of asymptomatic patients, about half of the lung cancers were an incidental finding on imaging. Most cancers were stage I at diagnosis, including 33% stage IA and 21% stage IB; 17% had advanced disease.

U.S. Study Details Dr. Pelosof and her team reviewed NSCLC cases identified in cancer registries at the UT Southwestern, Parkland Hospital in Dallas, and Vanderbilt University in Nashville—areas that represented a large, geographically and demographically diverse population, she noted. Investigators examined data from 1990 to 2013 and identified 10,593 patients with NSCLC and 1,510 with small cell lung cancer. The proportion of nonsmokers with NSCLC increased in all three registries, with the largest rise observed in the UT Southwestern cohort—from 8.9% for the period 1990 to 1995 to 19.5% during 2011 to 2013 (P < .0001). The results held true in a multivariate analysis that controlled for age and gender (P < .0001), she added. “The proportion of never-smokers with NSCLC is increasing, but not necessarily the incidence,” Dr. Pelosof stressed. “The study definitely stresses the need for more research in this area.” The never-smokers with NSCLC were more likely to be female (65%) than males (P < .0001). Although the frequency of early-stage disease decreased over time, stage IV disease at diagnosis increased. This finding could indicate that the increased rate in nevcontinued on page 9

borderline statistical significance, Dr. Hirsch noted, commenting, “The data from a statistical point of view is not statistically significant. But is it clinically meaningful? I would say yes.” n

Disclosure: Drs. Herbst and Hirsch reported no potential conflicts of interest.

References 1. Herbst R, Redman MW, Kim ES, et al: A randomized, phase III study comparing carboplatin/paclitaxel or carboplatin/paclitaxel/bevacizumab with or without concurrent cetuximab in patients with advanced non-small cell lung cancer (NSCLC): SWOG S0819. 16th World Conference on

Lung Cancer. Abstract PLEN04.01. Presented September 9, 2015. 2. Hirsch FR, Boyle TA, Thatcher N, et al: EGFR IHC and FISH correlative analyses (SQUIRE trial): Necitumumab + gemcitabine-cisplatin vs gemcitabine-cisplatin in 1st-line squamous NSCLC. 16th World Conference on Lung Cancer. Abstract ORAL32.05. Presented September 9, 2015. 3. Thatcher N, Hirsch FR, Luft AV, et al: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial. Lancet Oncol 16:763-774, 2015.

ARE YOU TESTING FOR RAS ? Amgen is committed to the integration of RAS testing into routine clinical practice, which may help oncologists select an appropriate first-line treatment plan for their patients with mCRC.

KRAS and NRAS are part of the RAS family of oncogenes1

KRAS

EXON 2

NRAS

EXON 2

EXON 3 59

EXON 4 117 146

• A mutation on the RAS gene can continuously activate intracellular signaling, leading to increased cell growth and proliferation. The EGFR pathway is always “turned on,” and the cell keeps growing and dividing regardless of anti-EGFR therapy2 • Patients with mutant-type RAS tumors should not be treated with Vectibix®2 • In addition, in an exploratory subgroup analysis of Study 3,* overall survival was shorter in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone2

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

Important Safety Information WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. • In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• Vectibix® is not indicated for the treatment of patients with colorectal

cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as“RAS”.

• Retrospective subset analyses across several randomized clinical trials

were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR- related adverse reactions without clinical benefit from these agents.

• Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors

received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01–1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.

Important Safety Information (continued) • Progressively decreasing serum magnesium levels leading to severe

(grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of

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

• Severe

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

• Fatal

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

• In

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

• Exposure

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

• Keratitis

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

• In

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

with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). • NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate

in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As

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

• Advise patients of the need for adequate contraception in both males

and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

• Because

many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women

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

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

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

• In

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

Visit Vectibix.com to learn more

*A phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone.2 EGFR = epidermal growth factor receptor; mCRC = metastatic colorectal cancer; Q2W = every two weeks. References: 1. Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–1034. 2. Vectibix® (panitumumab) prescribing information, Amgen. Please see Brief Summary of full Prescribing Information on adjacent pages.

KING SIZE (6 pt condensed type) S:9.25”

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

VECT15CDLA0437_B_Vectibix_BS_9.25x13_v23_Mar2015_r11_MBS.indd 1

Study 1

SYSTEM ORGAN CLASS Preferred Term

Vectibix® Plus Best Supportive Care (N = 229)

Best Supportive Care (N = 234)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

1 (< 1)

EYE DISORDERS Growth of eyelashes

13 (6)

GASTROINTESTINAL DISORDERS Nausea

52 (23)

2 (< 1)

37 (16)

Diarrhea

49 (21)

4 (2)

26 (11)

Vomiting

43 (19)

6 (3)

28 (12)

Stomatitis

15 (7)

2 (< 1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue

60 (26)

10 (4)

34 (15)

Mucosal inflammation

15 (7)

1 (< 1)

2 (< 1)

57 (25)

4 (2)

7 (3)

INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea

41 (18)

12 (5)

30 (13)

Cough

34 (15)

1 (< 1)

17 (7)

Erythema

150 (66)

13 (6)

2 (< 1)

Pruritus

132 (58)

6 (3)

4 (2)

Acneiform dermatitis

131 (57)

17 (7)

2 (< 1)

Rash

51 (22)

3 (1)

2 (< 1)

Skin fissures

45 (20)

3 (1)

1 (< 1)

Exfoliative rash

41 (18)

4 (2)

Acne

31 (14)

3 (1)

Dry skin

23 (10)

Nail disorder

22 (10)

Skin exfoliation

21 (9)

2 (< 1)

Skin ulcer

13 (6)

1 (< 1)

8 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)]. In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix ®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®. Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3) Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

58 (18)

5 (2)

10 (3)

Diarrhea

201 (62)

59 (18)

169 (52)

29 (9)

Stomatitis

87 (27)

15 (5)

42 (13)

1 (< 1)

EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation

82 (25)

14 (4)

53 (16)

1 (< 1)

Asthenia

79 (25)

16 (5)

62 (19)

11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

Anorexia

116 (36)

14 (4)

85 (26)

6 (2)

INFECTIONS AND INFESTATIONS Paronychia

Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1)

24 (7)

1 (< 1)

10 (3) 4 (1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1)

30 (9)

4 (1)

9 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix ® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix ®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Hypomagnesemia

96 (30)

21 (7)

26 (8)

1 (< 1)

Hypokalemia

68 (21)

32 (10)

42 (13)

15 (5)

Dehydration

26 (8)

8 (2)

10 (3)

5 (2)

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

46 (14)

30 (9)

This brief summary is based on the Vectibix ® Prescribing Information v23, 03/15. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2015 Amgen Inc. All rights reserved. v23 03/15

4/27/15 6:12 PM

S:13”

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS ” [see Indications and Usage (1.1), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage (1.1), and Clinical Pharmacology (12.1)]. Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone [see Indications and Usage (1.1)]. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.1) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)]

• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

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World Conference on Lung Cancer Thoracic Cancer

Nivolumab in Lung Cancer Supported by Updated Trial Data By Caroline Helwick

or the treatment of advanced squamous non–small cell lung cancer (NSCLC), the programmed cell death protein 1 (PD-1) antibody nivolumab (Opdivo) continues to show results in key trials that now report 18-month data. The updates were reported at the 16th World Conference on Lung Cancer in Denver, Colorado. In another trial reported at this meeting, CheckMate 012, the combination of nivolumab plus ipilimumab (Yervoy) showed encouraging activity and less-than-expected toxicity. (The study results were reported in the September 25 issue of The ASCO Post.) Squamous cell histology constitutes about 20% of NSCLC cases, heralds a poor prognosis, and has few effective treatment options. Second-line docetaxel typically extends survival 6 to 8 months, speakers said at the meeting. The immune checkpoint inhibitor nivolumab has demonstrated activity in both squamous and nonsquamous NSCLC. It is now approved by the U.S. Food and Drug Administration for patients with squamous NSCLC that progresses during or after platinumbased chemotherapy.

CheckMate 017 at 18 Months In the 18-month follow-up of the phase III CheckMate 017 trial, involving 272 previously treated patients with advanced squamous NSCLC, nivolumab improved overall survival from 6.0 months with docetaxel to 9.2 months; this represented a 38% reduction in death that was highly significant (P = .0004), reported K aren Reckamp, MD, of City of Hope Comprehensive Cancer Center, Duarte, California.1 “The study shows an

Lung Cancer in Nonsmokers continued from page 5

er-smokers is not the result of more incidental findings of early-stage disease.

What Can Be Done? Early detection is important but challenging in this population, Dr. Lim noted. “Clearly, it is not going to be costeffective to screen the entire population of nonsmokers for lung cancer,” he pointed out. The group lacks risk factors that would target them for screening. Congress Co-Chair Everett Vokes, MD, the John Ultmann Professor and Chair of the Department of Medicine at

unprecedented overall survival at 18 months—28%,” she noted. “The nivolumab benefit was independent of PD-L1 [ligand of PD-1] expression and was seen across all predefined clinical subgroups,” Dr. Reckamp added. “The safety profile of nivolumab continues to be favorable

vored across all prespecified subgroups, including age, geographic location, performance status, and prior therapy. “Moreover, the survival benefit was independent of PD-L1 expression,” noted Dr. Reckamp. Patients treated with nivolumab had substantially fewer treatment-

The nivolumab benefit was independent of PD-L1 expression and was seen across all predefined clinical subgroups. —Karen Reckamp, MD

vs docetaxel and consistent with prior studies.” The majority of patients who developed treatment-related adverse events on nivolumab did so within the first 3 months, she said. At the 2015 ASCO Annual Meeting, preliminary results from the trial showed a 1-year survival of 42% with nivolumab, vs 24% with docetaxel, and a median progression-free survival of 9.2 vs 6.0 months, respectively.2 The objective response rate was 20% vs 9% (P = .0083), for the nivolumab vs docetaxel arms, respectively. Longer follow-up has confirmed the superiority of nivolumab over docetaxel, including the primary endpoint of median overall survival. At 18 months, the overall survival rate was 28% vs 13%; the progression-free survival rate was 17% vs 2.7%; the median progression-free survival was 3.5 vs 2.8 months (P = .0008). The anti–PD-1 antibody was fathe University of Chicago, moderated a press briefing where the results were presented. He noted that the reasons for the increase in NSCLC among nonsmokers are unknown. “What is causing that rise is very speculative at this point,” Dr. Vokes said. “Secondhand smoke exposure still exists and may also have occurred many years ago. Radon is still around, but that wouldn’t necessarily explain an increase because radon exposure is likely remaining constant or decreasing in homes. Then there are factors related to small particles and carcinogens in air pollution that we don’t understand enough.”

related adverse events, including any adverse event (59% vs 87%), grade 3–5 adverse events (8% vs 58%), and adverse events leading to treatment discontinuation (5% vs 10%). No treatment-related deaths occurred in the nivolumab arm, compared with 2% of docetaxel patients.

Similar Findings From CheckMate 063 Updated analysis of the phase II, single-arm CheckMate 063 trial were reported by Leora Horn, MD, of Vanderbilt-Ingram Cancer Center, Nashville.3 The study involved 117 patients with advanced/metastatic squamous NSCLC that had progressed after at least two prior therapies; 65% of patients had received at least three prior therapies. The primary endpoint, objective response, was observed in 15% of patients, three-quarters of which were “If the overall incidence of lung cancer is going down, which it likely will as smoking habits change, at least in this country, then proportions might change as non–smoking-related lung cancers rise,” he said. “Historical perspectives on this are not easy because genetic analyses of tumors and current complex computational analyses are new. Mutation analysis was introduced in the past 10 years, so the data are emerging.” n Disclosure: Dr. Lim disclosed relevant relationships with Strategen, Abbott Molecular, GlaxoSmithKline, Pfizer, Novartis, Covidien, Ethicon, Roche, Imidex, Eli Lilly, Medella Health, Boehringer Ingelheim, ScreenCell, Informative

ongoing at analysis. Responses were observed across all predefined subgroups, including age, number of prior therapies, performance status, and level of PD-L1 expression, Dr. Horn reported. The median time to response was 3.3 months, and the median duration of response has yet to be reached (range, 1.9–11.5 months). Median progression-free survival in this heavily pretreated population was 1.9 months, with a 1-year progression-free survival of 20%. Survival data at 18 months included a median overall survival of 8.1 months, 1-year overall survival rate of 39%, and 18-month survival rate of 27%. Grade 3–4 adverse events occurred in 17% of patients. As in CheckMate 017, clinical benefit with nivolumab was observed independently of PD-L1 expression in CheckMate 063.

Nivolumab in a ‘Real-Life’ Setting Maen Hussein, MD, of Florida Cancer Specialists, Lady Lake, Florida, provided data from CA209-153, a largely community-based cancer center trial of 824 previously treated patients with advanced/metastatic squamous and nonsquamous NSCLC.4 Responses were observed in 12% of patients, and 44% achieved stable disease. Grade 3–5 treatment-related adverse events were observed in 8%, and only 2% of patients discontinued treatment as a result. “Safety analyses are consistent with our prior nivolumab study experience, and no new safety signals have been identified in this trial…. We showed continued on page 10

Genomics, and the BUPA Cromwell Lung Cancer Screening Programme. Drs. Pelosof and Vokes reported no potential conflicts of interest.

References 1. Proli C, Cufari ME, Phull H, et al: Increasing incidence of non-smoking lung cancer: Presentation of patients with early disease to a tertiary institution in the UK. 16th World Conference on Lung Cancer. Abstract ORAL24.03. Presented September 8, 2015. 2. Pelosof L, Ahn C, Horn L, et al: Increasing incidence of never smokers in non small cell lung cancer patients. 16th World Conference on Lung Cancer. Abstract ORAL22.01. Presented September 8, 2015.

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World Conference on Lung Cancer Updated Nivolumab Data continued from page 9

that nivolumab is actually safe to give in community research sites,” Dr. Hussein said. The study aimed to determine whether patients with a poor performance status suffered more on the drug, and the results were encouraging. The

frequency of treatment-related serious adverse events and select adverse events of interest was similar between patients with an Eastern Cooperative Oncology Group performance status of between 0 and 1 and those with a performance status of 2, he reported. “Early data [median follow-up of 10.4 weeks] from this large multi-

center trial suggest that patients with pretreated advanced NSCLC experience clinical benefit from nivolumab therapy regardless of histology type, performance status, EGFR/ALK mutation status, or number of prior therapies,” he said. “Interestingly, we saw responses in patients with EGFR or ALK muta-

tions, and this has not previously been seen.… We also still saw responses in patients with low PD-L1 expression,” concluded Dr. Hussein. n

Disclosure: Dr. Reckamp has received research funding from Bristol-Myers Squibb. Dr. Horn disclosed relationships with BristolMyers Squibb, Xcovery, Genentech, Merck, and AstraZeneca. Dr. Hussein is on the speakers bureau for Bristol-Myers Squibb.

Nivolumab in Squamous NSCLC ■■ Updates of key studies of the anti–PD-1 agent nivolumab were presented at the 16th World Lung Cancer Conference. ■■ Studies confirmed the safety and activity of nivolumab as a single agent in advanced/metastatic disease. ■■ CheckMate 017 found a 38% reduction in mortality (P = .0004) in the 18-month analysis; median overall survival was 9.2 months, vs 6.0 months with docetaxel. ■■ CheckMate 063, in more heavily pretreated patients, found a median overall survival of 8.1 months and an 18-month survival rate of 27%.

Don't Miss This Important Commentary

Solange Peters, MD, PhD, discusses the role of nivolumab in squamous cell non–small cell lung cancer. See pages 12-13, in this issue.

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World Conference on Lung Cancer References 1. Reckamp K, Spigel DR, Rizvi NA, et al: Phase 3 randomized trial (CheckMate 017) of nivolumab vs docetaxel in advanced squamous cell non-small cell lung cancer. 16th World Conference on Lung Cancer. Abstract ORAL02.01. Presented September 7, 2015. 2. Brahmer J, Reckamp KL, Baas P, et al:

Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123-135, 2015. 3. Horn L, Rizvi NA, Mazières J, et al: Longer-term follow-up of a phase 2 study (CheckMate 063) of nivolumab in patients with advanced, refractory squamous non-small cell lung cancer. 16th World Conference on Lung Cancer. Ab-

stract ORAL02.03. Presented September 7, 2015. 4. Hussein M, McCleod M, Chandler J, et al: Safety and efficacy of nivolumab in an ongoing trial of a PD-L1+/- patient population with metastatic non-small cell lung cancer. 16th World Conference on Lung Cancer. Abstract ORAL02.02. Presented September 7, 2015.

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World Conference on Lung Cancer EXPERT POINT OF VIEW

olange Peters, MD, PhD, of the Lausanne University Hospital, Switzerland, put these updates in context of what is known about programmed cell death protein 1 (PD1) antibodies in non–small cell lung

cancer (NSCLC), concluding that nivolumab (Opdivo) is “one of the best options” for advanced/metastatic disease. The CheckMate 017 and CheckMate 063 “tails of the curve” are consistent and suggest that long-

term survival may be achievable in at least one-quarter of patients, she noted. “In the past 15 years, there have been a number of randomized phase III trials challenging docetaxel as the

standard of care.… Some have been positive,” added Dr. Peters. These trials showed, in unselected squamous cell populations, median overall survival of 7.9 months with afatinib (Gilotrif), 6.8 months with

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World Conference on Lung Cancer erlotinib, 6.3 months with docetaxel alone, and 9.5 months with docetaxel plus ramucirumab (Cyramza). Nivolumab as a single agent yielded a median survival of 9.2 months in unselected patients, with much better tolerability than docetaxel, she pointed out.

“I can conclude two things,” stated Dr. Peters. “One is that nivolumab represents one of the best options you have for second-line treatment. Second is that unselected squamous cell cancer of the lung remains a disease characterized by a high unmet medical need.”

The community-based study also showed that “the elderly, PS2 [performance status of 2], pretreated patients, regardless of histology, can benefit from nivolumab, and with a similar safety profile,” she said, adding that it will be important to see patientrelated outcome data.

Search for the Right Biomarker The pressing question, Dr. Peters continued, is whether PD-L1 (ligand of PD-1) expression is the right biomarker for nivolumab. Other options to be considered include tumor mutational load, presence of tumor-infiltrating lymphocytes, and tumor molecular characteristics.

Solange Peters, MD, PhD

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Moreover, she emphasized that PD-L1 positivity is “a flexible concept” that depends on sampling, assays, interpretation, and more. The survival benefit with nivolumab has been independent of its expression in squamous cell cancers, she said. Dr. Peters suggested that immunotherapy must induce a T-cell response, and this may be more likely when PD-1 antibodies are combined with other immunotherapy strategies. Even then, patient selection may be a pipe dream. “Are we ready to select patients for these treatments?” she asked. “The complexity of immune surveillance and escape might prevent us from identifying a simple and unique predictive biomarker.” n Disclosure: Dr. Peters reported relationships with Bristol-Myers Squibb, F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer, Boehringer-Ingelheim, DaiichiSankyo, Morphotek, Merrimack, Merck Sharp and Dohme, and Merck Serono.

European Cancer Congress 2015 Watch for coverage from Vienna of the European Cancer Congress in The ASCO Post.

The ASCO Post | OCTOBER 10, 2015

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Best of ASCO® Survivorship

Patient and Survivor Care Studies Yield Useful Results to Improve Quality of Life By Charlotte Bath

ecent studies have yielded useful results that clinicians can put into practice, some right now, to help improve the quality of life for patients with cancer. Concerns addressed included cachexia, pain, “chemobrain,” and fertility preservation. At the Best of ASCO®/ Chicago meeting, Arif Kamal, MD, MHS, of Duke University, Durham, North Carolina, summarized the major findings from key patient and survivor studies presented at the 2015 ASCO Annual Meeting.

Stemming the Cachexia Cascade The first two studies presented found that anamorelin, an orally active ghrelin receptor agonist, increased lean body mass among patients with inoperable stage III or IV advanced non–small cell lung cancer (NSCLC) and cachexia.1 This is “an outcome of importance,” Dr. Kamal said, because loss of lean body mass among patients with advanced cancer often “leads to a cascade of events,” including reduced physical functioning and quality of life for these patients and “reduces our ability to give them chemotherapy that extends their lives or improves their lives.” There are “very few therapeutic options to stop this cascade when it goes into effect,” he added.

tients assigned to anamorelin also had a significant increase in body weight (2.2 vs 0.14 kg, P < .001 in ROMANA 1) and (0.95 vs –0.57 kg, P < .001) in ROMANA 2) and improvement in their anorexia/cachexia symptoms (4.12 vs 1.92, P < .001 in ROMANA 1) and (3.48 vs 1.34, P = .002 in ROMANA 2). There was no difference in handgrip strength, used as a surrogate measurement of physical function and one of the co-primary efficacy endpoints of the study. “There was no immediate change in survival or difference in survival seen,” Dr. Kamal noted, “but the extension study is ongoing, and that will be an important outcome.” Anamorelin was well tolerated, although there was a “slight increase” in nausea, Dr. Kamal noted. The most frequent drug-related adverse events were hyperglycemia and diabetes. (Clinical trial information: NCT01387269 and NCT01387282)

Less Frequent Dosing of Zoledronic Acid Administering zoledronic acid every 3 months is just as good as every month for reducing bone pain and skeletalrelated events in patients with bone metastases, according to a phase III Alliance study.2

Chemotherapy-related cognitive impairment affects many—and some say most—patients during the time they receive chemotherapy and for up to one-third of patients afterward. —Arif Kamal, MD, MHS

A total of 979 patients in the two studies (ROMANA 1 and 2) were randomly assigned to anamorelin at 100 mg orally once daily or placebo. The patients were mostly male, over 60 years old, weighed between 60 and 70 kg, and were predominantly white. Most patients were receiving concomitant platinum-based doublet therapy. After 12 weeks, patients receiving anamorelin had an increase in lean body mass, 1.10 vs –0.44 kg for those receiving placebo (P < 0.001) in ROMANA 1 and 0.75 vs –0.96 kg for those receiving placebo (P < .001) in ROMANA 2. Pa-

“This is not the first trial to look at this issue,” Dr. Kamal said, “but what makes this trial unique is that it is not limited to specific populations” with a single type of cancer but included patients with breast and prostate cancer, as well as multiple myeloma. “This is the first time that a plasma cell disorder has been included in one of these trials,” Dr. Kamal noted. The 1,822 study participants included 833 with breast cancer, 674 with prostate cancer, and 270 with myeloma. The mean age of the patients was 65 years old. Patients were required to have creatinine clearance ≥ 30 mL/min, and

Clinical Implications of Survivorship Study Findings

ased on study findings presented at the 2015 ASCO Annual Meeting, Arif Kamal, MD, MHS, of Duke University, Durham, North Carolina, listed six points for clinicians to consider that could change practice now or in the near future for cancer survivors. 1. “Drugs for cancer cachexia are on their way,” Dr. Kamal noted. “This is really exciting, because it gives us a new target to improve performance status of patients with supportive care drugs.” 2. “Zoledronic acid every 3 months is noninferior to once a month. It will be interesting to see how many people are actually changdose adjustments were based on calculated creatinine clearance. The mean creatinine clearance at baseline was 91 mL/min. All patients were encouraged to take calcium and vitamin D. The noninferiority trial randomized 911 patients to each of the two dosage groups from the beginning of the trial. Over the 24 months of the study, those in the monthly dosing group received a median total zoledronic acid dose of 56 mg, and those in the every-3-month group received a median total dose of 24 mg. This was less than a threefold difference due to more delays in the monthly dosing group, 62% vs 37% in the every-3-month group. Skeletal-related events occurred among 29.5% of patients receiving zoledronic acid monthly vs 28.6% of those receiving it every 3 months, demonstrating noninferiority. “This matches conclusions seen in the other trials regarding noninferiority of the administration of zoledronic acid from once a month to once every 3 months,” Dr. Kamal observed. “Optimal dosing has not yet been determined,” Dr. Kamal said. (Clinical trial information: NCT00869206)

The Effects of ‘Chemobrain’ “Chemotherapy-related cognitive impairment affects many—and some

ing their practice.” 3. Chemobrain has been validated as a multidomain clinical entity and should not be just “brushed off.” Oncologists should listen to and validate patients’ concerns about chemotherapy-related cognitive impairment. 4. “Children are less likely than ever before to die of cancer but have significant health morbidities,” Dr. Kamal noted. Modifying therapy for childhood cancer may reduce the occurrence of late effects and late mortality. 5. “My recommendation is to get rid of the neutropenic diet unless someone can show me a study that it does anything at all,” Dr. Kamal stated. 6. “Try some menthol” to prevent chemotherapy-induced neurotoxicity. say most—patients during the time they receive chemotherapy and for up to one-third of patients afterward,” Dr. Kamal reported. “Chemotherapy-related cognitive impairment is not one clinical entity,” he added, but impacts multiple domains, including executive function, memory, concentration, and attention. Using “an extensive battery of neuropsychological assessments of executive function, as well as blood collection to look at biomarkers,” as Dr. Kamal noted, researchers compared 366 women with nonmetastatic breast cancer with an equal number of controls.3 Exclusion criteria included neurodegenerative disease or any primary central nervous system disease/disorder. The mean age of patients was 52 years, and most were white. At the time of recruitment, the patients with breast cancer had not yet received any chemotherapy but were about to start. Within 1 week of starting chemotherapy and 4 weeks post chemotherapy, these patients underwent psychological testing in several domains, including executive function, verbal, memory, language, and learning. The patients also completed cognition self-reports. “This is a large study, certainly for this type of research,” Dr. Kamal said. continued on page 19

DID YOU KNOW? FOR NEARLY 15 YEARS (1999-2014), NO FDAAPPROVED, SECOND-LINE REGIMEN EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF PATIENTS WITH METASTATIC NSCLC1-4

NSCLC=non-small cell lung cancer.

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

ADVANCING THE SECOND-LINE TREATMENT OF METASTATIC NSCLC5 CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.5

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

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

• Serious, sometimes fatal, ATEs including myocardial infarction, cardiac

arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension

• An increased incidence of severe hypertension occurred in patients

receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue

CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs. Gastrointestinal Perforations

• CYRAMZA is an antiangiogenic therapy that can increase the risk of

gastrointestinal perforation, a potentially fatal event. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

• Impaired wound healing can occur with antibodies inhibiting the VEGF

pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis

• Clinical deterioration, manifested by new onset or worsening

encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

• RPLS has been reported at a rate of <0.1% in clinical studies with

CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

• Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio

for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

CYRAMZA plus docetaxel demonstrated a statistically significant improvement in overall survival vs docetaxel5 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

10.5

15% INCREASE IN MEDIAN OS

MONTHS

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

527

415

329

231

156

103

501

386

306

197

129

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)5 • Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively • ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progression-free survival; ORR=objective response rate. *Intent-to-treat population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.6 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253) The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.5 Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction

• Monitor thyroid function during treatment with CYRAMZA.

Embryofetal Toxicity

• Based on its mechanism of action, CYRAMZA can cause fetal harm

when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions

• The most commonly reported adverse reactions (all grades; grade 3/4)

occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/ mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

• The most common serious adverse events with CYRAMZA plus docetaxel

in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

• In patients ≥65 years of age, there were 18 (8%) deaths on treatment

or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

• Treatment discontinuation due to adverse reactions occurred more

frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

• For patients with nonsquamous histology, the overall incidence of

pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and

the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. • Clinically relevant adverse reactions reported in ≥1% and <5% of

CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions

• No pharmacokinetic interactions were observed between ramucirumab

and docetaxel.

Use in Specific Populations

• Pregnancy: Based on its mechanism of action, CYRAMZA can cause

fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

• Lactation: Because of the potential risk for serious adverse reactions in

nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

• Females of Reproductive Potential: Advise females of reproductive potential

that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page. RB-L HCP ISI 24APR2015 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/fda-docetaxel/print. Accessed August 26, 2014. 4. National Cancer Institute. Cancer drug information. FDA approval for ramucirumab. http://www.cancer.gov/ cancertopics/treatment/drugs/fda-ramucirumab#nsclc. Accessed May 4, 2015. 5. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 6. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. RB96549 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved. CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications. INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients. Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intratumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxeltreated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3. Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 CYRAMZA plus docetaxel Placebo plus docetaxel (N=627) (N=618) Adverse Reactions (MedDRA) System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10 Neutropenia 55 49 46 40 Thrombocytopenia 13 3 5 <1 Gastrointestinal Disorders Stomatitis/Mucosal inflammation 37 7 19 2 Eye Disorders Lacrimation increased 13 <1 5 0 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1 Vascular Disorders Hypertension 11 6 5 2 Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity. Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information. PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event. • Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment. • Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. Additional information can be found at www.CYRAMZAhcp.com.

RB-L HCP BS 04MAY2015

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Best of ASCO® Survivor Care Studies continued from page 14

Comparing patients before and after chemotherapy showed “across-theboard” changes in cognition, he added, with patients performing worse on all neuropsychological measures than controls. The largest effects were seen on the cognition self-report. Increased cognitive impairment was associated with increases in inflammatory biomarkers, with statistically significant increases in MCP-1 and interleukin-1 beta. This supports the hypothesis that inflammation mediates chemotherapy-induced cognitive impairment. “We often have patients come and talk to us about the changes they are having in cognitive function, and although we inherently know this to be true, there is very little, or not enough, evidence to demonstrate that this is a measurable thing,” Dr. Kamal noted. “I think it is important that as oncologists we not only listen to our patients, but validate their concerns” with data from this and other studies. (Clinical trial information: NCI UG1CA18996, K07CA168886)

Reducing Late Mortality in Childhood Cancer An update of the Childhood Cancer Survivor Study found that modifying therapy for childhood cancer to reduce the occurrence of late effects has resulted in a significant reduction in late mortality, including cardiac and pulmonary deaths.4 Although recurrence of cancer is the most common cause of death initially, deaths due to other causes increase over time. “When we look at cause-specific late mortality among these survivors, there is a plateau that occurs over time in terms of having a recurrence or progression of that primary cancer,” Dr. Kamal noted. “As we reach that plateau,” he said, there are other health and treatment-related issues “that we need to keep an eye on.” Overall childhood cancer survival “has been improving decade by decade,” Dr. Kamal said, and there are now an estimated half a million survivors of childhood cancer. (The updated study was reported in the July 10 issue of The ASCO Post.) Dr. Kamal pointed to trends in cancer-related therapy over time. For example, the use of radiation has declined from the 1970s through the 1990s. During that same period, the percentage of patients receiving anthracyclines increased, but the total cumulative doses

decreased. “We are getting a little more intelligent in how we are using our doses,” Dr. Kamal revealed.

Fertility Preservation Results from a study among women aged 24 to 45 with stage I to III breast cancer “essentially confirmed the safety of concurrent aromatase inhibitor and ovarian stimulation” to preserve fertility, Dr. Kamal stated. The study found that controlled ovarian stimulation with letrozole supplementation “is unlikely to cause substantially increased recurrence risk in breast cancer, even in the presence of BRCA gene mutations, and it results in the preservation of fertility in a majority of women.”5 There were no differences in survival whether a woman had or did not have BRCA mutations or received such treatment before or after breast surgery. Among 337 women, who enrolled in the study during fertility preservation consultation before chemotherapy, 120 elected to undergo ovarian stimulation with letrozole prior to chemotherapy; the remaining 217 served as controls. Those choosing ovarian stimulation with letrozole for fertility preservation were younger and had less frequent lymph node involvement. At a mean follow-up after diagnosis of 4.9 years for those in the ovarian stimulation with letrozole group and 6.2 years for the controls, the hazard ratio for recurrence among women choosing ovarian stimulation with letrozole was 0.77, and survival was not compromised compared with controls (P = .61). “Neither BRCA gene mutation status (P = .18) nor undergoing fertility preservation before breast surgery (P = .56) affected survival,” the authors reported. “Likewise, none of the tumor characteristics including the receptor status affected survival.” Among the 33 women attempting pregnancy with frozen embryos (15 using a gestational carrier), 17 had at least one child. The fertility preservation rate was 51.5%, and the live birth/embryo transfer rate was 45.0%. “The live birth rate was similar to an age-matched control group from a national in vitro fertilization database,” the researchers reported. “There were no recurrences among women who conceived.” (The data on pregnancy and birth were recently published in the Journal of Clinical Oncology.6) Based on the study results, the authors advocated making ovarian stimulation with letrozole more widely continued on page 20

The ASCO Post | OCTOBER 10, 2015

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Best of ASCO® Survivor Care Studies continued from page 20

available for young women with breast cancer, even before undergoing breast surgery. (Clinical trial information: NCT00504699)

‘Let Them Eat Fruit’ Do so-called neutropenic diets, which restrict fresh raw fruits, raw vegetables, raw meat, or soft cheeses, reduce the risk of infection for patients with cancer being treated with chemotherapy? A meta-analysis to determine whether a neutropenic diet was more effective than a regular diet of foods prepared within standardized U.S. Food and Drug Administration food safety guidelines identified four studies comparing regular and neutropenic diets.7 The three randomized trials and one observational study encompassed 918 patients with cancer or stem cell transplants. The primary outcomes were mortality of any cause, major infections (pneumonia, bacteremia, fungemia, or pneumonia accompanied with bacteremia or fungemia), and the composite outcome of neutropenic fever or major infections as defined here, minor infections, or fever. “What they found was really no change in the major infection rate with the neutropenic diet. Additionally, the risk of mortality was no different on a neutropenic diet,” Dr. Kamal said. “These results persisted after omitting the observational study from analysis,” the investigators noted. Analyzing the composite outcome of any infection or fever “found a slightly potentially increased risk” with the neutropenic diet,” Dr. Kamal added.

The results of the meta-analysis matched the results of the individual studies, Dr. Kamal noted. “For all of us who see these patients on the hospital side, this is an important piece of evidence that is starting to put this issue to rest—the folklore around the neutropenic diet is disproven. I would say let them eat fruit if they want to.” The study authors called for larger randomized controlled studies. However, “In the meantime, it may be time to relax the restrictions of the neutropenic diet to attain better nutrition.”

Menthol May Be Worth Trying Topical menthol can be useful for preventing chemotherapy-induced neurotoxicity, according to a phase II open-label study of patients with colorectal cancer being treated with regimens that include oxaliplatin.8 This is a follow-up to a phase II study finding that menthol reduced existing chemotherapy-induced neurotoxicity in 75% of patients. Derived from mint leaves, menthol “functions as an agonist of transient receptor potential melastatin-8 (TRPM8). TRPM-8 is distributed in peripheral nerves and has been shown to be associated with cold hypersensitivity, noxious cold and sensory disturbance. It is also related to the occurrence of chemotherapy-induced neurotoxicity,” the investigators explained. In this preventive phase II study, patients applied 1% topical menthol twice daily to their hands and feet from the start of regimens containing oxaliplatin. “This is a single layer, about ¼-inch thick,” of an over-the-counter preparation,” Dr. Kamal explained.

The study included 32 patients with colorectal cancer starting oxaliplatincontaining regimens: 22 in the adjuvant setting and 10 in the metastatic setting. The treatment regimens included capecitabine (Xeloda) and oxaliplatin (CapeOx), CapeOx plus bevacizumab (Avastin); and FOLFOX (folinic acid, fluorouracil, oxaliplatin) plus cetuximab (Erbitux). Eight patients terminated or changed their chemotherapy regimens before reaching a cumulative oxaliplatin dose of 500 mg/m2, which is reported to cause grade 2+ chemotherapy-induced neurotoxicity, and were excluded from analysis. Among those assessed, the frequency of grade 2 chemotherapy-induced neurotoxicity was 12.5% at the cumulative oxaliplatin dose of 500 mg/m2. “This was significantly lower than the expectation value (25%),” the authors stated. No adverse events were reported from menthol application. Dr. Kamal said that the reduction in grade 2 peripheral neurotoxicity means “overthe-counter menthol may be worth trying.”(Clinical trial information: UMIN000009655) n Disclosure: Dr. Kamal reported no potential conflicts of interest.

References 1. Temel JS, Currow DC, Fearon K, et al: Phase III trials of anamorelin in patients with advanced non-small cell lung cancer and cachexia (ROMANA 1 and 2). 2015 ASCO Annual Meeting. Abstract 9500. Presented June 1, 2015. 2. Himelstein AL, Qin R, Novotny PJ, et al: CALGB 70604 (Alliance): A randomized phase III study of standard dosing vs longer interval dosing of zoledronic acid

in metastatic cancer. 2015 ASCO Annual Meeting. Abstract 9501. Presented June 1, 2015. 3. Janelsins MC, Yao S, Mustian KM, et al: Chemotherapy-related cognitive impairment, and neurotransmitter signaling, longevity, and inflammation pathways in 366 breast cancer patients and 366 age-matched cancer-free controls: A prospective, nationwide, longitudinal URCC NCORP study. 2015 ASCO Annual Meeting. Abstract 9503. Presented June 1, 2015. 4. Armstrong GT, Yasui Y, Chen Y, et al: Reduction in late mortality among 5-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. 2015 ASCO Annual Meeting. Abstract LBA2. Presented May 31, 2015. 5. Oktay K, Turan V, Kim J: Long-term safety of fertility preservation by ovarian stimulation and concurrent aromatase inhibitor treatment in women with breast cancer. 2015 ASCO Annual Meeting. Abstract 9521. Presented May 30, 2015. 6. Oktay K, Turan V, Bedoschi G, et al: Fertility preservation success subsequent to concurrent aromatase inhibitor treatment and ovarian stimulation in women with breast cancer. J Clin Oncol 33:2424-2429, 2015. 7. Sonbol MB, Firwana B, Diab M, Witzig TE: Evaluating the effect of neutropenic diet on infection and mortality rate in cancer patients: A meta-analysis. 2015 ASCO Annual Meeting. Abstract 9619. Presented May 29, 2015. 8. Nakamura K, Nakamura M, Onikubo T, et al: Phase II study of preventive effect of topical menthol for chemotherapy-induced peripheral neurotoxicity. 2015 ASCO Annual Meeting. Abstract 9610. Presented May 29, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Steven A. Narod, MD, FRCPC, on Increased Risk of Death in Ductal Carcinoma in Situ see page 46

Julie M. Vose, MD, MBA, FASCO, on CMS Payment Policy see page 57

Antonio Ribas, MD, on Pebrolizumab in IpilimumabRefractory Advanced Melanoma see page 59

Chandrakanth Are, MBBS, MBA, FRCS, FACS, on Global Cancer Burden see page 66

Jamie H. Von Roenn, MD, on Managing Cancer-Related Pain see page 72

Laurence J. Heifetz, MD, on Cancer Care in Rural Areas see page 78

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | OCTOBER 10, 2015

PAGE 21

In the News

MMRF Announces Enrollment Completion of CoMMpass StudySM

he Multiple Myeloma Research Foundation (MMRF) announced that the MMRF CoMMpass StudySM, the most comprehensive long-term genomic study ever conducted in myeloma, has reached full enrollment, with 1,000 patients now participating. The

ment of Hematology and Medical Oncology and Chief Medical Officer at the Winship Cancer Institute of Emory University. “In fact, the MMRF C oMMpass Study will provide one of the most comprehensive clinical-genomic

Study Process

The MMRF CoMMpass Study will provide one of the most comprehensive clinical-genomic maps of any cancer. —Sagar Lonial, MD, FACP

global study is mapping the genomic profile of each enrolled patient with multiple myeloma in order to advance the understanding of disease progression, including patient response to therapies, and offering insights for the development of personalized treatments that target the underlying disease biology to lead to cures. “The promise of precision medicine and our ability to find a cure for multiple myeloma are reliant on big data and patient engagement. When it comes to a rare disease like multiple myeloma, achieving those numbers requires a significant degree of participation from the patient population, making the MMRF CoMMpass Study enrollment a tremendous milestone for the future of research in this area,” said MMRF CoMMpass Study Principal Investigator Sagar Lonial, MD, FACP, Professor and Executive Vice Chair in the Depart-

decisions for their patients through data that show which individual and combined therapies work based on a specific profile and will also help us identify mutations. This deep understanding ultimately leads to better, more precise care, as well as the promise of a cure.”

maps of any cancer,” he continued. “Beyond identifying novel biomarkers and therapeutic targets, the results will help physicians make more informed and customized treatment

In the study, each participating patient provides bone marrow samples when diagnosed and when they experience a change in their condition over the course of their disease progression. DNA sequencing then allows researchers to track how multiple myeloma progresses for each individual patient for at least 8 years, specifically analyzing how the disease is evolving, reacting to treatment, and changing over time. These data enable researchers to better understand the basis of the dis-

Kathy Giusti, Founder of and Executive Chairman of the Multiple Myeloma Research Foundation (MMRF) and the Multiple Myeloma Research Consortium (MMRC), was pleased to announce the recent completion of accrual of 1,000 patients to the MMRF CoMMpass Trial.

ease and, in turn, make multiple myeloma treatments more tailored for each patient. Outputs from the study are accessible publically through the MMRF Researcher Gateway to help advance investigations and, ultimately, clinical developments. “This critical milestone for the MMRF CoMMpass Study reflects our continued mission to advance precision medicine and accelerate breakthroughs for patients with myeloma and all can-

Walter M. Capone

cers,” said Walter M. Capone, CEO and President of the MMRF. “We extend our heartfelt gratitude to each patient in this study as their continued participation will help decode this devastating disease and usher in a new era of more precise and individualized treatments for multiple myeloma and other cancers, leading to cures. Additionally, the MMRF CoMMpass Study would not have been possible without the collective vision and support of researchers from the more than 100 collaborating centers and our pharmaceutical company and research institution partners, who are making this 8-year initiative a reality.” Visit www.themmrf.org/researchpartners/the-commpass-study to learn more about the study. n

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The ASCO Post | OCTOBER 10, 2015

FDA Update

FDA Approves New Oral Medication for the Treatment of Refractory Metastatic Colorectal Cancer

he U.S. Food and Drug Administration (FDA) has approved trifluridine/tipiracil (Lonsurf) for patients with metastatic colorectal cancer who have been previously treated with chemotherapy and biologic therapy and are no longer responding to treatment.

Mechanism of Action

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The new oral agent is a combination of trifluridine and tipiracil hydrochloride. Trifluridine is the active component of the combination and is directly incorporated into DNA, leading to DNA dysfunction. However, when trifluridine is taken orally it is largely degraded to an inactive form. Tipiracil hydrochloride prevents the degradation of trifluridine. “The past decade has brought a new understanding around colorectal cancer, in how we can both detect and treat this often devastating disease,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “But there are many patients who still need additional options, and [this recent] approval is a testament to the FDA’s commitment to work with companies to develop new drugs in disease areas where unmet needs remain.”

Study Details The efficacy and safety of trifluridine/ tipiracil were evaluated in an international, randomized, double-blind study involving 800 patients with previously treated metastatic colorectal cancer.1 Study participants received trifluridine/tipiracil plus best supportive care, or placebo plus best supportive care until their disease worsened or side effects became intolerable. The primary endpoint of the study was overall survival and the secondary endpoint was progression-free survival. Patients treated with trifluridine/tipiracil lived an average of 7.1 months compared to 5.3 months for those treated with placebo. On average, the time to disease progression was 2 months for patients on trifluridine/tipiracil compared to 1.7 months for patients receiving placebo.

Safety and Toxicity The most common side effects of treatment with trifluridine/tipiracil are anemia, neutropenia or thrombocytopenia, physical weakness, fatigue, nau-

sea, decreased appetite, diarrhea, vomiting, abdominal pain, and fever. The FDA recommends that healthcare providers obtain complete blood counts prior to starting each treatment cycle of trifluridine/tipiracil and monitor patients throughout treatment, as the drug may cause a severe decrease in blood cell and platelet production.

[Approval of trifluridine/ tipiracil (Lonsurf)] is a testament to the FDA’s commitment to work with companies to develop new drugs in disease areas where unmet needs remain. —Richard Pazdur, MD

Health-care providers are also encouraged to advise women of potential risks to developing fetuses when taking trifluridine/tipiracil. Women who are taking trifluridine/tipiracil should not breastfeed. Colorectal cancer is the third most common nonskin cancer in men and women in the United States, according to the National Cancer Institute. While it is still the second leading cause of cancer-related death in the United States, over the past 10 years the number of colorectal cancer cases and related deaths have decreased, due in part to screenings, such as colonoscopies. n Reference Yoshino T, Mayer R, Falcone A, et al: Results of a multicenter, randomized, double-blind, phase III study of TAS-102 vs placebo, with best supportive care, in patients with metastatic colorectal cancer refractory to standard therapies (RECOURSE). Ann Oncol 25(suppl 2):ii114, 2014. Presented at ESMO 16th World Congress on Gastrointestinal Cancer, June 25–28, 2014, Barcelona.

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NIH: Preventing Overdiagnosis Conference Cancer Screening

Better Definitions and Biomarkers Needed to Reduce Cancer Overdiagnosis By Kirsten Boyd Goldberg

t the third annual Preventing Overdiagnosis Conference, speakers described the prevalence and consequences of overdiagnosis in several medical specialties, including cancer. The Conference, which had the theme “Winding Back the Harms of Too Much Medicine,” was co-sponsored by the National Cancer Institute Division of Cancer Prevention and the University of Oxford Centre for Evidence-Based Medicine and drew about 350 international participants to the National Institutes of Health in Bethesda, Maryland.

Barry Kramer, MD, MPH

Defining Overdiagnosis Cancer overdiagnosis is defined as “the detection of asymptomatic cancers, often through screening efforts, which are either nongrowing or so slow growing that they never would have caused medical problems for the patient in the patient’s lifespan,” according to Barry Kramer, MD, MPH, Co-Chair of the Conference Planning Committee and Director of the Division of Cancer Prevention, National Cancer Institute. “They therefore represent an important cause of overtreatment, which can involve serious harms and toxicities such as deaths from surgery, major organ deformation or loss, and second cancers from radiation or chemotherapy.” Keynote speaker Otis W. Brawley, MD, MAACP, Chief Medical and Scientific Officer, American Cancer Society, said cancer overdiagnosis stems

Otis W. Brawley, MD, MAACP

from the 19th century definition of cancer pathologist Rudolph Ludwig Carl Virchow as always being a disease of uncontrolled cell growth. This led to

the concept that “all cancers are bad,” Dr. Brawley said. “The histologic definition of cancer used in 2015 is largely that of Virchow and colleagues, with very minor modifications.” Yet, with today’s technology, cancer can be diagnosed earlier in development than in Virchow’s day, Dr. Brawley said. “It is actually possible now through our new technologies to find a 5- or 6-mm lesion in a woman’s breast, stick a needle into it, biopsy it, send it to a pathologist who uses the same technologies developed in the 1850s and 1860s—a light microscope, which has evolved in that it now has an electric light bulb as a light source—and says, ‘This looks just like what Virchow said killed the woman who had the autopsy in 1853.’ It looks just like something that killed 162 years ago, and our assumption is that it’s going to kill now,” he said. “Those of you in the United States are familiar with racial profiling. This is pathologic profiling,” Dr. Brawley said. Some of these small, localized tumors are not genomically or genetically programmed to grow or spread, he added. “We are moving from a mid-19th century definition of cancer to a 21st century definition of cancer that includes not just histology, but also genomics and epigenomics, and we’re beginning to appreciate the biologic behaviors of tumors,” such that several distinct types of breast cancer and other cancers can be identified and treated differently, Dr. Brawley explained. Cancer overdiagnosis is estimated to occur in 10% to 20% of radiologically detected lung cancers, up to 50% of mammographically detected breast cancers, and 40% to 60% of prostate cancers, Dr. Brawley said. Better terminology and biomarker research could help reduce the rate of overdiagnosis, he added. Regarding whether ductal carcinoma in situ should be called a “cancer,” Dr. Brawley quoted the late University of Chicago Pathology Professor Seymour Glagov, MD, who held that true cancer is invasive and “in situ” means not invasive. “He insisted that ductal carcinoma in situ was not cancer,” Dr. Brawley said. “We need to get back to basic principles,” Dr. Brawley urged. “It’s likely that some things that are ductal carcinoma in situ under the microscope are cancers, but most things that are ductal carcinoma in situ under the microscope are not

cancers, and it is clear we have been overtreating ductal carcinoma in situ and doing a disservice to women by considering all ductal carcinoma in situ as cancer.”

Personalized Breast Cancer Screening Understanding the basis for overdiagnosis can drive solutions to mitigate harm, said Laura Esserman, MD, MBA, Professor of Surgery and Radiology and Director of the Carol Franc Buck Breast Care Center at University of California, San Francisco. One driving factor in overdiagnosis is overscreening, she said. Dr. Esserman and her team recently won a 5-year, $14.1-million award from the Patient-Centered Outcomes Research Institute to investigate whether a risk-based personalized approach to breast cancer screening is as safe and effective as annual mammograms. The WISDOM study will involve approximately 100,000 women between the ages of 40 and 80 years old from all five University of California medical centers and Stanford. Women at higher risk of breast cancer will be screened more often than those at lower risk (wisdomstudy.org).

Seymour Glagov, MD

“Risk-based screening has the potential to improve the way we think about tailoring prevention and treatment, because we are going to profile every tumor that is diagnosed on women on the trial” to identify groups that have lowerrisk tumors, Dr. Esserman said. “Maybe that’s the group of women where we can just stop screening or screen much less and eventually stop screening. Why should we be looking for little bitty calcifications? Let’s stop looking for things that don’t matter.” Women will be randomized either to the personalized or the annual screening arm. Participants in the personalized screening arm will receive a risk assessment evaluating family and medical histories, breast density, and tests for genes linked to the development of breast

Rudolph Ludwig Carl Virchow was a prominent and influential 19th century German physician renowned for his work in chemical and microscopic research, as well as his role in modernizing medical science. He was a founder of the journal Archives for Pathological Anatomy and Physiology and Clinical Medicine, which was later referred to as “Virchow’s Archives.” In 1849 Dr. Virchow became Germany’s first chair in pathological anatomy in Würzburg, in the region of Franconia, Northern Bavaria, Germany. Later, in 1854, he initiated a comprehensive, six-volume Handbook on Special Pathology and Therapeutics, and in 1858 published his classic textbook, Cellular Pathology. He died on September 5, 1902.

cancer. Those with the highest risk of developing breast cancer will receive recommendations to begin screening at an earlier age, have mammograms more often, and continue screening until they are older. Those with the lowest risk will begin screening later, have less frequent screening, and stop screening earlier. No woman will be screened less often than the U.S. Preventive Services Task Force recommendations. The two strategies will be compared to determine whether personalized screening is as safe as annual screening and whether it will reduce false-positive results and overdiagnosis. Mammographic screening currently costs the U.S. health-care system about $7.5 billion a year. If the U.S. Preventive Services Task Force guidelines were fully implemented, costs would fall to about $3 billion, Dr. Esserman said. n Disclosure: Drs. Kramer, Brawley, Glagov, and Esserman re-ported no potential conflicts of interest.

The ASCO Post | OCTOBER 10, 2015

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Adolescent and Young Adult Oncology Bridging the Gap Between Pediatric and Adult Oncology Care A Conversation With Simon Davies By Jo Cavallo

ccording to the National Cancer Institute (NCI), about 70,000 adolescents and young adults—defined by the NCI as those in the 15- to 39-year-old range—are diagnosed with cancer each year in the United States, about six times the number of cases diagnosed in children aged 0 to 14.1 And, although overall cancer survival rates continue to rise—there are nearly 14.5 million cancer survivors alive today2— survival rates for adolescents and young adults have seen little or no improvement in 4 decades. Each year, about 9,000 adolescents and young adults die from their disease, making cancer the leading cause of death in this age group after accidents, suicide, and murder. Exactly why adolescents and young adults do not fare as well as either younger or older adult cancer survivors is unknown, but likely possibilities include a limited understanding of the biology of cancer in this age group, delayed diagnosis and treatment, treatment noncompliance, unmet psychosocial and supportive care needs, lack of inclusion of adolescents and young adults in clinical studies, and fragmented care by pediatric and adult oncology specialists. To raise awareness of the unique clinical needs of adolescent and young adult survivors and improve their outcomes, in 2012, Roger Daltrey and Pete Townshend of the rock group The Who launched Teen Cancer America (teencanceramerica.org), an American version of their British charitable organization, Teenage Cancer Trust. The British counterpart was formed in 1989 to provide funding for the development of specialized facilities in cancer centers for teens and young adults between the ages of 13 and 25. According to Simon Davies, Executive Director of Teen Cancer America, Los Angeles, California, over the past 15 years, the Teenage Cancer Trust has partnered with 35 cancer centers across the United Kingdom to develop standards for age-specific care, improve collaboration between pediatric and adult oncology specialists, and provide services to accommodate the physical and psychosocial needs of adolescents and young adults. He aims to do the same here in the United States. In just 3 years, Teen Cancer America has partnered with 11 major cancer centers (see sidebar) across the United

When young people going through a similar experience get together, there is a sort of camaraderie that develops, and the more experienced patients will often help their newly diagnosed peers cope with cancer, giving them comfort, guidance, and support. —Simon Davies

States to build teen-friendly environments in both the inpatient and outpatient settings. Currently, 40 more cancer institutions have expressed interest in developing similar programs in their centers. Recently, the charity collaborated with Moffitt Cancer Center in Tampa, Florida, to raise funds to build the center’s first adolescent and young adult lounge, which provides patients with a dedicated area where they can meet other young survivors and interact during treatment. The lounge resembles a brightly decorated, well-equipped den, complete with computers and big screen televisions, tables, and couches (see photos) where adolescents and young adults can gather and socialize. The ASCO Post talked with Mr. Davies about the goals of Teen Cancer America and how the organization is changing health care for adolescents and young adults with cancer.

teams experienced in providing care for the specific needs of adolescents and young adults. Our programs also include a research component to encourage inclusion of adolescents and young adults in appropriate clinical trials, so we can gain

knowledge about this unique group of patients and their disease.

Multidisciplinary Teams What medical specialties are included in these multidisciplinary teams? Ideally, we like to have input from both pediatric and adult medical oncologists, because we are dealing with late-onset pediatric cancers and earlyonset adult cancers. However, it can be challenging. Traditionally, the care of adolescents and young adults has been divided between pediatric and medical oncologists, which can often lead to inconsistencies in treatment approaches. Research has shown that treating adolescents and young adults with a pediatric-directed approach in some cancers can lead to improved outcomes, continued on page 29

Social and Therapeutic Elements How are the specialized facilities for adolescents and young adults you are developing for cancer centers different from the normal hospital environment? There are both social and therapeutic elements to the program that are geared to teens in pediatric centers and to older teens and young adults in adult centers. Obviously, young people want to be together, and we want to support them while they are undergoing treatment by bringing them the best facilities and care to ease their burden during their stay. The specialized clinical units we have created have the latest electronic equipment and provide social opportunities for patients to interact with each other and with friends, but they also incorporate multidisciplinary medical

Moffitt Cancer Center’s first adolescent and young adult lounge, designed to be a place where adolescents and young adults with cancer can gather and socialize.

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Adolescent and Young Adult Oncology Simon Davies continued from page 28

especially in patients with acute lymphoblastic leukemia and lymphomas. There should be greater collaboration between the two specialties to capitalize on their expertise and develop the most effective treatment plan for each individual patient. Other members of the team include a lead nurse dedicated to this age group, social workers, integrative and complementary medicine experts (such as acupuncturists), and nutritionists, as well as psychologists and psychiatrists. Adolescent and young adult patients often feel a loss of control and anxiety, but they don’t want to burden their parents with their fears. Providing them with psychosocial and supportive care can alleviate some of their anxiety.

Camaraderie May Improve Outcomes How important is it for adolescents and young adults to be grouped together with people their age going through a similar situation rather than being in a treatment room with younger or older patients? It’s almost as important as having a multidisciplinary care team that is experienced in working with this age group. People this age are “tribal.” They are becoming more independent and are differentiating themselves from both children and older adults to create their own identity. Having people their age around them while going through treatment is incredibly supportive for them. There are experiences they will share with each other that they wouldn’t share with their parents or their medical team. The level of support they pro-

vide each other is so extraordinary it can impact their outcome. In our program in the United Kingdom, we found that issues such as treatment compliance improved in this age group when they were treated together. Teenagers and young adults can engage in risky behavior when they are faced with a disease like cancer, and they may stop taking their medication, drink alcohol, consume recreational drugs, or eat an unhealthy diet. When young people going through a similar experience get together, there is a sort of camaraderie that develops, and the more experienced patients will often help their newly diagnosed peers

cope with cancer, giving them comfort, guidance, and support.

Virtual Support Services In addition to the physical space provided in these specialized medical units, is there an online component to the program in which adolescents and young adults can communicate with each other? Yes. Social media is very important to this group, and we encourage virtual support services to be incorporated into the Teen Cancer America programs. For many young people, social media can provide a connection to friends they otherwise wouldn’t have while in isolation undergoing treatment. It is a

Teen Cancer America Partners With Cancer Centers

een Cancer America has partnered with the following major cancer centers across the United States to build teen-friendly environments in both the inpatient and outpatient settings. • Moffitt Cancer Center, Tampa, Florida • Ronald Reagan UCLA Medical Center, Los Angeles, California • Lucile Packard Children’s Hospital Stanford and Stanford Medical Center, Stanford, California • Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania • Comer Children’s Hospital and University of Chicago Medical Center, Chicago, Illinois

• Rainbow Babies & Children’s Hospital and University Hospitals Seidman Cancer Center, Cleveland, Ohio • Dana-Farber Cancer Institute, Boston, Massachusetts • Children’s Hospital at Vanderbilt and VanderbiltIngram Cancer Center, Nashville, Tennessee • Smilow Cancer Hospital at Yale-New Haven, New Haven, Connecticut • Cook Children’s Medical Center, Fort Worth, Texas • Texas Health Harris Methodist Hospital, Arlington, Texas and Baylor Fort Worth, For Worth, Texas • Memorial Sloan Kettering Cancer Center, New York, New York

lifeline, although it is also a constant reminder of what they are missing out on at home, school, or work.

Steps Toward a Specialized Program What is the process for cancer centers interested in developing a specialized program for the treatment of adolescents and young adults? When a cancer center contacts us, we suggest a telephone conference call with members of its multidisciplinary care team to learn about their needs and what they want to accomplish. Next, we arrange to visit the center to evaluate its infrastructure and meet with staff to develop a strategy for building a specialized treatment unit and program for adolescents and young adults. In addition to providing initial funding support, we also work with the center to raise funds for the facility and program. Our goal is to ensure that all adolescent and young adult patients with cancer have the medical and social resources they need throughout their treatment and beyond to optimize their outcome. n

Disclosure: Mr. Davies reported no potential conflicts of interest.

References 1. National Cancer Institute: Adolescents and Young Adults With Cancer. Available at cancer.gov/types/aya. Accessed September 23, 2015. 2. American Cancer Society: Cancer Treatment & Survivorship Facts & Figures, 2014-2015. Available at cancer.org/ research/cancerfactsstatistics/survivorfacts-figures. Accessed September 23, 2015.

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In patients 18 years and older...

DIFICID: Proven efficacy for treatment of Clostridium difficile–associated diarrhea (CDAD) Bactericidal therapy that targets C difficile Primarily active against species of clostridia, including C difficile, in vitro. The clinical significance of in vitro data is unknown.

DIFICID: Comparable initial clinical response rate vs vancomycin at end of 10-day treatment Clinical response rate

Hypothetical patient.

Patients (%)

Trial 1 (95% CI)a: 2.6% (-2.9%, 8.0%)

88%

86%

60 40 20

100 80 Patients (%)

100

Trial 2 (95% CI)a: 1.0% (-4.8%, 6.8%)

88%

87%

60 40 20 0

DIFICID 200 mg BID (n=289)

Vancomycin 125 mg QID (n=307)

DIFICID 200 mg BID (n=253)

Vancomycin 125 mg QID (n=256)

CI was derived using the Wilson score method.

Study description: Two Phase 3, randomized, double-blind, noninferiority studies (N=1,105) comparing the efficacy and safety of oral DIFICID 200 mg BID vs oral vancomycin 125 mg QID for 10 days for the treatment of adults (aged ≥18 years) with CDAD (defined by >3 unformed bowel movements or >200 mL of unformed stool for subjects having rectal collection devices in the 24 hours before randomization and presence of either C difficile toxin A or B in the stool within 48 hours of randomization). An additional efficacy end point was a sustained response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment. Sustained response was defined as clinical response at the end of treatment and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment.

Indication and Usage DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD). To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by C difficile.

Important Safety Information DIFICID is contraindicated in patients with hypersensitivity to fidaxomicin. DIFICID should not be used for systemic infections. Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Only use DIFICID for infection proven or strongly suspected to be caused by C difficile. Prescribing DIFICID in the absence of a proven or strongly suspected C difficile infection is unlikely to provide benefit to the patient and increases the risk of development of drugresistant bacteria. The most common adverse reactions reported in clinical trials are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%).

In the same studiesâ&#x20AC;Ś

Superior sustained response rate vs vancomycin through 25 days after end of treatment Sustained response rate Trial 1 (95% CI)b: 12.7% (4.4%, 20.9%)

100

70%

60 40

57%

Patients (%)

80 Patients (%)

Trial 2 (95% CI)b: 14.6% (5.8.%, 23.3%)

100

72%

60 40

57%

DIFICID 200 mg BID (n=289)

Vancomycin 125 mg QID

DIFICID 200 mg BID

Vancomycin 125 mg QID

(n=307)

(n=253)

(n=256)

CI was derived using the Wilson score method. Approximately 5% to 9% of the data in each trial and treatment arm were missing sustained response information and were imputed using the multiple imputation method.

Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained response were due to lower rates of proven or suspected CDAD during the follow-up period in DIFICID patients. In patients infected with a BI isolate, similar rates of clinical response at the end of treatment and during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients. However, DIFICID did not demonstrate superiority in sustained response when compared with vancomycin in these patients. Initial C difficile group BI isolates

Trial 1

Non-BI isolates BI isolates

Trial 2

Non-BI isolates

DIFICID n/N (%)

Vancomycin n/N (%)

Difference (95% CI)c

44/76 (58%)

52/82 (63%)

-5.5% (-20.3%, 9.5%)

105/126 (83%)

87/131 (66%)

16.9% (6.3%, 27.0%)

42/65 (65%)

31/60 (52%)

12.9% (-4.2%, 29.2%)

109/131 (83%)

77/121 (64%)

19.6% (8.7%, 30.0%)

CI was derived using the Wilson score method. Interaction test between the effect on sustained response rate and BI vs non-BI isolates using logistic regression (P values: trial 1: 0.009; trial 2: 0.29). Approximately 25% of the mITT population were missing data for the REA group.

Important Safety Information (continued) Among patients receiving DIFICID, 33 (5.9%) withdrew from trials as a result of adverse reactions. Vomiting was the primary adverse reaction leading to discontinuation of dosing (incidence of 0.5% for both DIFICID and vancomycin patients). The safety and effectiveness of DIFICID in patients <18 years of age have not been established.

Please see the Brief Summary of Prescribing Information on adjacent page. BID=twice a day; mITT=modified intent to treat; QID=4 times a day; REA=restriction endonuclease analysis.

Product support and access for patients A program that provides patients with product support and access related to researching insurance benefits, information on co-pay assistance for eligible privately insured patients, product distribution questions, and alternate independent sources of funding.

For insurance coverage and reimbursement information, please visit www.accessdificid.com or call 1-844-282-4782 (M-F, 8 AM-8 PM; Sat, 9 AM-1 PM, ET). Eligibility restrictions apply for the Co-pay Assistance Program and the Patient Assistance Program. Please see Terms and Conditions for the Co-pay Assistance Program, available on the Enrollment Form.

BRIEF SUMMARY OF PRESCRIBING INFORMATION DIFICID (fidaxomicin) tablets, for oral use INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID® and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile. Clostridium difficile-Associated Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD). CONTRAINDICATIONS Hypersensitivity to fidaxomicin. WARNINGS AND PRECAUTIONS Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections. Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions. Development of Drug-Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice. The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment. Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies. Table 1. Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials DIFICID (N=564) n (%) Blood and Lymphatic System Disorders Anemia 14 (2%) Neutropenia 14 (2%) Gastrointestinal Disorders Nausea 62 (11%) Vomiting 41 (7%) Abdominal Pain 33 (6%) Gastrointestinal Hemorrhage 20 (4%) System Organ Class Preferred Term

Vancomycin (N=583) n (%) 12 (2%) 6 (1%) 66 (11%) 37 (6%) 23 (4%) 12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash Post Marketing Experience Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible. Hypersensitivity reactions (dyspnea, angioedema, rash, and pruritus) have been reported. DRUG INTERACTIONS Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract. Cyclosporine Cyclosporine is an inhibitor of multiple transporters, including P-gp. When cyclosporine was co-administered with DIFICID, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range. Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials. Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively. The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether fidaxomicin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman. Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established. Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects. In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age). However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

Before prescribing DIFICID, please read the full Prescribing Information, available at dificid.com. 0500004-00 Revised: 04/2014 Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. AINF-1158143-0000 08/15

ASCOPost.com | OCTOBER 10, 2015

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Journal Spotlight Breast Cancer

EBCTCG Meta-analyses Show Improved Outcomes With Aromatase Inhibitors vs Tamoxifen and a Potential Benefit of Adjuvant Bisphosphonates Limited to Postmenopausal Women By Matthew Stenger

he Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) patient-level meta-analyses, concurrently reported in The Lancet, sought to clarify the effects of adjuvant aromatase inhibitor vs tamoxifen treatment and adjuvant bisphosphonate treatment in early breast cancer.1,2 The endocrine treatment analysis indicated that 5 years of aromatase inhibitor treatment significantly reduced recurrence risk vs 5 years of tamoxifen therapy during the first 5 years and reduced 10-year breast cancer mortality vs tamoxifen.1 In trials where a comparator group received 2 to 3 years of tamoxifen followed by an aromatase inhibitor, recurrence rates were lower with aromatase inhibitors during the period that treatment differed between groups. The bisphosphonate analysis suggested a reduced risk of bone recurrence and breast cancer mortality, with the benefit limited to women who were postmenopausal at the start of treatment.2

Endocrine Therapy Study Details The meta-analysis1 included individual data on 31,920 postmenopausal women with estrogen receptor–positive early breast cancer in randomized trials evaluating 5 years of an aromatase inhibitor vs 5 years of tamoxifen, 5 years of an aromatase inhibitor vs 2 to 3 years of tamoxifen then an aromatase inhibi-

cantly reduced with aromatase inhibitors during years 0 to 1 (RR = 0.64, 95% confidence interval [CI] = 0.52– 0.78) and 2 to 4 (RR = 0.80, 95% CI = 0.68–0.93) and nonsignificantly thereafter. Ten-year breast cancer mortality was 12.1% vs 14.2% (RR = 0.85, P = .009). In the comparison of 5 years of an aromatase inhibitor vs 2 to 3 years of tamoxifen followed by an aromatase inhibitor to year 5, recurrence was significantly reduced with aromatase inhibitors during years 0 to 1 (RR = 0.74, 95% CI = 0.62–0.89) but not while both groups received aromatase inhibitors during years

In the comparison of 5 years of an aromatase inhibitor vs 5 years of tamoxifen, recurrence was signifi-

nificantly reduced with aromatase inhibitors during periods when treatments differed (RR = 0.70, 95% CI = 0.64–0.77) but not significantly thereafter (RR = 0.93, P = .08). Breast cancer mortality was reduced with aromatase inhibitors when treatments differed (RR = 0.79, 95% CI = 0.67– 0.92), subsequently (RR = 0.89, 95%

■■ Five years of aromatase inhibitors reduced recurrence risk vs 5 years of tamoxifen during the first 4 years and reduced 10-year breast cancer mortality. ■■ In trials comparing 5 years of aromatase inhibitors or tamoxifen with tamoxifen followed by an aromatase inhibitor, recurrence risk was reduced with aromatase inhibitors during the periods in which treatments differed. ■■ Among postmenopausal women, but not premenopausal women, bisphosphonate treatment was associated with reduced risk of recurrence, distant recurrence, bone recurrence, and breast cancer mortality.

2 to 4 or thereafter. In these trials, risk of recurrence was lower with 5 years of aromatase inhibitors vs tamoxifen followed by aromatase inhibitors (RR = 0.90, P = .045), but the reduction in 10-year breast cancer mortality was not significant (RR = 0.89, P = .11).

—Early Breast Cancer Trialists’ Collaborative Group

Comparison of Outcomes

—Early Breast Cancer Trialists’ Collaborative Group

New Data in Early Breast Cancer

Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. tor to year 5, and 2 to 3 years of tamoxifen then an aromatase inhibitor to year 5 vs 5 years of tamoxifen. Outcomes were analyzed on an intent-to-treat basis stratified by age, nodal status, and trial, yielding aromatase inhibitor vs tamoxifen first-event rate ratios (RRs; P values are two-sided).

Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter.

In the comparison of 2 to 3 years of tamoxifen and then an aromatase inhibitor to year 5 vs 5 years of tamoxifen, risk of recurrence was significantly reduced with aromatase inhibitors during years 2 to 4 (RR = 0.56, 95% CI = 0.46–0.67) but not thereafter. Ten-year breast cancer mortality was lower with switching to aromatase inhibitors vs remaining on tamoxifen (8.7% vs 10.1%, P = .015). When all three types of comparison were pooled, recurrence was sig-

CI = 0.81–0.99), and for all periods combined (RR = 0.86, P = .0005). All-cause mortality was also reduced (RR = 0.88, P = .0003). Aromatase inhibitor treatment was associated with reduced risk for endometrial cancers (10-year incidence = 0.4% vs 1.2%, RR = 0.33, 95% CI = 0.21–0.51) and increased risk of bone fractures (5-year risk = 8.2% vs 5.5%, RR = 1.42, 95% CI = 1.28–1.57). The investigators concluded: “Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. Five years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment.”

Bisphosphonate Study Details The meta-analysis included data on 18,766 women, including 18,206 in randomized trials of 2 to 5 years of

bisphosphonate treatment, with a median follow-up of 5.6 woman-years, 3,453 first recurrences, and 2,106 subsequent deaths. Analysis used intention-to-treat log-rank methods to yield bisphosphonate group vs control group (open label or placebo, with no bisphosphonate) first-event rate ratios (P values are twosided P values).

Reduced Risks in Postmenopausal Women Overall, bisphosphonate treatment was associated with modest reductions in risk of recurrence (RR = 0.94, P = .08), distant recurrence (RR = 0.92, P = .03), and breast cancer mortality (RR = 0.91, P = .04) and a more definite reduction in risk for bone recurrence (RR = 0.83, P = .004). There was no apparent effect of bisphosphonate treatment on any outcome among premenopausal women. Among 11,767 postmenopausal women, bisphosphonate treatment was associated with significant reductions in risk of recurrence (RR = 0.86, P = .002), distant recurrence (RR = 0.82, P = .0003), bone recurrence (RR = 0.72, P = .0002), and breast cancer mortality (RR = 0.82, P = .002). Tests for heterogeneity of benefit in bone recurrence, the outcome with the greatest evidence of benefit, were significant by age (2P = .03) and menopausal status (2P = .06), but not bisphosphonate class, treatment schedule, estrogen receptor status, nodal status, tumor grade, or concomitant chemotherapy. Bisphosphonate treatment had no effect on distant recurrence at extraosseus metastatic sites, locoregional recurrence, or the development of a new contralateral breast primary either overall or in the postmenopausal subgroup. No differences were observed in non–breast cancer mortality. Bisphosphonate treatment was associated with reduced risk of bone fractures continued on page 34

The ASCO Post | OCTOBER 10, 2015

PAGE 34

Perspective

Adjuvant Treatment of Early-Stage Breast Cancer: Meta-analyses Provide More Clarity By Aju Mathew, MD, MPhil, and Adam Brufsky, MD, PhD

he Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) continues its practice of being a lighthouse, shedding its beacon of light on the vast ocean of breast cancer research through the publication of two large, individual patient level–data metaanalyses on the management of women with early-stage breast cancer.1,2 The first publication described the effects of aromatase inhibitors compared with tamoxifen in postmenopausal women, and the second article investigated the antitumor role of bisphosphonates. The analyses are summarized in this issue of The ASCO Post.

Aromatase Inhibitors Impress Again Aromatase inhibitors reduced both breast cancer and all-cause mortality compared with tamoxifen.1 Although patients were on an aromatase inhibitor vs tamoxifen, a 30% proportional reduction in risk for recurrence was observed. As expected, all three aromatase inhibitors (anastrozole, letrozole, and exemestane) produced similar outcomes. There was a carry-over effect for up to 5 years from stopping the medication, similar to that with tamoxifen. None of the traditionally known prognostic markers (age, body mass index, nodal status, grade, progesterone receptor status, HER2 status) had a predictive effect. However, a greater absolute risk reduction was seen in patients with at least four positive nodes or one to three positive nodes compared with node-negative disease (number needed to treat to prevent one recurrence was 15, 27, and 83, respectively). Although the meta-analysis noted Dr. Mathew is Assistant Professor of Medicine at Markey Cancer Center, University of Kentucky, Lexington, and Dr. Brufsky is Professor of Medicine and Associate Chief of Hematology and Oncology at MageeWomens Hospital of the University of Pittsburgh Medical Center and Cancer Institute.

EBCTCG Meta-analyses continued from page 33

(RR = 0.85, P = .02). The investigators concluded: “Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer sur-

no increased cardiovascular risk and found significantly fewer uterine cancers compared with tamoxifen use, there were more bone fractures in patients on aromatase inhibitors, both during the treatment period and for 5 years after stopping the medication. Concurrent use of bone-modifying agents may help prevent bone loss due to aromatase inhibitor therapy and may decrease the incidence of fractures. The recently published results from

is on aromatase inhibitor therapy. There may be more than just a boneprotective effect for such a strategy, as the EBCTCG bisphosphonate metaanalysis demonstrates. In light of the meta-analysis, aromatase inhibitor treatment for 5 years should be the preferred adjuvant endocrine treatment strategy for postmenopausal women. For those who cannot tolerate such a therapy, a switch strategy with sequential use of tamoxifen and aromatase

Regardless of the several unanswered questions, one thing is certain—aromatase inhibitors and bisphosphonates continue to prove their mettle. —Aju Mathew, MD, MPhil (top), and Adam Brufsky, MD, PhD

the ABCSG-18 trial are especially important in the context of bone health.3 In this trial, postmenopausal women on adjuvant aromatase inhibitor therapy were randomized to receive either denosumab (60-mg dose given subcutaneously once every 6 months) or placebo. Denosumab (Xgeva) decreased the incidence of clinical fractures (hazard ratio = 0.50, 95% confidence interval [CI] = 0.39–0.65, P < .0001). Upfront use of zoledronic acid may be another option, especially for women who have baseline osteopenia or osteoporosis.4,5 Therefore, we recommend obtaining a bone density scan at baseline and at 2-year intervals while a patient

vival, but there is definite benefit only in women who were postmenopausal when treatment began.” n Disclosure: Both studies were funded by Cancer Research UK, Medical Research Council. For full disclosures of the study authors, visit www.thelancet.com.

inhibitors for up to 5 years is a reasonable option. Clearly, adjuvant tamoxifen therapy is suboptimal in postmenopausal women, unless they cannot tolerate aromatase inhibitors, in which case tamoxifen is better than nothing at all. Therefore, careful assessment for tolerability and compliance is of crucial importance.

The Final Whistle for Bisphosphonates? Over the years, bisphosphonates have moved from being used in metastatic disease to the adjuvant setting, primarily as a means of protecting bones from aromatase inhibitor–induced bone loss.6 However, does it also have an effect

References 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet. July 23, 2015 (early release online).

on breast cancer recurrences and maybe even mortality? The AZURE (zoledronic acid) and NSABP B-34 (clodronate) trials suggested a beneficial effect on breast cancer recurrences in postmenopausal women.7,8 In the ZO-FAST trial, postmenopausal women treated with an aromatase inhibitor had improved disease-free survival with the upfront use of zoledronic acid compared with its use in a delayed manner.5 However, several other studies have failed to show any effect on recurrence.6 To investigate a putative antitumor effect for bisphosphonates, a large, patient level–data meta-analysis of 26 trials was conducted by the EBCTCG— providing greater power to perform subgroup analysis (especially as to the intriguing question on the role of menopausal status) and also investigate overall survival.2 For the sake of analysis, postmenopausal status was defined as those who were at least 55 years old or who reported postmenopausal status at study entry and also included younger women who underwent suppression of ovarian function. The meta-analysis found highly significant reductions in bone recurrence (28%, P = .0002) and breast cancer mortality (18%, P = .002) with the adjuvant use of bisphosphonates in postmenopausal women. At 10 years, the absolute reduction in bone recurrence and breast cancer mortality were 2.2% and 3.3%, respectively (number needed to prevent one death due to breast cancer was 30). Premenopausal women did not benefit from the addition of bisphosphonates to adjuvant therapy. No other predictive factors were identified in the study. The results were similar regardless of estrogen receptor status, nodal status, type of bisphosphonate, and intensity of therapy. Nonbone recurrences were not reduced, suggesting that the antitumor effect is likely mediated through manipulation of the bone microenvironment. continued on page 35

2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Adjuvant bisphosphonate treatment in early breast cancer: Meta-analyses of individual patient data from randomized trials. Lancet. July 23, 2015 (early release online).

ASCOPost.com | OCTOBER 10, 2015

PAGE 35

Perspective

Aju Mathew, MD, MPhil, and osteoporosis at baseline and in patients tors could also be efficacious.10 Adam Brufsky, MD, PhD It is hoped that the NSABP B-42 and with a high risk of recurrence. For all continued from page 34

Bisphosphonate therapy did not decrease the incidence of contralateral breast cancers, signifying the absence of a chemopreventive role for it. With regard to the safety of bisphosphonates, a careful oral examination and regular monitoring will prevent the development of the extremely rare adverse effect of osteonecrosis of the jaw. Otherwise, bisphosphonates are extremely safe and well tolerated. So, is this the final whistle? Have bisphosphonates won the day? The data are quite compelling to start bisphosphonate therapy in postmenopausal women with early-stage breast cancer. The mortality reduction is similar to that achieved with the use of anthracycline-based chemotherapy over a nonanthracycline-based regimen.9 At the same time, it also warrants an individualized approach. Bisphosphonate therapy should be strongly considered in women with osteopenia or

women with early-stage disease, a discussion of the benefits and risks of therapy must ensue, based on the results of this well-conducted meta-analysis. As far as further research is concerned, we may not see any more large clinical trials in this field of research, especially with the drugs going off patent.

What’s Next? These two large meta-analyses provide much clarity for clinicians. However, they have also expanded the horizons of research to some areas where the beacon does not fall. Will longer follow-up (beyond 10 years) unravel more significant beneficial effects or maybe show increased fracture rates? How do the trials of extended tamoxifen use (ATLAS) fit in with the upfront use of aromatase inhibitors? With around 90% of participants in that trial being postmenopausal at study entry, it can be thought that extended endocrine treatment with aromatase inhibi-

MA-17R trials will evaluate the efficacy and safety of 10 years of aromatase inhibitors vs 5 years. Similarly, the D-CARE and the ABCSG-18 trials will investigate an antitumor effect for denosumab. Regardless of the several unanswered questions, one thing is certain—aromatase inhibitors and bisphosphonates continue to prove their mettle. n

Disclosure: Dr. Mathew reported no potential conflicts of interest. Dr. Brufsky has served as a consultant for Novartis.

References 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Aromatase inhibitors versus tamoxifen in early breast cancer. Lancet. July 23, 2015 (early release online). 2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Adjuvant bisphosphonate treatment in early breast cancer. Lancet. July 23, 2015 (early release online). 3. Gnant M, et al: Adjuvant denosumab in breast cancer (ABCSG-18). Lancet 386:433-443, 2015. 4. Brufsky AM, et al: Final 5-year re-

sults of Z-FAST trial. Cancer 118:11921201, 2012. 5. Coleman R, et al: Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study). Ann Oncol 24:398-405, 2013. 6. Mathew A, Brufsky A: Bisphosphonates in breast cancer. Int J Cancer 137:753-764, 2015. 7. Coleman RE, et al: Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365:1396-1405, 2011. 8. Paterson AH, et al: Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34). Lancet Oncol 13:734-742, 2012. 9. Peto R, et al: Comparisons between different polychemotherapy regimens for early breast cancer. Lancet 379:432-444, 2012. 10. Davies C, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer. Lancet 381:805-816, 2013.

Chief Executive Officer The American Society of Clinical Oncology (ASCO) is seeking an accomplished leader in clinical oncology to serve as their next Chief Executive Officer (CEO). ASCO is a professional society committed to conquering cancer through research, education, prevention, and delivery of high quality patient care. Founded in 1964, ASCO today counts more than 36,000 members worldwide and has an annual budget of $100M. The CEO works with a distinguished Board of Directors, a talented professional staff of more than 350 individuals, and hundreds of dedicated volunteers to envision and implement a strategic plan that engages and serves all physicians as they work to fight cancer. The CEO provides leadership and vision on the execution of strategic plans and oversees the fiscal health of the organization while building and supporting a highly committed and capable management team. The CEO must ensure that ASCO’s current major initiatives are successful and also guide a conversation about new opportunities for ASCO to support the field in a dynamic healthcare environment. All of these efforts will be sustained by responsible management of internal resources and diligent philanthropic efforts. The successful candidate for this prestigious position will have experience as a leader in clinical oncology with a deep passion for, commitment to, and track record of accomplishments in cancer clinical medicine. The candidate should have working knowledge of and some experience in the many areas in which ASCO plays an important role in improving cancer care, including clinical and translational research, physician and public education and communication, cancer care delivery, governmental affairs and policy, and global health. A prior leadership role with ASCO in a volunteer or board capacity is strongly desired as is an in-depth understanding of the current trends and issues affecting oncology clinical practice and clinical research today. A medical degree is required. The ideal candidate must have a demonstrated track record of managing and leading a large and complex organization with a comparably sized budget and a highly educated, high intellect professionals. The CEO also serves as CEO of the affiliated Conquer Cancer Foundation, and experience with philanthropy is beneficial. This position is based at ASCO headquarters in Alexandria, Virginia. Candidates from all oncology disciplines and sub-specialties, domestic and international, are encouraged to apply. ASCO is proud to be an Equal Opportunity Employer (EOE).

Isaacson, Miller has been retained for this important recruitment and all nominations, inquiries, and applications should be directed in confidence to: www.imsearch.com/5499.

The ASCO Post | OCTOBER 10, 2015

PAGE 36

Expert’s Corner Breast Cancer

Male Breast Cancer: An Understudied Disease and Clinical Challenge A Conversation With Larissa A. Korde, MD, MPH By Ronald Piana

Larissa A. Korde, MD, MPH

ale breast cancer is an uncommon disease, although the incidence has increased over the past couple of decades. As with many other “orphan” diseases, male breast cancer is understudied, especially in randomized controlled trials. Although it shares similarities with female breast cancer, some important differences have emerged. To shed light on this intriguing clinical challenge, The ASCO Post recently spoke with male breast cancer researcher Larissa A. Korde, MD, MPH, Associate Professor, Department of Medicine, Division of Oncology, University of Washington, Seattle.

Training at NCI Please tell the readers a bit about your background and current work. I am a medical oncologist by training and specialize in breast cancer. I did my residency at Georgetown University Hospital Center and my fellowship at the National Cancer Institute (NCI), which is where I developed my interest in breast cancer. At the NCI, I worked in the Clinical Genetics Branch in the Division of Cancer Epidemiology and Genetics, where I did research on familial cancer syndromes. And that is where my interest in male breast cancer really accelerated.

International Research Collaboration Please describe your current research activities. While at the NCI, I received funding to organize a workshop on male breast cancer, bringing together male breast cancer researchers from all over the world. We had a series of comprehensive discussions about the state of the science and what needed to be done as we moved forward. In part, the workshop helped with an ongoing parallel effort in which a consortium was being formed to engage in highly coordinated

research in male breast cancer. The European consortium is led by Fatima Cardoso, MD, and the American side is led by Sharon Giordano, MD, from MD Anderson Cancer Center. The result of this collaboration is a large study in three parts with a retrospective component that has already been presented at the ASCO Annual Meeting.1 The second component is an ongoing prospective study, which will eventually lead to the third arm, a clinical trial in male breast cancer. One goal of the prospective element is to bring together a variety of researchers interested in male breast cancer and examine the current and potential interventions in this disease, rather than just extrapolate from the work in female breast cancer. Naturally, one of the difficulties in studying a rare disease such as male breast cancer is accruing enough patients

move the clinical trial process ahead. For instance, MD Anderson Cancer Center has a very large population of patients with male breast cancer, as does Memorial Sloan Kettering Cancer Center. Identifying these centers with high male breast cancer populations in the United States as well as those in Europe has put some big numbers on the disease, which has given us some strong conclusions about its pathology and biology.

Searching for Genetic Clues Have genetic risk factors for male breast cancer been identified? Although breast cancer is fairly uncommon in men, we know that the development of this disease in men is associated with BRCA2 gene mutations. The work on other risk factors has been through retrospective epidemiologic studies. I think the genetic component

International collaborative efforts will help us build the complicated infrastructure needed to develop future clinical trials in rare diseases such as male breast cancer. —Larissa A. Korde, MD, MPH

to power a trial. However, by collaborating with a group of physicians, even if each researcher can only provide eight or ten patients, when you have an international collaboration that aggregates all the small groups into one, it gives you enough patients to power the study.

Clinical Trials Model Clinical trial accrual in the major cancers is a formidable challenge. How do you approach accrual in a rare disease such as male breast cancer? In the past, the data on male breast cancer have been gathered retrospectively. If one site sees only five or six cases a year, developing a trial becomes very difficult. In fact, about 5 years ago, the Southwest Oncology Group endeavored to perform a prospective clinical trial in male breast cancer but failed to do so due to poor accrual. That is why we are hopeful that the three-step collaborative process might provide a model for clinical trials in rare malignancies such as male breast cancer. There are several sites across the country and the world that see a largerthan-normal number of cases of male breast cancer, so getting a cooperative atmosphere with these sites will help

will come along, because during the current international multi-institutional studies, DNA will be collected, and that will allow for multigene sequencing, which has not previously been done on a large scale for male breast cancer. And we are very interested in determining whether there are mutations in genes other than BRCA2 that predispose men to breast cancer. There are some clues gathered from the retrospective studies that have been done, but nothing concrete has been discovered. Emerging data suggest that there are several notable differences between male and female breast cancer, including a higher rate of hormone positivity, lower HER2 positivity, and more advanced disease at the time of diagnosis. Have any studies showed a risk factor for men with higher hormone levels? Not that I know of. However, we do know that men with gynecomastia have an increased risk of male breast cancer, which may be reflective of estrogen exposure.

BRCA Mutation Testing How has identifying BRCA2 as a risk factor for male breast cancer affected clinical practice?

Clinical practice guidelines currently recommend BRCA mutation testing for all men who are diagnosed with breast cancer. The guidelines take into account personal cancer history, family history, age at cancer diagnosis, ethnicity, and history of risk-reducing surgeries.

Treatments for Men vs Women Please discuss the current treatment options in male breast cancer. For the most part, we extrapolate treatments from what we see in female breast cancer. We use a variety of chemotherapies in more aggressive disease, and the mainstay for earlier-stage disease would be hormone therapy with tamoxifen. Perhaps one of the big differences in treating male breast cancer vs female breast cancer is that aromatase inhibitors are commonly prescribed for postmenopausal women. However, in men, we do not have enough data to be sure how aromatase inhibitors will work in male breast cancer. In fact, there may be some biologic reasons why aromatase inhibitors do not work in male breast cancer, and that is an important area that needs more study. Therefore, it is essential to get the message out to community practitioners that tamoxifen is the standard of care for male breast cancer, and aromatase inhibitors should only be used in combination with a gonadotropin-releasing hormone agonist.

Closing Thoughts Do you have any final comments on male breast cancer? The current international Male Breast Cancer Coalition will help us make great strides in understanding the unique biology, genetics, and optimal treatment for men with breast cancer. Equally important, international collaborative efforts will help us build the complicated infrastructure needed to develop future clinical trials in rare diseases such as male breast cancer. Our consortium has multiple sites across the country, all of which will gather crucial data that will ultimately translate into better care for our patients, so stay tuned. n

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

Reference 1. Korde LA, Zujewski JA, Kamin L, et al: Multidisciplinary meeting on male breast cancer: Summary and research recommendations. J Clin Oncol 28:2114-2122, 2010.

ASCOPost.com | OCTOBER 10, 2015

PAGE 37

Journal Spotlight Genitourinary Cancer

Adding Docetaxel to Androgen-Deprivation Therapy Prolongs Overall Survival in Metastatic Prostate Cancer By Matthew Stenger

n a phase III trial (E3805) reported in The New England Journal of Medicine, Christopher J. Sweeney, MBBS, of Dana-Farber Cancer Institute, Boston, and colleagues found that chemohormonal therapy with docetaxel plus androgen-deprivation therapy produced a significant 13.6-month increase in median overall survival vs androgendeprivation therapy alone in men with metastatic prostate cancer.1 Dr. Sweeney emphasized to The ASCO Post, “The data are relevant for patients who are fit for chemotherapy.”

Study Details In this open-label trial, 790 patients were randomized between July 2006 and December 2012 to receive standard androgen-deprivation therapy alone (n = 393) or combined with docetaxel 75 mg/ m2 every 3 weeks for 6 cycles (n = 397).

primary endpoint was overall survival. The androgen-deprivation therapy plus docetaxel and androgen-deprivation therapy–alone groups were generally balanced for age (median, 64 and 63 years), race (87% and 84% white, 10% and 9% black), ECOG performance status (0 for 70% and 69%, 1 for 29% in both), metastasis volume (high in 66% and 64%), and visceral metastases (14% and 17%). The groups were also generally balanced for Gleason score, median prostate-specific antigen (PSA) level (50.9 and 52.1 ng/mL), prior treatment, adjuvant androgen-deprivation therapy, median time from start of androgendeprivation therapy to randomization, and no receipt of androgen-deprivation therapy before randomization. At a planned interim analysis in October 2013, 53% of overall survival information had been obtained, and

The clinical benefit [of standard androgen-deprivation therapy and docetaxel] at this early analysis was more pronounced among patients with a higher burden of disease. —Christopher J. Sweeney, MBBS, and colleagues

Patients receiving docetaxel were premedicated with dexamethasone 8 mg at 12, 3, and 1 hour before docetaxel infusion. Stratification factors included age, Eastern Cooperative Oncology Group (ECOG) performance status, planned use of combined androgen blockade for more than 30 days, use of zoledronic acid or denosumab (Xgeva), duration of prior adjuvant androgen-deprivation therapy, and high volume (visceral metastases or ≥ four bone lesions with at least one beyond the vertebral bodies and pelvis) vs low volume of metastatic disease. Patients were enrolled by ECOG-ACRIN, Southwest Oncology Group, Alliance for Clinical Trials in Oncology, and NRG Oncology. The

prespecified criteria for significance had been met. The current report included data with a cutoff date for survival of December 23, 2013, representing a median follow-up of 28.9 months. All other data reflected the database as of December 23, 2014.

Improved Overall Survival Overall, 86% of patients in the combination group completed 6 cycles of docetaxel. Median overall survival was 57.6 months in the androgen-deprivation therapy plus docetaxel group vs 44.0 months in the androgen-deprivation therapy–alone group (hazard ratio [HR] = 0.61, P < .001). Benefit was more pronounced

Chemohormonal Therapy in Metastatic Prostate Cancer ■■ The addition of docetaxel to androgen-deprivation therapy significantly prolonged overall survival in men with hormone-sensitive metastatic prostate cancer. ■■ The benefit of docetaxel was more pronounced in patients with highvolume disease; median overall survival was not reached in those with low-volume disease.

among patients with high-volume disease, with median overall survival of 49.2 vs 32.2 months (HR = 0.60, P < .001). At the time of analysis, median overall survival had not been reached among patients with low-volume disease in either group (HR = 0.60, 95% confidence interval = 0.32–1.13). A survival benefit of combined treatment was detected in all analyzed subgroups.

Reduced Progression Median time to castration-resistant disease (biochemical, symptomatic, or radiographic progression) was 20.2 vs 11.7 months (HR = 0.61, P < .001), and median time to clinical progression was 33.0 vs 19.8 months (HR = 0.61, P < .001). PSA level < 0.2 ng/mL was achieved at 12 months in 27.7% vs 16.8% of patients (P < .001). After progression, 54 patients in the combination group and 137 in the androgen-deprivation therapy–alone group received docetaxel, 57 and 37 patients received cabazitaxel ( Jevtana), and 29 and 27 patients received mitoxantrone or platinum chemotherapy. Hormonal therapy with abiraterone (Zytiga) or enzalutamide (Xtandi) was received by 105 and 104 patients, respectively, and with an antiandrogen or ketoconazole by 80 and 91 patients, respectively. Immunotherapy with sipuleucel-T (Provenge) was received by 22 patients in the combination group and 19 patients in the androgen-deprivation therapy– alone group. Radiotherapy was received by 69 and 79 patients, respectively. Overall, 150 and 187 patients received at least one agent shown to prolong overall survival in metastatic castration-resistant

prostate cancer and 71 and 83 patients received at least two such agents.

Adverse Events Among patients in the combination group, 16.7% had grade 3, and 12.6% had grade 4 adverse events. The most common grade 3 adverse events were fatigue (4.1%), febrile neutropenia (3.8%), and neutropenia (3.1%); the most common grade 4 events were neutropenia (9.0%) and febrile neutropenia (2.3%). Grade 3 or 4 infection with neutropenia occurred in 2.3%, grade 3 or 4 allergic reaction occurred in 2.1%, grade 3 sensory neuropathy occurred in 0.5%, and grade 3 motor neuropathy occurred in 0.5%. Grade 3 or 4 thromboembolism occurred in three patients (< 1%). One patient (0.3%) died from sudden death considered possibly related to docetaxel treatment. The investigators concluded: “[T] he combination of standard androgen-deprivation therapy and six cycles of docetaxel resulted in significantly longer overall survival than that with standard androgendeprivation therapy alone in men with hormone-sensitive metastatic prostate cancer. The clinical benefit at this early analysis was more pronounced among patients with a higher burden of disease.” n

Disclosure: The study was funded by the National Cancer Institute and others. Sanofi provided docetaxel and a grant to ECOGACRIN. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Sweeney CJ, Chen YH, Carducci M, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737-746, 2015.

Docetaxel Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer Oscar B. Goodman, Jr, MD, PhD, of the Comprehensive Cancer Centers of Nevada and US Oncology, offers his perspective on the phase III E3805 trial discussed above. See page 41.

When faced with overactive signaling . . .

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi

Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

Inhibit the JAK pathway* in polycythemia vera not controlled with hydroxyurea 1-3

Jakafi® (ruxolitinib) is the first and only FDA-approved treatment for patients who have had an inadequate response to or are intolerant of hydroxyurea3 Jakafi demonstrated superior results in a phase 3 trial vs best available therapy3,4†

Primary Response at Week 323,4 80

* Ruxolitinib, a kinase inhibitor, inhibits JAK1 and JAK2 (Janus-associated kinases 1 and 2), which mediate the signaling of cytokines and growth factors important for hematopoiesis and immune function.3 A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy (BAT) in 222 patients. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy, and exhibited splenomegaly. The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both hematocrit (Hct) control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a ≥35% reduction from baseline in spleen volume at week 32). Phlebotomy eligibility was defined as Hct >45% that is ≥3 percentage points higher than baseline or Hct >48% (lower value).3,4

P < 0.0001

Jakafi (n = 110) BAT (n = 112)

(n = 66)

38%

21%

20 0

Individual Components of Primary End Point

60%

Patients (%)

†

Composite Primary End Point

(n = 23)

1%b

(n = 22)

(n = 1)

Hct Control + Spleen Volume Reduction

95% CI, 14%-30%

When discontinuing Jakafi, myeloproliferative neoplasmrelated symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non‐melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations The three most frequent non-hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy

20%

(n = 42)

(n = 1)

Hct Control Without Phlebotomy

≥35% Spleen Volume Reduction

95% CI, 0%-5%

Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed

Please see Brief Summary of Full Prescribing Information for Jakafi on the following page. References: 1. Rampal R et al. Blood. 2014;123(22):e123-e133. 2. Keohane C et al. Biologics. 2013;7:189-198. 3. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation. 4. Vannucchi AM et al. N Engl J Med. 2015;372(5):426-435.

Review the clinical trial data at

www.jakafidata.com

Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakafi (N=110) BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1)]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1)]. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] • Risk of Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)] • Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi (N=155) Adverse Reactions

Adverse Events

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Headache

Abdominal Painb

Diarrhea

Dizzinessc

Fatigue

Pruritus

Dyspnead

Muscle Spasms

Nasopharyngitis

Constipation

Cough

Edemae

Arthralgia

Asthenia

Epistaxis

Herpes Zosterf

Nausea

a b c d e f

Laboratory Parameter

Grade 3 (%)

Grade 4 (%)

All Grades (%)

Anemia

Thrombocytopenia

Placebo (N=151)

Neutropenia

Hypercholesterolemia

Elevated ALT

Elevated AST

Hypertriglyceridemia

Grade 4 (%)

Bruisingb

Dizzinessc

Headache

Urinary Tract Infectionsd

Weight Gaine

Flatulence

Herpes Zosterf

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present includes weight increased, abnormal weight gain includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya Jakafi (N=155) Laboratory Parameter

All Gradesb (%)

Grade 3 (%)

Placebo (N=151) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Thrombocytopenia

Anemia

Neutropenia

a b

Grade 4 (%)

Chemistry

Grade 3 (%)

Hematology

All Grades (%)

Best Available Therapy (N=111)

All Gradesb (%)

Grade 4 (%)

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes abdominal pain, abdominal pain lower, and abdominal pain upper includes dizziness and vertigo includes dyspnea and dyspnea exertional includes edema and peripheral edema includes herpes zoster and post-herpetic neuralgia

Jakafi (N=110)

Grade 3 (%)

Grade 3-4 (%)

Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were: Weight gain, hypertension, and urinary tract infections Clinically relevant laboratory abnormalities are shown in Table 4. Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatmenta

All Gradesa (%)

Best Available Therapy (N=111)

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi.

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 52% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Jakafi is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013 © 2011-2014 Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428a

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PAGE 41

Perspective

Docetaxel Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer By Oscar B. Goodman, Jr, MD, PhD

weeney et al reported on the results of a seminal phase III trial (E3805) of chemohormonal therapy vs androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer in a recent issue of The New England Journal of Medicine,1 and the study is summarized in this issue of The ASCO Post.

efit was retained for men ≥ 70 years of age (hazard ratio [HR] = 0.43). Of the 789 patients randomized, 575 (72.8%) had not received prior local therapies. The majority of the patients on this study, 65.7%, had high-volume metastatic disease. Almost three-quarters of the patients in both arms had not received prior treatment for prostate

Cytoreduction resulting from docetaxel administration specifically targets the biologically aggressive disease compartment that ultimately gives rise to lethal castrationresistant prostate cancer. —Oscar B. Goodman, Jr, MD, PhD

This open-label trial randomized 790 men with metastatic hormonesensitive disease within 120 days of starting androgen-deprivation therapy to either androgen-deprivation therapy plus docetaxel every 3 weeks for 6 cycles or androgen-deprivation therapy alone. The primary endpoint of the study was overall survival, with secondary endpoints including nadir prostate-specific antigen < 0.2 ng/mL and biochemical, clinical, or radiographic time to development of castration-resistant prostate cancer. Overall, combined treatment was well tolerated, with 86% of patients completing all 6 cycles of docetaxel.

Patient Population and Clinicopathologic Implications The patients in this study were younger than typical patients with prostate cancer, reflecting the predominance of aggressive disease in a younger population and limiting the applicability of the study to older populations. However, it should be noted that based on a subgroup analysis, a clinical benDr. Goodman is an oncologist at Comprehensive Cancer Centers of Nevada and US Oncology.

cancer, indicative of de novo presentation in both arms. As noted, the patients were about 5 years younger (63 to 64 years) than those typically presenting with prostate cancer, suggesting a potentially more aggressive biology. The use of prior adjuvant androgen-deprivation therapy was around 4% in both arms, concordant with its primary use in conjunction with definitive radiation, which was received by approximately 7% in the combined arm and approximately 8% in the androgen-deprivation therapy–alone arm. Taken together, these data suggest that the patients on this study had an inherently more aggressive biology associated with their disease and that chemohormonal therapy may be more applicable to these men. The use of combined androgen blockade for more than 30 days did not impact outcomes based on the subgroup analysis.

Treatment Rationale and Mechanistic Implications Metastatic prostate cancer is unique among human cancers in that its natural history is profoundly influenced by therapy, in this case androgen-deprivation therapy. Although

the clinical benefit of androgen-deprivation therapy is pronounced, with a 90% to 95% response rate—among the highest of all human cancer therapies—its effects are short-lived, with progression typically seen within 18 to 24 months of therapy. The tumor burden is usually reduced significantly on the order of 1 to 2 log10 units. Hypothetically, if more of these cells could be eliminated upfront, progression-free survival, time to castrationresistant prostate cancer, and overall survival would increase, and this could be accomplished by the addition of therapies that impact the tumor burden in a noncross-resistant additive, or ideally, synergistic manner. The data from the E3805 trial indicate the lack of cross-resistance between docetaxel and androgen-deprivation therapy. In comparing the clinical benefit of docetaxel in hormone-sensitive prostate cancer (in E3805) vs its U.S. Food and Drug Administration–approved use in castration-resistant prostate cancer (based on the TAX 3272 and SWOG 99163 trials), early use of docetaxel imparts a longer median overall survival benefit (13 months vs about 3 months in castration-resistant prostate cancer). This is true despite the fact that almost 40% (137 of 393) of the men randomized to androgendeprivation therapy alone in E3805 received subsequent docetaxel.

Predominance of Benefit in High-Volume Disease Although a survival benefit was observed in all subgroups, the benefit was most pronounced in the highvolume subgroup, defined as those patients with extensive osseous or visceral metastatic disease. This, together with a delayed time to castration-resistant prostate cancer, argues that the cytoreduction resulting from docetaxel administration specifically targets the biologically aggressive disease compartment that ultimately gives rise to lethal castration-resistant prostate cancer. However the median

overall survival was not reached in the low-volume subgroup, limiting the power of this subgroup analysis.

Impact of Subsequent Therapies Delivery of subsequent therapies was fairly well balanced between the groups, with the predictable exceptions of more docetaxel given to the androgen-deprivation therapy–alone group and more cabazitaxel ( Jevtana) given to the combination arm. There was, however, about 20% more use of life-prolonging therapy in the androgen-deprivation therapy–alone arm. Although not prospectively validated, these findings suggest that docetaxel administration has the potential to be cost-effective in that it may reduce the need for subsequent therapies without compromising survival benefit.

Future Directions and Conclusions Docetaxel delivered as chemohormonal therapy is well tolerated and provides a greater clinical benefit than when it is delivered in the setting of castration-resistant prostate cancer. This therapy should be considered for all patients with newly diagnosed metastatic prostate cancer initially, particularly those with high-volume disease. n

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

References 1. Sweeney CJ, Chen YH, Carducci M, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737-746, 2015. 2. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004. 3. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004.

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | OCTOBER 10, 2015

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JCO Spotlight Geriatric Oncology

ASCO Statement: Improving the Evidence Base for Treating Older Adults With Cancer By Matthew Stenger

lder persons are the fastest-growing segment of the U.S. population and account for the majority of cancer diagnoses and deaths and the majority of cancer survivors. However, since this population is underrepresented in clinical trials, the evidence base for treating older patients is poor. As reported in the Journal of Clinical Oncology by co–first authors Arti Hurria, MD, of City of Hope, and Laura A. Levit, JD, of ASCO, and their colleagues, ASCO has issued a statement designed to encourage improvement of the evidence base for treating older adults with cancer.1 The statement includes five basic recommendations and associated action items, as reproduced below. “Some of the recommendations are

tions. Researchers should provide a rationale, informed by input from experts in aging and geriatric oncology, when trials include eligibility criteria that are restricted based on these factors. • The National Cancer Institute (NCI), U.S. Food and Drug Administration (FDA), and other organizations that are developing common sets of data elements for researchers to collect in clinical trials should include measures from the geriatric assessment domains. • Funders of cancer clinical trials in which tumor specimens are studied should require researchers to report the age distribution of samples studied and whether this is reflective of the age distribution of the population enrolled

Given the rapidly aging population, this is a crucial time to act to ensure all patients with cancer receive highquality, evidence-based care. —Arti Hurria, MD, Laura A. Levit, JD, and colleagues Arti Hurria, MD

achievable in a short timeframe. Others will require longer-term commitments and the collaboration of multiple stakeholders involved in clinical research,” noted the authors. “Given the rapidly aging population, this is a crucial time to act to ensure all patients with cancer receive high-quality, evidence-based care.” Recommendation 1: Use clinical trials to improve the evidence base for treating older adults with cancer. Action Items • Regulatory agencies, funders of cancer clinical research, and researchers should carefully consider whether there is evidence supporting limitations to eligibility criteria based on age, performance status, or comorbid condi-

onto the trial and the population with the disease overall. • The NCI should collaborate with the National Institute on Aging, National Institutes of Health (NIH), and other funders of cancer clinical research to encourage and incentivize research involving older adults. Recommendation 2: Leverage research designs and infrastructure to improve the evidence base for treating older adults with cancer. Action Items • Researchers and funders of cancer clinical research should use the full range of research designs, including innovative trial designs, to fill knowledge gaps in the treatment of older adults with cancer.

• Funders of comparative-effectiveness research should require researchers evaluating the role of a standard or novel cancer treatment to include a plan to study a population that mirrors the age distribution and health risk profile of patients with the disease. • Developers of research and clinical databases should ensure that their systems collect geriatric assessment data and have the functionality to support studies designed to improve the evidence base supporting the treatment of older adults with cancer. • The Centers for Medicare & Medicaid Services (CMS) should use its coverage with evidence development authority to cover the off-label use of marketed drugs in select cancer clinical trials. The CMS should work with the NIH, patients, and researchers to prioritize trials for this additional coverage. Recommendation 3: Increase the authority of the FDA to incentivize and require research involving older adults with cancer. Action Items • Congress should provide the FDA authority to require a drug or biologic marketing application to contain a plan to gather data and develop recommendations on safety, efficacy, and dosing in older adults. • Congress should grant the FDA authority to create incentives for companies that conduct clinical trials of new cancer treatments in older adults. • The FDA should include experts in aging and geriatric oncology on its advisory boards to provide advice on the assessment of novel agents and emerging federal policies. Recommendation 4: Increase clinician recruitment of older adults with cancer to clinical trials. Action Items • Professional societies should develop educational materials for clinicians and

researchers to encourage recruitment of older adults to clinical trials. • The American Medical Association should establish new common procedural terminology codes to reimburse clinicians who offer older patients the opportunity to participate in clinical trials, enroll them onto these trials, and conduct management and follow-up of these patients for the additional time and effort involved. These codes should be reimbursed by Medicare, Medicaid, and third-party payers. Recommendation 5: Use journal policies to incentivize researchers to consistently report the age distribution and health risk profiles of research participants. Action Items • Authors should be required to submit and report the detailed age distribution (by decade) of the population included in the study, not just the age ranges of population, and data analyses that could potentially yield valuable age-related information, including age-based analyses of response, benefit, and toxicity. • Geriatric oncology experts should be included in the pool of editorial board members who serve as peer reviewers of manuscripts. • Peer reviewers should be instructed to consider whether the authors have adequately reported the age distribution of the population included in the study, the generalizability of the results to the population with the disease, and data analyses that could potentially yield valuable age-related information. n

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

Reference 1. Hurria A, Levit LA, Dale W, et al: Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement. J Clin Oncol. July 20, 2015 (early release online).

For more information, visit http://www.siog.org

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Perspective

Older Patients With Cancer: A Growing Population in Need of Evidence-Based Care By Laura A. Levit, JD, and Arti Hurria, MD

he 2013 Institute of Medicine (IOM) report Delivering High Quality Cancer Care: Charting a New Course for a System in Crisis1 identified the dearth of evidence on older adults as a major quality-of-care issue. The U.S. population is aging at a rapid rate, and cancer is a disease that primarily affects older adults. More than 50% of cancer diagnoses and nearly 70% of cancer deaths occur in individuals aged 65 and older.2 The majority of cancer survivors are also in this age range. Recent projections of cancer incidence anticipate a 67% increase in cancer diagnoses in patients aged 65 and older between 2010 and 2030 but only an 11% increase in younger adults. Despite the strong association between cancer and aging, older adults are routinely underrepresented in cancer clinical research. Multiple studies have found that people aged 65 and older are underrepresented in both cancer registration trials and the National Clinical Trial Network’s trials (formerly the Cooperative Groups), and there has been little improvement over time. Trials focused exclusively on older adults are also rare.

Improving Our Evidence Base As a result, medical oncologists do not have the information needed to make evidence-based treatment decisions in older adults with cancer. Moreover, there is a projected shortage of health-care providers with geriatric expertise. The IOM report made two recommendations to improve our evidence Ms. Levit is Associate Director of Research and Analysis at ASCO, and Dr. Hurria is Director of Cancer and Aging Research Program, City of Hope, Duarte, California.

base and strengthen the national workforce that cares for older patients with cancer: (1) increase the breadth of collected data by matching the

Actionable Strategies The ASCO Statement makes five overarching recommendations that address key strategies to improve the

The ASCO statement lays out a blueprint for ensuring that all patients have access to evidencebased care, including the growing older population of patients. —Laura A. Levit, JD, and Arti Hurria, MD Laura A. Levit, JD

characteristics of the study population to those of patients with the disease (ie, enroll more elderly patients onto clinical trials), and (2) increase the depth of collected data by capturing a more detailed characterization of the study population through evaluation tools, such as a comprehensive geriatric assessment. It is important to understand, however, that the IOM issues recommendations to address pressing policy issues but does not take steps to implement those recommendations. Thus, in response to the IOM’s report, ASCO formed a working group composed of 11 individuals with expertise in geriatric oncology to review the IOM report and to identify actionable strategies for improving research on older adults with cancer. After more than a year of deliberations, conference calls, and approval from ASCO’s Cancer Research Committee and Board Executive Committee, the working group published the article Improving the Evidence Base for Treating Older Adults With Cancer: American Society for Clinical Oncology Statement.3 The statement is summarized in this issue of The ASCO Post.

evidence base for the treatment of older adults with cancer through advocacy, research, and education. Each recommendation includes a list of specific action items. In particular, the recommendations include: • Increase the U.S. Food and Drug Administration’s (FDA’s) authority to incentivize and require research on older adults with cancer. • Use clinical trials to improve the evidence base for treating older adults with cancer. • Leverage the full range of research designs and infrastructure for generating evidence on older adults with cancer. • Increase clinicians’ recruitment of older adults with cancer to clinical trials. • Utilize journal policies to improve researchers’ reporting on the age distribution and health-risk profiles of research participants. The first recommendation entails policy and/or legal changes to the FDA’s authority to require and incentivize clinical trials that include older adults, which can be achieved through the engagement of the multiple stakeholders involved in cancer clinical research. The concept is modeled after the strategy used in pediatrics to increase research on children.

For more on Geriatric Oncology, visit ASCOPost.com and search “Geriatrics for the Oncologist.”

For example, the Best Pharmaceuticals for Children Act provides industry with the financial incentive of an additional 6 months of market exclusivity for studying a product in children. The Pediatric Research Equity Act requires pharmaceutical companies to test their products in children under certain circumstances when submitting new drug applications. These acts have successfully increased pediatric research and, if adapted to geriatrics, would likely produce a similar increase in clinical trials studying older adults. ASCO’s advocacy department is in the process of developing an advocacy strategy for addressing this component of the statement. Recommendations two, three, and four speak to the need for increased research to guide evidencebased care of older patients. Aging is a heterogeneous process, and many older adults are able and willing to participate in clinical trials. Recent articles in the Journal of Clinical Oncology4,5 provided recommendations on designing clinical trials in older adults with cancer. A key component of clinical trials in older adults is the inclusion of a geriatric assessment, which provides clinicians with information on the heterogeneity of the aging process beyond chronologic age. Many of the domains of a geriatric assessment, including functional status, comorbidity, and psychosocial status, can be collected through patient-reported questionnaires. Predictive models have been developed that include geriatric assessment items (Cancer Aging Research Group6 and CRASH7 score) to identify a patient’s risk for severe chemotherapy toxicity. Further research is underway to understand how the information garnered from continued on page 44

The ASCO Post | OCTOBER 10, 2015

PAGE 44

Perspective

Laura A. Levit, JD, and Arti Hurria, MD continued from page 43

these tools can be utilized to inform clinical decision-making and guide interventions to improve outcomes in older adults receiving chemotherapy. Recommendation five leverages information collected in ongoing research studies through improved reporting of clinical trials in medical journals on the age distribution and health-risk profiles of research participants and age-related data analyses. Substantial evidence is being collected on older adults that is not reported in a format that has the potential to inform clinical care. Providing more detailed information on the age distribution of trial participants (not just the age ranges of the population), as well as any preplanned or hypothesis-generating outcomes by age, could inform clinicians about important agerelated efficacy, safety, and dosing considerations.

Society of Clinical Oncology statement. J Clin Oncol. July 20, 2015 (early release online). 4. Wildiers H, Mauer M, Pallis A, et al: End points and trial design in geriatric oncology research: A joint European organisation for research and treatment of cancer—Alliance for Clinical Trials in Oncology—International Society of Ge-

riatric Oncology position article. J Clin Oncol 31:3711-3718, 2013. 5. Hurria A, Dale W, Mooney M, et al: Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations. J Clin Oncol 32:2587-2594, 2014. 6. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in

older adults with cancer: A prospective multicenter study. J Clin Oncol 29:34573465, 2011. 7. Extermann M, Boler I, Reich RR, et al: Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for HighAge Patients (CRASH) score. Cancer 118:3377-3386, 2012.

Moving Forward The ASCO statement lays out a blueprint for ensuring that all patients have access to evidencebased care, including the growing older population of patients. Medical oncologists and oncology health-care providers play a key role in developing this muchneeded evidence. Together with patient advocates, regulatory bodies, research institutions, and medical journals, we can fill the knowledge gap needed to improve the care of our growing population of older adults with cancer. n

Disclosure: Ms. Levit reported no potential conflicts of interest. Dr. Hurria has received research funds to City of Hope from Celgene and GlaxoSmithKline and is also a consultant for GTx, Inc., Boehringer Ingelheim Pharmaceuticals, and On Q Health.

References 1. Institute of Medicine: Delivering high-quality cancer care: Charting a new course for a system in crisis, in Levit L, Balogh E, Nass S, et al (eds). Washington, DC, National Academies Press, 2013. 2. National Cancer Institute: SEER Stat Fact Sheets: All cancer sites. Available at http://seer.cancer.gov/statfacts/ html/all.html, 2015. Accessed September 22, 2015. 3. Hurria A, Levit LA, Dale W, et al: Improving the evidence base for treating older adults with cancer: American

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Announcements

Bart Barolgie, MD, Joins Tisch Cancer Institute at Mount Sinai

art Barlogie, MD, a myeloma expert who introduced the first curative therapy for multiple myeloma, a multidrug regimen known as Total Therapy 3, is joining the faculty of Tisch Cancer Institute of the Icahn School of Medicine at

Mount Sinai (ISMM. Dr. Barlogie will serve as Director of Research in the Myeloma Program led by Sundar Jagannath, MD, Professor of Hematology and Medical Oncology at ISMM. “I am excited to collaborate with

Sundar and other elite scientists to find novel approaches for patients with high-risk myeloma. We have a unique opportunity to move the field forward, and our understanding of the underlying mechanisms in the transition to malignant disease,” said Dr. Barlogie. Bart Barlogie, MD

IN ONCOLOGY, HAVE WE

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REFERENCE: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119.

Dr. Barlogie’s work has focused on biologic and therapeutic research, including chemotherapy, immunotherapy, and hematopoietic stem cell transplantation. Among his seminal contributions are the developments of the VAD regimen for refractory myeloma, autologous stem cell supported high dose therapy, tandem transplants, and thalidomide. Many new biologic insights have been gained through Dr. Barlogie’s research, notably, the identification of chromosome 13 deletions as a separate high-risk entity in myeloma, and more recently, the identification of distinct risk-stratified subgroups of myeloma.

Earlier Work Prior to joining Mount Sinai, Dr. Barlogie served for 20 years as Director of Myeloma Institute for Research & Therapy at University of Arkansas for Medical Sciences (UAMS), an Institute he founded. Under his leadership, the Institute became a worldrenowned program and was recently awarded a $10 million grant to create the Bart Barlogie Center for Molecular Diagnostics and the Celgene Distinguished Endowed Chair in Molecular Therapeutics at UAMS. Dr. Barlogie is a Fellow of the American College of Physicians, and has served on the Board of Directors of the International Myeloma Foundation. He currently serves on the editorial boards of Annals of Hematology, Blood, Clinical and Experimental Medicine, Clinical Cancer Research, Clinical Lymphoma & Myeloma, Current Cancer Therapy Reviews, Clinical Myeloma, International Journal of Clinical Oncology, Oncologie, and The Oncologist. Dr. Barlogie earned his postgraduate degrees at Heidelberg University and the Max Planck Institute for Medical Research in Germany. Following residency at the Universities of Munich and Muenster, he joined MD Anderson Hospital and Tumor Research Institute as a fellow. n

The ASCO Post | OCTOBER 10, 2015

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Journal Spotlight Breast Cancer

Increased Risk of Death From Breast Cancer for Women With Ductal Carcinoma in Situ vs General Population No Mortality Reduction With Reduction of Invasive Recurrence By Matthew Stenger

n a study reported in JAMA Oncology, Steven A. Narod, MD, FRCPC, of Women’s College Research Institute, Women’s College Hospital, and the University of Toronto, and colleagues found that the risk of breast cancer mortality

with increasing age, from 17.0 among women aged < 35 years (1.2% of study population) to 1.4 among those aged > 65 years. The 10-year breast cancer mortality rate was 1.1%. On multivariate analysis, 20-year

The outcome of breast cancer mortality for [ductal carcinoma in situ] patients is of importance in itself and potential treatments that affect mortality are deserving of study. —Steven A. Narod, MD, FRCPC, and colleagues

was elevated in patients with ductal carcinoma in situ compared with the general population, with risk being higher among younger vs older women and black vs white women.1 Approximately half of breast cancer deaths occurred without development of in-breast invasive recurrence. Breast cancer mortality was not reduced with the prevention of ipsilateral invasive recurrence by the addition of radiotherapy to lumpectomy or with unilateral mastectomy vs lumpectomy.

Study Details The study involved Surveillance, Epidemiology, and End Results (SEER) 18 registries data on 108,196 women diagnosed with ductal carcinoma in situ from 1988 to 2011. Patients had a mean age at diagnosis of 53.8 years (range = 15–69 years), and mean duration of follow-up was 7.5 years (range = 0–23.9 years). Among all patients, estrogen receptor status was positive in 43%, negative in 8%, and unknown in 49%; tumor grade was low in 10%, intermediate in 30%, high in 34%, and unknown in 26%; 45% received radiotherapy, 69% had lumpectomy, 21% had unilateral mastectomy, 6.6% had bilateral mastectomy, and 2.4% had no surgery; and 7.1% had a second primary breast cancer.

Mortality and Risk Factors At 20 years, overall breast cancer– specific mortality was 3.3% (95% confidence interval [CI] = 3.0%–3.6%), with risk being 1.8 times higher vs the general population (standardized mortality ratio = 1.8, 95% CI = 1.7–1.9). The standardized mortality ratio decreased

risk was significantly higher for women diagnosed at age < 35 years vs older women (7.8% vs 3.2%; hazard ratio [HR] = 2.58, P < .001) and for black vs white women (7.0% vs 3.0%; HR = 2.55, P < .001). Other factors that predicted breast cancer mortality included tumor size (HR = 1.28, P = .02 for 1.0– 1.9 cm; HR = 1.58, P < .001 for 2.0–4.9 cm; and HR = 1.8, P < .001 for ≥ 5.0 cm, all vs < 1.0 cm), grade (HR = 1.73, P < .001 for poorly vs well differentiated), estrogen receptor status (HR = 0.61, P < .001 for positive vs negative), and comedonecrosis (HR = 1.20, P = .02 vs solid-type intraductal histology).

Recurrence and Mortality Among 42,250 women who received lumpectomy and radiotherapy, 547 (1.3%) developed ipsilateral invasive recurrence and 163 (0.4%) died from breast cancer. Among 19,762 women who received lumpectomy without radiotherapy, 595 (3.0%) developed ipsilateral invasive recurrence, and 102 (0.5%) died from breast cancer. Among 25,527 who received unilateral or bilateral mastectomy, 200 (0.8%) had

ipsilateral invasive recurrence and 154 (0.6%) died from breast cancer. Among all patients, estimated 20-year risks were 5.9% for ipsilateral invasive recurrence and 6.2% for contralateral invasive recurrence, with estimated risks of 9.5% among patients with breast-conserving surgery without radiotherapy and 4.5% among those with breast-conserving surgery with radiotherapy. Risk of death from breast cancer increased after ipsilateral invasive recurrence (HR = 18.1, P < .001) and contralateral invasive recurrence (HR = 13.8, P < .001) but not after ductal carcinoma in situ ipsilateral or contralateral recurrence.

No Invasive Recurrence in Half of Deaths A total of 956 women died from breast cancer; of them, 517 (54%) did not develop in-breast invasive recurrence and 395 (41%) developed ipsilateral (n = 210) or contralateral (n = 165) invasive recurrence. No in-breast invasive recurrence before death was observed in 94 (58%) of 163 who received lumpectomy and radiotherapy, 51 (50%) of 102 who received lumpectomy without radiotherapy, and 112 (73%) of 154 who received unilateral or bilateral mastectomy.

No Survival Benefit With Reduced Recurrence Risk Among patients who received lumpectomy, 10-year risk of ipsilateral invasive recurrence was significantly reduced among those receiving vs not receiving radiotherapy (2.5% vs 4.9%; adjusted HR = 0.47, P < .001), but no reduction in risk of death from breast cancer was observed (0.8% vs 0.9%; adjusted HR = 0.81, P = .10). The 10-year risk of ipsilateral invasive recurrence was significantly lower among women receiving unilateral mastectomy vs lumpectomy (1.3% vs 3.3%; adjusted

Ductal Carcinoma in Situ and Subsequent Risks ■■ Risk of breast cancer mortality was elevated in patients with ductal carcinoma in situ compared with the general population, with risk being higher in younger vs older women and black vs white women. ■■ Approximately half of breast cancer deaths occurred without development of in-breast invasive recurrence. ■■ Breast cancer mortality was not reduced with prevention of ipsilateral invasive recurrence with the addition of radiotherapy to lumpectomy or with unilateral mastectomy vs lumpectomy.

HR = 0.81, P < .001). On unadjusted analysis, breast cancer mortality at 10 years was significantly higher in those receiving unilateral mastectomy (1.3% vs 0.8%; unadjusted HR = 1.45, P < .001), but the increased risk was no longer significant after adjustment for age at diagnosis, year of diagnosis, income, estrogen receptor status, tumor size, tumor grade, and ethnicity (HR = 1.20, P = .11). The investigators observed: [A]lthough it is accepted that, for women with invasive breast cancer, prevention of in-breast recurrence does not prevent death, this has not been widely accepted for women with [ductal carcinoma in situ]. Also, for women with invasive cancers it is accepted that, in terms of survival, lumpectomy is equivalent to mastectomy, even though patients who undergo mastectomy experience fewer local recurrences. In the SEER database, these relationships between local recurrence and mortality hold equally well for patients with [ductal carcinoma in situ].

They concluded: The risk of death increases after a diagnosis of an ipsilateral second primary invasive breast cancer, but prevention of these recurrences by radiotherapy does not diminish breast cancer mortality at 10 years.

In addition, they noted: Some cases of [ductal carcinoma in situ] have an inherent potential for distant metastatic spread. It is therefore appropriate to consider these as de facto breast cancers and not as preinvasive markers predictive of a subsequent invasive cancer. The outcome of breast cancer mortality for [ductal carcinoma in situ] patients is of importance in itself and potential treatments that affect mortality are deserving of study. n Disclosure: Dr. Narod holds a Canada Research Chair in Breast Cancer, and coauthor Javaid Iqbal, MD, has received a Canada Graduate Scholarship (Master’s) from the Canadian Institute of Health Research. No other potential conflicts of interest were reported.

Reference 1. Narod SA, Iqbal J, Giannakeas V, et al: Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. August 20, 2015 (early release online). Commentary by Laura Esserman, MD, MBA, Jasmine Wong, MD, Cheryl Ewing, MD, and Michael Alvarado, MD, begins on page 1

ASCOPost.com | OCTOBER 10, 2015

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Perspective

Ductal Carcinoma in Situ: Where We Have Been and Where We Can Be By Laura Esserman, MD, MBA, Jasmine M. Wong, MD, Cheryl Ewing, MD, and Michael Alvarado, MD continued from page 1

What We Have Learned We learned from this study that over a long period, ductal carcinoma in situ confers a risk for bilateral cancer. This means ductal carcinoma in situ is much like other risk factors that we do not consider cancer—such as lobular carcinoma in situ or atypia. This bilateral risk finding is what reinforces the concept that ductal car-

Jasmine M. Wong, MD

that are not high risk, since it does not impact mortality. • Low- and intermediate-grade ductal carcinoma in situ do not need to be a target for screening and early detection. • We should continue to improve our understanding of the biology of the highest-risk ductal carcinoma in situ (large, high-grade, hormone receptor-negative, HER2-positive

Cheryl Ewing, MD

cinoma in situ should be considered more of a risk factor than an indicator for targeted intervention. One of the reasons it is so challenging to differentiate low-grade ductal carcinoma in situ from atypia is that they likely reflect the same or similar biology. This should propel us to think about ductal carcinoma in situ as an opportunity to institute a preventive strategy, to test these cases, and to find additional biomarkers that might indicate responsiveness to interventions.

How We Should Proceed Several suggestions for how to proceed were presented in the JAMA Oncology editorial2 and appear here: • Much of ductal carcinoma in situ should be considered a “risk factor” for invasive breast cancer and an opportunity for targeted prevention. • Radiation therapy should not be routinely offered after lumpectomy for ductal carcinoma in situ lesions Dr. Esserman is Director, Carol Franc Buck Breast Care Center, University of California San Francisco. Dr. Wong is Assistant Professor of Clinical Surgery, Division of General Surgery, University of California San Francisco. Dr. Ewing is Professor of Clinical Surgery, University of California San Francisco. Dr. Alvarado is Associate Professor, Department of Surgery, University of California San Francisco.

Michael Alvarado, MD

disease, especially in very young and African American women) and test targeted approaches to reduce death from breast cancer.

Where the Challenges Lie We think the most challenging areas will be the following two specific recommendations: (1) to abandon the use of radiation therapy as a standard practice and (2) to avoid screening patients with low-grade ductal carcinoma in situ. First, we know that radiation decreases the “local” recurrence risk of both ductal carcinoma in situ and invasive cancer. However, the goal should be to avoid invasive cancer. The impact of radiation in reducing the chance of invasive cancer for a low-grade lesion is < 10%, and there is no impact on mortality. Additionally, if a person develops cancer, previous radiation therapy may preclude lumpectomy as a choice and may reduce the chance of a successful or straightforward reconstruction strategy. There is now an increasing amount of evidence that radiation therapy should not be offered as standard treatment for ductal carcinoma in situ and should only be considered for use in high-risk cases. Second, we should not be recommending biopsies for amorphous calcifications that are unlikely to be cancer and, if anything, are likely to be

low- or intermediate-grade ductal carcinoma in situ. There does not appear to be any good reason to know this early on. This approach would help us to avoid the many false-positive biopsies and take away the angst associated with a diagnosis of low-grade ductal carcinoma in situ and the difficult choices that follow for these women. A recent article suggested that we spend $4 billion in the evaluation of mammographic findings that turn out to be benign.3 These data should provide comfort to the imaging community; there is no urgency to know about low-grade ductal carcinoma in situ. Over time, if tiny amorphous calcifications continue to evolve and become more suspicious, a biopsy can be recommended. This is reminiscent of how we used to worry that tiny lung nodules represented metastatic cancer. Now we ignore the ones we see on chest computed tomography scans. So giving radiologists permission to avoid ordering or recommending a biopsy for these very low-risk lesions would improve the experience and outcome of screening. Together, as a community, we should establish better targets for screening.

Let’s Not Call It Cancer The majority of ductal carcinoma in situ is not likely to be associated with a future cancer. Over the past 20 years, we have surgically treated approximately 1 million patients with ductal carcinoma in situ, so-called stage 0. However, we have not seen a big drop in the rate of invasive cancers, as we should have if most ductal carcinoma in situ is a precursor to cancer. Instead, the incidence of breast cancer has continued to increase, in contrast to what we have seen with the removal of colon polyps and cervical intralesional neoplasia and the lowering of the rates of colon cancer and cervical cancer, respectively. The numbers for “stage 0 cancer” do not add up. The word carcinoma is not warranted for these conditions (with the exception of the highest-risk lesions). Clearly, the majority of these lesions are IDLE (indolent lesions of epithelial origin). We should push to change the terminology for the vast majority of the ductal carcinoma in

situ lesions we diagnose. Ductal carcinoma in situ should not be called cancer. We need to acknowledge the uncertainty in the benefit of intervention when we discuss all the options of treatment with our patients.

The Right Ingredients for Shared Decision-Making Surgical excision of ductal carcinoma in situ is not necessarily overtreatment, but it is an option, just as less treatment is an option. We have to help women navigate the options while understanding what makes the most difference to them: avoiding screening, avoiding a diagnosis of cancer in the future, or avoiding death from cancer. Each treatment option has a different impact on these goals. We need to help each woman understand the impact of these treatments based on the type of ductal carcinoma in situ she has in the context of her underlying breast cancer risk and other health conditions. Those are the right ingredients for shared decision-making. We have to support physicians who take the time to work with women this way and to provide the necessary shared decision-making tools. Understanding our patients’ goals provides an opportunity to start to do less for low-risk cases in controlled settings and learn more about the natural history of these lesions.

Clinical Trials and Registries The optimal way to move the field forward is to set up and encourage participation in clinical trials and registries. Through the upcoming WISDOM study (Women Informed to Screen Depending on Measures of Risk), the Athena Breast Health Network4 is comparing personalized screening to annual screening. In the personalized arm, we will use: (1) comprehensive risk assessment (all of the known genes that increase risk for breast cancer, including the recently described single nucleotide polymorphisms or small changes from one person to the other); (2) breast density; and (3) exposures (based on a health questionnaire) to assign women when to start screencontinued on page 48

The ASCO Post | OCTOBER 10, 2015

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Perspective

Laura Esserman, MD, MBA, and colleagues continued from page 1

ing, when to stop, how often to screen, and what modality to use. We will learn whether this approach is safe, preferred, less morbid (associated with fewer false-positive results), and associated with greater uptake of prevention. Perhaps most important, we will learn who is at risk for what type of cancer and how better to triage women with ductal carcinoma in situ. Background risk may be important and may influence outcome. To try to better understand that background risk, we are initiating a ductal carcinoma in situ registry across the Athena Breast Health Network under the leadership of Michael Alvarado, MD, at the University of California San Francisco and Rick Bold, MD, at the University of California Davis. We will be analyzing the pathology (how it looks under the microscope), integrating new multigene assays (On-

cotype DX® Breast Cancer Assay for Ductal Carcinoma in Situ), and giving women options based on their total picture. We will change the terminology for those with the lowest-risk lesions and offer active surveillance and prevention interventions as appropriate (such as tamoxifen for premenopausal women and raloxifene or exemestane for postmenopausal women). We believe it is safe to offer those women who wish to wait to intervene an opportunity to be screened and followed. This concept is not unlike that for women who have a BRCA1 or BRCA2 mutation, who are offered high-risk screening even though they likely have a fourfold higher risk than a woman with low-grade ductal carcinoma in situ.

Time for a Change We should not be afraid to step up and use these data. The Narod et al article showed that women with ductal carcinoma in situ have a 3% risk of dying of breast cancer, which

is the quoted figure for the average person’s risk of dying of breast cancer on the American Cancer Society website.5 These data should give us courage to offer options that are less aggressive and likely just as safe. If we do not do something different, we cannot hope to create a better future for women with ductal carcinoma in situ. The facts have been accumulating for many years now. It is time for a change. Women with ductal carcinoma in situ certainly are confronted with uncertainty. However, we have the tools now to practice medicine with precision and personalization, and that is precisely what we should do. We should acknowledge the uncertainty regarding the value of early intervention (and that the risk in watching is quite low), offer options, and discuss the associated outcomes. We especially need to let women know that there is plenty of time to consider their options and make a decision consonant with their values. n

Visit ASCOPost.com for Video Interviews Recorded During the 2015 European Cancer Congress The ASCO Post presents these and other important discussions: ■■

■■ ■■

■■

Robert J. Motzer, MD, on Phase III Results of CheckMate 025: Nivolumab vs Everolimus in Advanced Renal Cell Carcinoma Lisa Carey, MD, on Molecular Screening for Breast Cancer Treating Lymphoid Malignancies in Children and Adults With the Same Protocols Results of the KEYNOTE-001 Clinical Trial in Non–Small Cell Lung Cancer Oliver Sartor, MD, on Results of the ALSYMPCA Trial for Castration-Resistant Prostate Cancer

Visit The ASCO Post online at ASCOPost.com

Disclosure: Drs. Esserman, Wong, Ewing, and Alvarado reported no potential conflicts of interest.

References 1. Narod SA, Iqbal J, Giannakeas V, et al: Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. August 20, 2015 (early release online). 2. Esserman L, Yau C: Rethinking the standard for ductal carcinoma in situ treatment. JAMA Oncol. August 20, 2015 (early release online). 3. Ong MS, Mandl KD: National expenditure for false-positive mammograms and breast cancer overdiagnoses estimated at $4 billion a year. Health Aff (Millwood) 34:576-583, 2015. 4. Athena Breast Health Network: Available at http://athenacarenetwork. org/. Accessed September 14, 2015. 5. American Cancer Society: Lifetime risk of developing or dying from cancer. Available at www.cancer.org/cancer/cancerbasics/ lifetime-probability-of-developing-or-dyingfrom-cancer. Accessed September 14, 2015.

BECAUSE YOU CAN’T DO THIS TO FL…

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ZYDELIG is a PI3Kδ inhibitor indicated for Relapsed FL after ≥2 systemic therapies Accelerated approval was granted for FL based on overall response rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. FL=follicular B-cell non-Hodgkin lymphoma; PI3Kδ=phosphatidylinositol 3-kinase delta.

IMPORTANT SAFETY INFORMATION BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended • Fatal and serious intestinal perforation can occur in ZYDELIG-treated patients. Discontinue ZYDELIG for intestinal perforation

Please see the following pages for additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING.

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FDA approved in relapsed FL after ≥2 systemic therapies

Imagine what’s possible: ZYDELIG®—A first-in-class PI3Kδ inhibitor ZYDELIG is the FIRST AND ONLY

KINASE INHIBITOR APPROVED IN FL.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) RECOMMEND IDELALISIB MONOTHERAPY AS AN OPTION for appropriate patients with relapsed/refractory FL.1*

ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCCN®=National Comprehensive Cancer Network®. *Please see the complete version of the NCCN Guidelines® for Non-Hodgkin’s Lymphomas available on NCCN.org for specific recommendations.

IMPORTANT SAFETY INFORMATION (cont'd) Contraindications • History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN) Warnings and Precautions • Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3× upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5× ULN, withhold ZYDELIG and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs • Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea • Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5% • Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting • Severe cutaneous reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development

of severe cutaneous reactions and discontinue ZYDELIG if a reaction occurs • Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue ZYDELIG permanently and institute appropriate supportive measures if a reaction occurs • Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31% of ZYDELIG-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly • Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ZYDELIG and to use effective contraception during and at least 1 month after treatment with ZYDELIG Adverse Reactions • Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash • Most frequent serious adverse reactions (SAR) were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients and 53% of patients discontinued or interrupted therapy due to adverse reactions • Most common lab abnormalities (incidence ≥30%; all grades) were neutrophils decreased and ALT/AST elevations

Powerful efficacy, chemotherapy free Demonstrated single-agent efficacy in an open-label, pivotal, phase 2 trial2† ZYDELIG in FL (n=72)

POWER of response

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CI=confidence interval; CR=complete response; DoR=duration of response; ORR=overall response rate; PR=partial response. †Results of a single-arm, open-label trial of ZYDELIG (150 mg, twice daily) in patients with FL who failed to respond or relapsed after ≥2 prior therapies (which must have included both rituximab and an alkylating agent). Primary end point was ORR, as assessed by an independent review committee. ORR was defined as the proportion of subjects who achieved CR or PR. Secondary end point was DoR. DoR was measured from the onset of first documented response (CR or PR) to disease progression or death.2

• Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash; 53% of patients discontinued or interrupted therapy due to adverse reactions Drug Interactions • CYP3A inducers: Avoid coadministration with strong CYP3A inducers • CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for ZYDELIG toxicity • CYP3A substrates: Avoid coadministration with CYP3A substrates Dosage and Administration • Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown • Dose modification: Consult the ZYDELIG full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations,

bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, ZYDELIG should be permanently discontinued Please see the following pages for Brief Summary of full Prescribing Information, including BOXED WARNING. VISIT ZYDELIG.COM

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S:9.5” ZYDELIG® (idelalisib) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and serious pneumonitis can occur in ZYDELIG-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and serious intestinal perforation can occur in ZYDELIGtreated patients. Discontinue ZYDELIG for intestinal perforation [See Warnings and Precautions]. INDICATIONS AND USAGE: • ZYDELIG is indicated in combination with rituximab for the treatment of adults with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other comorbidities. • ZYDELIG is indicated for the treatment of adults with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received ≥2 prior systemic therapies. • ZYDELIG is indicated for the treatment of adults with relapsed small lymphocytic lymphoma (SLL) who have received ≥2 prior systemic therapies. • Accelerated approval was granted for FL and SLL based on overall response rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

See Warnings and Precautions, Adverse Reactions, and Use in Specific Populations for additional information. Adult Starting Dose: One 150 mg tablet taken orally twice daily (BID), swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who required treatment longer than several months is unknown.

Severe diarrhea or colitis (≥Grade 3) occurred in 14% of ZYDELIG-treated patients across clinical trials. ZYDELIG-induced diarrhea can occur at any time and responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month following ZYDELIG interruption with or without enteric or systemic corticosteroids. Avoid concurrent use of ZYDELIG with drugs that cause diarrhea. [See Dosage and Administration]. Fatal and serious pneumonitis occurred in ZYDELIG-treated patients. Patients taking ZYDELIG who present with pulmonary symptoms (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, >5% decrease in oxygen saturation) should be evaluated for pneumonitis. If pneumonitis is suspected, withhold ZYDELIG until etiology of pulmonary symptoms has been determined. Patients thought to have ZYDELIG-induced pneumonitis were treated with ZYDELIG discontinuation and corticosteroids. Fatal and serious intestinal perforation occurred in ZYDELIG-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Permanently discontinue ZYDELIG in patients who experience intestinal perforation. Severe Cutaneous Reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions (dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, skin disorder) have been reported. Monitor patients for severe cutaneous reactions and discontinue ZYDELIG. Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported in ZYDELIG-treated patients. Permanently discontinue ZYDELIG and institute appropriate supportive measures in patients who develop serious allergic reactions. Neutropenia: Treatment-emergent neutropenia (Grade 3 or 4) occurred in 31% of ZYDELIG-treated patients across clinical trials. Monitor blood counts every 2 weeks for the first 3 months, and weekly when neutrophils are <1 Gi/L [See Dosage and Administration]. Embryo-fetal Toxicity: Idelalisib is teratogenic in rats and may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after treatment [See Use in Specific Populations]. ADVERSE REACTIONS: See BOXED WARNING and Warnings and Precautions for additional serious adverse reactions.

Dose Modifications:

Subjects with Relapsed CLL:

• Pneumonitis: discontinue ZYDELIG for any symptomatic pneumonitis

The safety assessment of ZYDELIG 150 mg BID + rituximab (up to 8 doses) is based on data from 110 adult subjects with relapsed CLL (Study 1). The median duration of exposure to ZYDELIG was 5 months.

• Hepatotoxicity: – ALT/AST >3 to 5x ULN or bilirubin >1.5 to 3x ULN: maintain ZYDELIG dose; monitor weekly until ≤1x ULN – ALT/AST >5 to 20x ULN or bilirubin >3 to 10x ULN: withhold ZYDELIG; monitor weekly until ≤1x ULN then resume ZYDELIG 100 mg BID – ALT/AST >20x ULN or bilirubin >10x ULN: permanently discontinue ZYDELIG • Diarrhea: – Moderate (increase of 4-6 stools/day over baseline): maintain ZYDELIG dose; monitor weekly until resolved – Severe (increase of ≥7 stools/day over baseline) or hospitalization: withhold ZYDELIG; monitor weekly until resolved then resume ZYDELIG 100 mg BID – Life-threatening: permanently discontinue ZYDELIG • Neutropenia: – ANC 1 to <1.5 Gi/L: maintain ZYDELIG dose – ANC 0.5 to <1 Gi/L: maintain ZYDELIG dose; monitor weekly – ANC <0.5 Gi/L: withhold ZYDELIG; monitor weekly until ≥0.5 Gi/L then resume ZYDELIG 100 mg BID • Thrombocytopenia: – Platelets 50 to <75 Gi/L: maintain ZYDELIG dose – Platelets 25 to <50 Gi/L: maintain ZYDELIG dose; monitor weekly – Platelets <25 Gi/L: withhold ZYDELIG; monitor weekly until ≥25 Gi/L then resume ZYDELIG 100 mg BID • For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce dose to 100 mg BID if resuming treatment. Permanently discontinue ZYDELIG if severe or life-threatening toxicities recur upon rechallenge. CONTRAINDICATIONS: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis (TEN). WARNINGS AND PRECAUTIONS: Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. ALT or AST >5x ULN have occurred, usually within the first 12 weeks of treatment and were reversible with dose interruption. Upon resuming

• Adverse Reactions: Most common (≥2%) serious adverse reactions reported in 49% of subjects were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%). Most common adverse reactions (incidence ≥5% and occurring at ≥2% higher incidence in ZYDELIG-treated subjects; all Grades) were pyrexia (35%), nausea (25%), pneumonia (23%), diarrhea (21%), chills (21%), rash (18%), vomiting (13%), headache (10%), sepsis (8%), sinusitis (8%), pain (7%), arthralgia (7%), GERD (6%), stomatitis (6%), bronchitis (6%), nasal congestion (5%), and urinary tract infection (5%). Most common adverse reactions leading to dose reductions in 15% of subjects were elevated transaminases, diarrhea or colitis, and rash. Most common adverse reactions leading to discontinuation in 10% of subjects were hepatotoxicity and diarrhea/colitis. • Laboratory Abnormalities: Treatment emergent laboratory abnormalities (incidence ≥10% and occurring at ≥5% higher incidence in ZYDELIG-treated subjects; all Grades) were decreased neutrophils (60%), hypertriglyceridemia (56%), hyperglycemia (54%), increased ALT (35%), increased GGT (26%), increased lymphocytes (25%), increased AST (25%), decreased lymphocytes (20%), hyponatremia (20%), and hypoglycemia (11%).

• Laboratory Abnormalities: Treatment emergent laboratory abnormalities (all Grades) were decreased neutrophils (53%), increased ALT (50%), increased AST (41%), decreased hemoglobin (28%), and decrease platelets (26%). DRUG INTERACTIONS: • CYP3A Inducers: Strong CYP3A inducers decreased idelalisib AUC by 75%. Avoid coadministration with strong CYP3A inducers (e.g., rifampin, phenytoin, St. John’s wort, carbamazepine). • CYP3A Inhibitors: Strong CYP3A inhibitors increased idelalisib AUC 1.8-fold. Monitor for signs of ZYDELIG toxicity during coadministration and follow dose modifications for adverse reactions [See Dosage and Administration]. • CYP3A Substrates: ZYDELIG is a strong CYP3A inhibitor. Avoid coadministration with CYP3A substrates as AUC of sensitive CYP3A substrates increased 5.4-fold when coadministered. USE IN SPECIFIC POPULATIONS: Pregnancy: ZYDELIG is Pregnancy Category D and may cause fetal harm. In pregnant rats, embryo-fetal toxicities were observed, including decreased fetal weights, external malformations (short tail), skeletal variations (delayed ossification and/or unossification of the skull, vertebrae and sternebrae), urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, microphthalmia/anophthalmia). Women who are or become pregnant during ZYDELIG treatment should be apprised of the potential hazard to the fetus [See Warnings and Precautions]. Nursing Mothers: It is not known whether idelalisib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ZYDELIG, a decision should be made whether to discontinue nursing or ZYDELIG, taking into account the importance of ZYDELIG to the mother. Pediatric Use: Safety and effectiveness of ZYDELIG in children <18 years of age have not been established. Geriatric Use: In clinical trials of ZYDELIG in patients with FL, SLL, and CLL, 63% of patients were ≥65 years old; no major differences in effectiveness were observed. • In patients with iNHL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (28% vs. 20%), serious adverse reactions (64% vs. 37%), and death (11% vs. 5%). • In patients with CLL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (11% vs. 5%), serious adverse reactions (51% vs. 43%), and death (3% vs. 0%). Contraception in Females of Reproductive Potential: ZYDELIG may cause fetal harm. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after taking the last dose of ZYDELIG. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking ZYDELIG [See Warnings and Precautions]. Renal Impairment: No dose adjustment of ZYDELIG is necessary for patients with creatinine clearance ≥15 mL/min. Hepatic Impairment: Idelalisib AUC increased up to 1.7-fold in subjects with ALT, AST, or bilirubin >ULN compared to healthy subjects with normal ALT, AST, or bilirubin. Safety and efficacy data are not available in patients with baseline ALT or AST >2.5x ULN or bilirubin >1.5x ULN as these patients were excluded from Studies 1 and 2. Monitor patients with baseline hepatic impairment for signs of ZYDELIG toxicity and follow dose modifications for adverse reactions [See Warnings and Precautions, Dosage and Administration]. 205858-GS-000-PI July 2014

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.1.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed January 7, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018.

Subjects with Indolent Non-Hodgkin Lymphoma (iNHL): The safety assessment of ZYDELIG 150 mg BID is based on data from 146 adult subjects with iNHL. The median duration of exposure to ZYDELIG was 6.1 months (range: 0.3 to 26.4 months). • Adverse Reactions: Most common serious adverse reactions reported in 50% of subjects were pneumonia (15%), diarrhea (11%), and pyrexia (9%). Most common adverse reactions (incidence ≥10%; all Grades) were diarrhea (47%), fatigue (30%), cough (29%), nausea (29%), pyrexia (28%), abdominal pain (26%), pneumonia (25%), rash (21%), dyspnea (17%), decreased appetite (16%), vomiting (15%), upper respiratory tract infection (12%), asthenia (12%), night sweats (12%), insomnia (12%), headache (11%), and peripheral edema (10%). Most common adverse reactions leading to dose interruption or discontinuation in 53% of subjects were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

© 2015 Gilead Sciences, Inc. All rights reserved. ZYDP0192 08/2015 ZYDELIG, ZYDELIG logo, GILEAD and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its related companies. All other marks are the property of their respective owners.

S:13”

DOSAGE AND ADMINISTRATION:

treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use of ZYDELIG with hepatotoxic drugs. In all patients, monitor ALT and AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. If ALT or AST >3x ULN, monitor weekly until elevation resolves; if ALT or AST >5x ULN, withhold ZYDELIG and monitor AST, ALT and total bilirubin weekly until elevation resolves [See Dosage and Administration].

ASCOPost.com | OCTOBER 10, 2015

PAGE 53

Direct From ASCO

Focus on Geriatric Oncology: ASCO Prepares for an Aging Nation

he United States—and much of the world—is experiencing unprecedented demographic shifts in the population of older people, defined as people age 65 and over. In 2012, the population of older people in the United States reached a never-before seen height of 43.1 million, a number that will more than double to a projected 83.7 million, by 2050.1 From an oncology perspective, the aging of the population is already acutely felt. After all, people age 65 and older account for 60% of cancer diagnoses, 69% of cancer deaths, and more than 60% of all survivors.2 Combine these cancer statistics with the reality of a rapidly growing aging population, and it is easy to see how the field of geriatric oncology will become a defining concern for oncologists worldwide over the next few decades.

Needs of the Older Patient With Cancer

T:13.75”

In some ways, older patients with cancer have an advantage over younger patients, with studies showing that older age bestows upon patients a greater ability to

Arti Hurria, MD

face the psychological challenges that attend a cancer diagnosis.3 In other ways, however, older patients are at a disadvantage: As age goes up, so does the risk of developing toxicity as a result of treatment. Older patients are also more likely to develop numerous toxicities, including febrile neutropenia, anemia, osteoporosis, depression, and fatigue— conditions that interact with, and are complicated by, the presence of age-related diseases, such as diabetes and cardiac disease. Treating older patients is also complicated by the fact that as people grow older, chronologic age is no longer a reliable indicator of overall health, said Arti Hurria, MD, leader in the field of geriatric oncology and medical oncologist and Director of

PREPARING FOR AN AGING NATION

THE RISE OF OLDER ADULT PATIENTS WITH CANCER IN THE UNITED STATES

the Cancer and Aging Research Program at City of Hope National Medical Center. “At 40, we’re probably physiologically very similar, but as we age, there’s a lot more heterogeneity — the number 70 or 80 can no longer really reflect what that individual’s physiologic reserve is,” said Dr. Hurria, who is also the Past President of the International Society of Geriatric Oncology (SIOG) and Founder and Current Director of the Cancer and Aging Research Group (CARG). In addition, older patients’ goals for treatment may differ from those of patients in an earlier stage of life. For example, when deciding on a treatment plan, an older patient might place much more weight on how a specific drug is likely to affect his or her independence and/or cognitive function than on whether it can bring about cure or remission.4

on early-career oncologists’ time means this kind of in-depth geriatric knowledge is not provided. In order to address this educational gap, ASCO has placed geriatric oncology at the front and center of its efforts, launching initiatives such as the Journal of Clinical Oncology (JCO) “Special Series on Geriatric Oncology;” spearheading educational efforts to integrate geriatric oncology into general sessions at the Annual Meeting and into ASCO University® modules; addressing the oncology workforce shortage; bringing awareness to research needs in geriatric oncology; and introducing early-career oncologists to research on aging through the Leadership Development Program and the Conquer Cancer Foundation of ASCO’s Young Investigator Award (YIA) and Career Development Award (CDA).

Integrating Geriatric Oncology Into ASCO Programs

Addressing a Gap in the Research

Caring for older patients with cancer demands that clinicians acquire a strong knowledge base and skill set in geriatric oncology. But often, the multiple demands

ASCO leadership and volunteers are working to address one of the main challenges facing geriatric oncolcontinued on page 54

In 2012, the population of older people in the United States—defined as people ages 65 and older—reached the neverbefore-seen figure of 43.1 million, a number that will more than double to 83.7 million, by 2050.1 This boom in the older adult population will bring significant challenges in all provisions of health care. Oncology, specifically, has already been acutely affected by this population maturation. People ages 65 and older account

for 60% of cancer diagnoses.1

“

„

THE IMPLICATION OF TOXICITIES

All oncologists are geriatric oncologists, Stuart M. Lichtman, MD, FACP, Memorial Sloan Kettering Cancer Center, whether they know it or not.

BY THE NUMBERS

COMORBIDITIES AMONG ELDERLY PATIENTS

In the United States, people ages 65 and older account for

68%

60%

OF ALL CANCER DEATHS2

2014 B. J. Kennedy Award for Scientific Excellence in Geriatric Oncology Recipient

53%

in the United States will likely develop an invasive form of cancer at age 70 or older.3

Estimated New Cancer Cases in the United States in 2014, by Age4 Men All Ages

1 IN 3 MEN

TREATMENT AND SURVIVAL IN OLDER ADULTS

Given that comorbidity prevalence increases with age, the number of patients with cancer and comorbidity will increase concomitantly.

Older adult patients included in clinical trials are in the minority due to many factors, including enrollment exclusion because of comorbidities, transportation and mobility limitations affecting access to research centers, and the fear of cancer treatment–related toxicity.

than younger patients.8 98.7% of patients ages 60 or older who have a limited life expectancy because of cancer would choose to receive low-burden treatment

Enrollment in Registration Trials for New Cancer Therapies, By Age10

100%

90%

Clinical Trial Enrollment

All Ages

484,340 65+

419,410

Age 75+

60%

20%

Older Patients Wishing to Receive Treatment 0%

100%

98.7%

88.8%

have at least 1 comorbidity.5 0%

Cancer Population

100%

Approximately

1 IN 4 WOMEN

Age 70

with the restoration of current health.9

of people with cancer ages 65 or older

810,320

Women

Age 65

Older patients are less likely to desire life-prolonging treatment

More than

855,220 65+

related mortality.7

BARRIERS TO CLINICAL TRIAL ENROLLMENT

OF ALL CANCER SURVIVORS2

1 in 3 men and 1 in 4 women

of older adults with cancer who were deemed “fit” based on the Karnofsky Performance Status Scale experienced grade 3–5 toxicity. Among this group, there was a 2% incidence of treatment-

30%

of patients over the age of 65 have

5 other chronic conditions in addition to cancer.5

Patients on Medicare with 5 or more chronic conditions see anywhere from

5–16 different physicians each year at 3–9 different practices.6

36%

46%

74.4%

31%

Fear of inducing toxicity is a top reason doctors do not enroll older patient into trials.11

Of these 98.7%, however, 88.8% and 74.4%, respectively, would not choose low-burden treatment if the outcome was survival with severe cognitive impairment or survival with severe functional impairment.9

References: United States Census Bureau. “An aging nation: The older population in the United States: Population estimates and projections.” census.gov/prod/2014pubs/p25-1140.pdf. Accessed January 11, 2015.

2 Rowland JH, Bellizzi KM. “Cancer survivorship issues: Life after treatment and implications for an aging population.” J Clin Oncol. 2014;32:2662-2668. 3 American Cancer Society, Surveillance Research, 2014. cancer.org/acs/groups/content/@research/documents/ document/acspc-041784.pdf. Accessed January 11, 2015.

American Cancer Society, Surveillance Research, 2014. cancer.org/acs/groups/content/@research/documents/ document/acspc-041776.pdf. Accessed January 11, 2015.

Chronic Conditions Among Medicare and Medicaid Beneficiaries Chartbook: 2012 Edition. Centers for Medicare and Medicaid Services website. cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/ Chronic-Conditions/Downloads/2012Chartbook.pdf Accessed January 11, 2015.

6 Pham HH, Schrag D, O'Malley AS, et al. “Care patterns in Medicare and their implications for pay for performance.” N Engl J Med. 2007;356:1130-1139.

Hurria A, Togawa K, Mohile SG, et al. “Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study.” J Clin Oncol. 2011;29:3457-3465.

The influence of age on the likelihood of receiving end-of-life care consistent with patient treatment preferences.” J Palliat Med. Jun 2010;13:719-726.

8”

Fried TR, Bradley EH, Towle VR, Allore H. “Understanding the treatment preferences of seriously ill patients.” N Engl J Med. 2002;346:1061-1066.

Kemeny MM, Peterson BL, Kornblith AB, et al. “Barriers to clinical trial participation by older women with breast cancer.” J Clin Oncol. 2003;21:2268-2275.

11 Talarico, Chen G, Pazdur R. “Enrollment of elderly patients in clinical trials for cancer drug registration: A 7-year experience by the US Food and Drug Administration.” J Clin Oncol. 2004;22:4626-4631.

The ASCO Post | OCTOBER 10, 2015

PAGE 54

Direct From ASCO Focus on Geriatric Oncology continued from page 53

ogy: Older people with cancer are not enrolled onto studies in proportion to their numbers, resulting in a lack of evidence to help guide treatment decisions in the geriatric population. A 2004 study in JCO reported that while older patients comprise 60% of patients with cancer in the United States, they represent only 36% of patients enrolled onto trials. This discrepancy between the actual number of older patients with cancer and their representation on trials only increases with age.5 Earlier this year, ASCO issued a position statement, “Improving the Evidence Base for Treating Older Adults with Cancer,” calling for federal agencies and the cancer research community to

broaden clinical trials to include older adults. The position statement makes the five following overarching recommendations: • Use clinical trials to improve the evidence base for treating older adults. • Leverage research designs and infrastructure to improve the evidence base for treating older adults. • Increase U.S. Food and Drug Administration (FDA) authority to incentivize and require research on older adults with cancer. • Increase clinicians’ recruitment of older adults with cancer into clinical trials. • Utilize journal policies to incentivize researchers to consistently report on the age distribution and health risk profiles of research participants. Through its efforts to integrate ge-

riatric oncology learning into all of its educational endeavors and improve the evidence base for treating older adults with cancer, ASCO is working to fulfill its vision—that “all patients with cancer will have lifelong access to high-quality, effective, affordable, and compassionate care.” n

www.census.gov/prod/2014pubs/p251140.pdf. Accessed Oct 5, 2014. 2. Hurria A: Improving the evidence-base for treating older adults with cancer. [PowerPoint]. Alexandria, VA: Cancer Research Committee Meeting; September 30, 2014. 3. Rowland JH, Bellizzi KM: Cancer survivorship issues: Life after treatment and implications for an aging population. J Clin Oncol 32:2662-2668, 2014. 4. Hurria A, Dale W, Mooney M, et al: Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations. J Clin Oncol 32:2587-2594, 2014. 5. Talarico L, Chen G, Pazdur R: Enrollment of elderly patients in clinical trials for cancer drug registration: A 7-year experience by the US Food and Drug Administration. J Clin Oncol 22:4626-4631, 2004.

Selected portions reprinted from ASCO Connection. © American Society of Clinical Oncology. “Focus on Geriatric Oncology: ASCO Prepares for an Aging Nation.” ASCO Connection, December 2014. All rights reserved. References 1. United States Census Bureau: An aging nation: The older population in the United States: Population estimates and projections.

Journal of Oncology Practice to Expand in 2016: New Section Dedicated to Practical, Authoritative Clinical Reviews

n early 2016, readers of Journal of Oncology Practice ( JOP) will be greeted with an expanded journal, featuring a new section of succinct, focused, practical clinical reviews authored by expert opinion leaders in oncology. These reviews are designed to provide busy, full-time clinicians with authoritative opinions on some of the thorny clinical problems faced by oncologists and will include evidence-based suggestions to guide decision making in patient care. Many of the reviews will tie in with issues of care delivery highlighted by original research presented in JOP. This clinical review content will help further JOP’s mission of providing evidence-based knowledge to guide and improve the delivery of high-quality,

improvement science; and business and socioeconomics.

Filling a Need

efficient care. At the same time, JOP will continue featuring original research and perspectives on care delivery; quality and value of care; performance of clinical trials; health policy;

This expansion of JOP’s pages addresses a need among physicians, nurses, pharmacists, practice managers, and other clinicians for insight into the clinical thought processes that guide key opinion leaders through challenging clinical problems. These reviews will also highlight literature perhaps not as well known to readers, thus giving clinicians new insights into the care of patients. With the addition of this new section, JOP—now in its 10th year of publication—will be characterized by a unique mix of research on all aspects of healthcare delivery (as well as reviews) with a clinical focus. The new content will serve

as a springboard for discussing perspectives on the value and quality of care. “JOP is enhancing its content to include very pointed and practical reviews on topics that are pertinent to any oncologic clinician,” said JOP Editor-in-Chief John V. Cox, DO, MBA, FACP, FASCO. “Our current content, which is focused on care delivery, is a perfect platform for including these practical reviews. “JOP is very focused on original research that helps clinicians gain insight into how to deliver care,” Dr. Cox said. “That we now include content to help inform the clinical practice of oncology will make JOP even more valuable to the practicing physician.” Each monthly issue of JOP will incontinued on page 55

Save the Date Genitourinary Cancers Symposium

Cancer Survivorship Symposium

Quality Care Symposium

January 7–9, 2016

January 15–16, 2016

January 26–27, 2016

Moscone West Building

San Francisco Marriott Marquis

JW Marriott Phoenix Desert Ridge

San Francisco, California

Phoenix, Arizona

ASCOPost.com | OCTOBER 10, 2015

PAGE 55

Direct From ASCO JOP Clinical Expansion continued from page 54

clude two to three clinical review articles with expert commentary, penned by leaders in the field. The reviews will make reference to and highlight similar themes covered in current and past JOP articles, thus integrating the reviews into the larger landscape of JOP.

features such as highlighted text boxes that summarize key findings, as well as synopses of studies, will enable readers to quickly extract the main points of JOP articles. Readers will be able to find the entire full-length reports online, representing the PubMed indexed paper of record. As in the past, JOP will continue to publish nearly all

of its content online, ahead of print. “We recognize that most researchers seek a large and vigorous audience for their work,” Dr. Cox said. “By providing a short summary, we feel JOP will enlarge the audience that reads an individual report. In addition, should readers or researchers need to read the fulllength version, the full report is easily

available in the online presentation of JOP, which is the journal of record.” n Originally printed in the ASCO Daily News. © American Society of Clinical Oncology. “ JOP to Expand in 2016: New Section Dedicated to Practical, Authoritative Clinical Reviews.” am.asco.org/dn. ASCO Daily News. 30 May 2015. All rights reserved.

John V. Cox, DO, MBA, FACP, FASCO

“ASCO, as the leading voice of oncology in the world, is in a unique position to wed these short, practical vignettes of clinical practice with robust original research on delivery of care,” Dr. Cox said.

Looking Ahead In addition to new clinical reviews, JOP will also introduce new formats for all content, with the goal of providing content that is more accessible and immediately meaningful to readers. Most original reports will be presented in print as short summary reports, allowing busy clinicians to easily glean key research findings and takeaways in a short amount of time. Similarly,

Updated Resource for Your Patients: Advanced Cancer Care Planning Booklet

he latest version of ASCO Answers Advanced Cancer Care Planning is now available. This booklet contains comprehensive information about how patients can communicate directly and honestly about advanced cancer and end-of-life care with friends, family, children, and the health-care team. This booklet is available as a printable PDF at www.cancer.net/advancedcancer or at cancer.net/estore as bound copies for your office or waiting room (ASCO members save 20%). n

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 cases of progression with ﬁrstgeneration EGFR TKIs are related to the T790M mutation1,2

NEARLY 2 OUT OF 3

CASES ARE RELATED TO T790M

T790M is an acquired mutation and has been identified as the most common mechanism of acquired resistance in nearly 2 out of 3 patients with advanced NSCLC.1,2 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).3 Find out how the T790M mutation could affect the future of NSCLC at: EGFRevolution.com.

AstraZeneca is conducting ongoing research to understand the science of the T790M mutation

as a driver of resistance. References: 1. Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19: 2240-2247. 2. Arcila ME, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. ©2015 AstraZeneca. All rights reserved. 3140405 6/15

The ASCO Post | OCTOBER 10, 2015

PAGE 56

Direct From ASCO

ASCO, ACS, ASTRO Study Finds Increased Travel Distance Affects Whether Patients Receive Adjuvant Chemotherapy

new study conducted by ASCO in collaboration with the American Cancer Society (ACS) and the American Society for Radiation Oncology (ASTRO) and published in the Journal of Clinical Oncology1 found that patients who have to travel farther to appointments are less likely to receive adjuvant chemotherapy, regardless of whether or not they are insured. Evidence-based treatment guidelines recommend the use of adjuvant chemotherapy in many cancer patients within 90 days after surgery. But studies show that in many cases, patients do not receive it. To explore the role geographic access to care plays, researchers compared patients’ travel distance,

insurance status, and an area’s density of oncologists to the likelihood patients received adjuvant chemotherapy within 90 days of surgery for colon cancer. The data used in the study captured about 70% of newly diagnosed cancer cases in the United States. Of 34,694 patients in the study cohort, three-quarters (75.7%) received adjuvant chemotherapy within 90 days of surgery. Patients who traveled 50 to 249 miles were 13% less likely to receive adjuvant chemotherapy than those whose travel distance was less than 12.5 miles. Patients who had to travel 250 miles or more were nearly two-thirds less likely to receive adjuvant chemotherapy. While density level of oncologists

alone was not statistically associated with receipt of adjuvant chemotherapy, patients who had either no insurance or public (nonprivate) insurance and also resided in areas with low density of oncologists were 15% less likely to receive adjuvant chemotherapy. To read the full article, go to: jco.ascopubs.org/content/early/ 2015/08/21/JCO.2015.61.1558. n

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al

Be a Voice in The Campaign to Conquer Cancer

e’ll provide the resources. You provide the voice. The Campaign to Conquer Cancer is raising $150 million to support a world free from the fear of cancer. Our potential to raise money increases with every new person who learns about our work. We need the most trusted leaders in the oncology community to share the message about our critical movement—that’s you. Most people outside the oncology community are unaware that in just 15 years, the Conquer Cancer Foundation (CCF) has granted more than $150 mil-

lion to fund patient and caregiver education, boost the careers of young oncologists, and support clinical research around the world. Let the people who turn to you for advice on medicine and health know CCF resources are at the core of cancer treatment and discoveries. To learn more, sign up at conquer. org/asco, and we’ll share some ways you can help us connect others to The Campaign to Conquer Cancer. n

Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

© 2015. American Society of Clinical Oncology. All rights reserved. Reference 1. Lin CC, Bruinooge SS, Kirkwood MK, et al: Association between geographic access to cancer, insurance, and receipt of chemotherapy: Geographic distribution of oncologists and travel distance. J Clin Oncol. August 24, 2015 (early release online).

5 most-accessed Top 10 Top most-accessed articles recentlyinpublished articles published 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

What’s Hot in

JCO JCO.org

Addition of Bevacizumab to Chemotherapy for Treatment of Solid Tumors: Similar Results but Different Conclusions

Prostate Cancer: Evolution or Revolution?

FOLFIRINOX: A Small Step or a Great Leap Forward?

Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

ASCOPost.com | OCTOBER 10, 2015

PAGE 57

Issues in Oncology Health-Care Policy

ASCO Asks CMS to Revisit Its Payment Policy to Support Optimal Cancer Care

SCO has called on the Centers for Medicare & Medicaid Services (CMS) to reconsider revisions to payment policies that could be administratively burdensome to oncology practices and result in reimbursement that inadequately supports optimal cancer patient care. In a comment letter to CMS on the Proposed Rule for the Medicare Physician Fee Schedule, ASCO makes 23 specific recommendations that focus on patient care, physician payment, quality of care, and other important issues.

notes that it would be extremely disruptive, counterproductive, and inefficient to require the same physician both to order and supervise “incident to” services, such as chemotherapy administration. Yet, under the new CMS rule, the billing physician must be the person who supervises auxiliary personnel who are performing “incident to” services. The rule further eliminates language that permits an ordering and supervising physician to be different providers. ASCO is concerned this may cause ambiguity and compliance difficulties for oncology practices in providing efficient cancer treatment.

Potentially Misvalued Codes

Julie M. Vose, MD, MBA, FASCO

ASCO raises concerns, specifically, about changes in rules on “incident to” billing, the methodology used to identify potentially misvalued reimbursement codes, the elimination of the cancer staging measure in the CMS quality reporting system, and new requirements for chronic care management. “CMS payment policies should support this nation’s transition to a healthcare system that provides high-quality, high-value cancer care for all patients with cancer,” said ASCO President Julie M. Vose, MD, MBA, FASCO. “We believe that many of the proposed 2016 fee schedule policies will be foundational to changes planned for 2019 and beyond. We strongly encourage CMS to implement policies that move us closer to the agency’s own stated goals for transforming the cancer care delivery system—rather than creating barriers.”

ASCO Concerns and Related Recommendations ‘Incident To’ Billing ASCO Recommendation: CMS should not implement its proposal to change the incident to rules without clarifying that the ordering physician may differ from the supervising physician for chemotherapy administration. Background: Modern oncology practices treat patients by working as integrated teams in which oncologists often supervise several clinical sites, and ASCO

ASCO Recommendation: CMS should use methodologies other than the “high expenditure by specialty screen” to identify potentially misvalued codes. Background: By law, CMS must reduce expenditures by revaluing misvalued reimbursement codes in order to meet targeted cost savings and avoid across-the-board reimbursement cuts. In 2015, CMS added the “high expenditure by specialty” screen for identifying services that are potentially misvalued. According to ASCO, the methodology proposed by CMS is overly inclusive, fails to target codes that are likely to be misvalued, and places unnecessary administrative burdens on CMS staff and medical societies. ASCO is also concerned that the CMS-proposed rule specifically lists a number of chemotherapy administration codes as being potentially misvalued. Reducing reimbursement for these codes would leave practices with fewer resources for providing chemotherapy to patients who need it, ASCO contends. Furthermore, ASCO recommends that CMS keep the Refinement Panel— a group of medical professionals who help CMS determine the value of CPT codes—as an additional way to evaluate codes. Public comment does not replace the independent and reasoned consideration of a diverse set of medical professionals, notes ASCO.

Cancer Staging Measure ASCO Recommendation: CMS should not finalize its proposal to eliminate the cancer staging measure from registry reporting in the Physician Quality Reporting System (PQRS). ASCO urges CMS to retain this measure and consider refining it to apply only to a period of time following the initial office visit.

Background: ASCO asserts that CMS has wrongly determined that the cancer staging quality reporting measure does not add clinical value to PQRS. The cancer staging measure is clinically important to PQRS, because capturing a patient’s initial treatment stage is critical for providers to assess prognosis and appropriate treatment options, and it is one of the few oncology-specific measures in a system that lacks adequate measures of high-quality cancer care.

Chronic Care Management ASCO Recommendation: Chronic care management (CCM) services have the potential to provide meaningful opportunities to improve oncology care management and lower Medicare’s overall expenditures. CMS should continue to focus resources on providing beneficiaries with access to medical advice and eliminating counterproductive administrative burdens on providers that hamper patient access. Background: According to ASCO, oncologists have been undermined while trying to implement CCM services by overly burdensome and confusing administrative requirements and a limitation permitting only one provider to deliver CCM services to a Medicare beneficiary, unnecessarily limiting patient access to these important services. The care of individuals with cancer is complex and often includes managing multiple comorbidities by multiple providers. ASCO also notes that current CMS policy does not ensure that the most appropriate physician is receiving CCM reimbursement, and that reimbursement levels are inadequate to support compliance with all requirements, including having adequate health information technology, providing 24/7 beneficiary access, providing nursing staff, and covering related overhead costs.

Other Recommendations Valuation of Radiation Oncology Services: ASCO advises CMS to be more prudent about developing policies on radiation oncology reimbursement and urges the agency not to finalize its proposed policies that would threaten patient access to radiation oncology services, especially in community-based settings. Implementing Policies That Ensure Fair and Adequate Reimbursement for Biosimilars: ASCO supports fair and adequate reimbursement of biosimilar biological drugs to promote patient ac-

cess to all medically necessary options for treating cancer. Biosimilars are an important tool in cancer treatment, and supporting patient access to these drugs through adequate reimbursement may result in lower out-of-pocket costs for Medicare beneficiaries who are treated with biosimilars and for the Medicare program as a whole. ASCO recommends that CMS establish and revisit its reimbursement policies with an emphasis on supporting patient access while incentivizing biosimilar development, innovation, and cost-effectiveness.

Common Ground in the Proposal ASCO also highlights three specific areas in which the Society supports the CMS proposed physician fee schedule proposal, but recommends additional efforts that are needed:

Reimbursement for Advance Care Planning As oncologists are key sources of information for end-of-life care and planning, ASCO strongly supports the CMS proposal to provide reimbursement for advance care planning. ASCO also applauds the CMS proposal for allowing patients to receive advance care planning services from more than one provider, permitting beneficiaries to seek advice from multiple medical professionals before making decisions regarding complex clinical issues. The Society recommends, however, that CMS issue clear and comprehensive guidance at the national level to avoid geographic disparities in Medicare beneficiary access to advance care planning.

Cognitive Work ASCO is encouraged by CMS’s acknowledgement that resources are scarce for some specialists who perform extensive planning and critical thinking about the individual chronic care needs of particular subsets of Medicare beneficiaries, and recommends that CMS establish new codes and payments for cognitive services performed in oncology care in a way that promotes highquality, high-value treatment. ASCO further notes in its comment letter that medical oncology care “requires extensive cognitive work that is not captured by the face-to-face patient encounters and drug administration services that the current, outdated system recognizes.” Cognitive services, including continued on page 58

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Issues in Oncology CMS Payment Policy continued from page 57

treatment planning and monitoring, are critical to cancer patients because these services improve the quality of care, avoid costly complications and interventions, and promote efficient clinical management of comorbidities.

Improving and Measuring Quality and Value In responding to the CMS request for comments on the implementation of the Merit Based Incentive Payment System, ASCO urges CMS to place emphasis on improving healthcare quality through measures that are specifically “tailored to oncology specialists’ day-today practices”, as opposed to requiring adherence to measures outside cancer care providers’ scope of practice. The Society encourages CMS to continue to use and further integrate into Medicare’s quality reporting programs qualified clinical data registries, such as ASCO’s Quality Oncology Practice Initiative (QOPI), the nation’s leading quality measurement and quality assurance program for medical oncology care.

Alternative Payment Models In its comment letter, the Society also calls on CMS to implement and evaluate, as soon as possible, the ASCO Patient-Centered Oncology Payment model, which promotes access to the full range of services needed by individuals with cancer, reduces overall expenditures, and fosters high-quality care. ASCO asserts that the Patient-Centered Oncology Payment model “provides an effective pathway for medical oncologists to participate in alternative payment models in 2019,” as called for and defined under the Medicare Access and CHIP Reauthorization Act of 2015. The CMS Center for Medicare and Medicaid Innovation is currently implementing its Oncology Care Model in an effort to explore specialty-specific payment models. ASCO notes, however, that the Oncology Care Model has significant shortcomings that the PatientCentered Oncology Payment model can address, and that CMS “should avoid a narrow approach that only tests one model for improving oncology care. Testing the Patient-Centered Oncology Payment model alongside the Oncology Care Model would provide the Innovation Center with comparative data on the two models, as well as significantly increase participation by oncologists in [alternative payment models],” writes Dr. Vose. The proposed 2016 Medicare Physi-

cian Fee Schedule is the first opportunity for CMS to gather feedback on the changes in physician payment policy rising from the Medicare Access and CHIP Reauthorization Act. ASCO has devoted considerable resources to developing oncology payment and quality assurance models that improve care coordination and management and pro-

mote high-quality, high-value practices in oncology care. The end products of these efforts are Patient-Centered Oncology Payment, QOPI, and CancerLinQ. These innovative programs, notes ASCO, provide CMS with a roadmap for transforming oncology payment policies as required by the Medicare Access and CHIP Reauthorization

Act and should be included in the final 2016 Medicare Physician Fee Schedule. Review all 23 ASCO recommendations to CMS in the full-text comment letter at http://www.asco.org/ sites/www.asco.org/files/cms_payment_policies_9.8.15.pdf ?et_ cid=36647465&et_rid=466246220&li nkid=comment+letter. n

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Journal Spotlight Dermatologic Oncology

Pembrolizumab Increases Progression-Free Survival in Ipilimumab-Refractory Advanced Melanoma By Matthew Stenger

n a randomized phase II trial (KEYNOTE-002) reported in The Lancet Oncology, Antoni Ribas, MD, of

UCLA Jonsson Comprehensive Cancer Center, Los Angeles, and colleagues found that treatment with the anti–

PD-1 (programmed cell death protein 1) antibody pembrolizumab (Keytruda) prolonged progression-free survival vs

investigator-choice chemotherapy in patients with advanced melanoma procontinued on page 60

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Journal Spotlight Pembrolizumab continued from page 59

gressing on ipilimumab (Yervoy) and, if BRAF V600-mutant positive, a BRAF or MEK inhibitor.1

Study Details A total of 540 patients with progressive disease within 24 weeks after

at least two ipilimumab doses and, if BRAF V600-mutant positive, previous treatment with a BRAF or MEK inhibitor or both took part in this open-label trial. They were randomized 1:1: between November 2012 and November 2013 to receive pembrolizumab 2 mg/ kg (n = 180) or 10 mg/kg (n = 181) every 3 weeks or investigator-choice

chemotherapy (n = 179, including 42 to paclitaxel plus carboplatin, 28 to paclitaxel, 13 to carboplatin, 45 to dacarbazine, and 43 to temozolomide). Patients had to have resolution of all ipilimumab-related adverse events to grade 0 or 1 and prednisone ≤ 10 mg/d for at least 2 weeks. Randomization was stratified by Eastern Cooperative

Oncology Group performance status, lactate dehydrogenase (LDH) concentration, and BRAF V600-mutation status. Patients were masked to the dose of pembrolizumab. The primary endpoint was progression-free survival in the intent-to-treat population. Patients had a median age of 60 to 63 years, 96% to 99% were white, 58% to 64% were male, 54% to 55% had a performance status of 0, 76% to 78% had wild-type BRAF, 55% to 60% had normal LDH levels, 82% to 83% had stage M1c disease, 36% to 44% had two lines and 30% to 33% had at least three lines of prior therapy, 46% to 50% had received chemotherapy, and 24% to 26% had received a BRAF or MEK inhibitor.

Progression-Free Survival At the prespecified second interim analysis, at a median follow-up of 10 months, progression-free survival on independent central review was significantly prolonged in the pembrolizumab 2-mg/kg group (hazard ratio [HR] = 0.57, P < .0001) and in the pembrolizumab 10-mg/kg group (HR = 0.50, P < .0001) compared with the chemotherapy group. There was no significant difference for the 10-mg/ kg dose vs the 2-mg/kg dose (HR = 0.91, 95% confidence interval [CI] = 0.71–1.16). More than half of all patients had progressed by 12 weeks, the time of the first tumor assessment. Median progression-free survival was 2.9 months (95% CI = 2.8–3.8 months) and 2.9 months (95% CI = 2.8–4.7 months) in the pembrolizumab groups (2-mg/kg dose and 10-mg/kg dose, respectively) vs 2.7 months (95% CI = 2.5–2.8 months) in the chemotherapy group. Six-month progression-free survival was 34% (95% CI = 27%–41%) in the 2-mg/kg group and 38% (95% CI = 31%–45%) in the 10-mg/kg group vs continued on page 61

Study Update on Pembrolizumb in Advanced Melanoma ■■ Progression-free survival was significantly increased at both pembrolizumab doses (2 mg/kg and 10 mg/kg) vs chemotherapy. ■■ Six-month progression-free survival was 34% with 2 mg/kg of pembrolizumb and 38% with 10 mg/kg of pembrolizumab vs 16% with chemotherapy.

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Perspective

Anti–PD-1 Superior to Chemotherapy in the KEYNOTE-002 Trial By Douglas B. Johnson, MD, MSCI

mmunotherapy, once considered a niche treatment for a few specific cancers, has rapidly emerged as an additional pillar of cancer therapeutics. With the proliferation of promising results, clinical trials, and new drug approvals, one cannot help but be amazed that only 3 years have elapsed since Dr. Topalian and colleagues’ seminal study of nivolumab’s (Opdivo) activity1 and only 2 years have passed since the first description of pembrolizumab (Keytruda; previously known as lambrolizumab).2 Over that short period, agents targeting programmed cell death protein 1 receptor (PD-1) and its ligand (PD-L1) have demonstrated clinical activity in cancers originating from at least nine different organ systems, and several promising combination regimens have also emerged.3,4

KEYNOTE-002 Trial Among the highest response rates for anti–PD-1 have been observed in advanced melanoma. This issue of The ASCO Post summarizes another example of anti–PD-1’s efficacy in this disease: a phase II study of pembrolizumab vs investigator’s choice chemotherapy in treatment-refractory melanoma.5 Dr. Johnson is Assistant Professor of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Pembrolizumab continued from page 60

16% (95% CI = 10%–22%) in the chemotherapy group. In post hoc analysis, restricted mean progression-free survival was 5.8 and 6.5 vs 3.7 months, respectively. The benefit of both pembrolizumab doses was observed in all prespecified subgroups, including BRAF and LDH status subgroups. On independent central review, response was observed in 21% of patients in the pembrolizumab 2-mg/kg group and 25% of the 10-mg/kg group vs 4% of the chemotherapy group (P < .0001 for both comparisons). Overall survival analysis is awaited.

Adverse Events The most common treatment-related grade 1 or 2 adverse events among pembrolizumab patients were fatigue

In this study, Dr. Ribas and colleagues reported the results for 540 patients who had previously received ipilimumab (Yervoy) and, in patients with a BRAF V600 mutation, BRAF inhibitors with or without MEK inhibitors. Two doses of pembrolizumab (2 mg/ kg every 3 weeks—the now U.S. Food and Drug Administration–approved dose—and 10 mg/kg every 3 weeks) were compared with investigator’s

pared with chemotherapy. Median progression-free survival by investigator review (3.7 and 5.4 months vs 2.6 months), progression-free survival at 6 months (34% and 38% vs 16%), and overall response rate (21% and 26% vs 4%) were all improved in the pembrolizumab arms. In addition, grade 3 to 4 toxicities were less frequent with both doses of pembrolizumab (11% and 14% vs 26%). This study established

A number of critical questions remain surrounding front-line therapy for patients with advanced melanoma…. In this treatmentrefractory setting, however, the data are clear and unequivocal: pembrolizumab (and nivolumab) should be strongly preferred over cytotoxic chemotherapy. —Douglas B. Johnson, MD, MSCI

choice of several different chemotherapeutic agents, including dacarbazine, temozolomide, carboplatin, paclitaxel, or the latter two in combination. This study found that both doses of pembrolizumab produced superior progression-free survival, objective response rate, and toxicities com(21% and 28% vs 32% of the chemotherapy group) and pruritus (21% and 23% vs 4% of the chemotherapy group); among patients receiving chemotherapy, nausea was the most common adverse event (30%, vs 4% and

pembrolizumab as a new standard of care in ipilimumab-refractory melanoma and led to the drug’s regulatory approval in 2014.

Results in Context Although the superiority of pembrolizumab compared with cytotoxic kg group, 14% of the pembrolizumab 10-mg/kg group, and 26% of the chemotherapy group, with the most common in pembrolizumab patients being fatigue (1% and < 1% vs 5%) and the most common in the chemotherapy

These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumabrefractory melanoma. —Antonio Ribas, MD, and colleagues

8% in the pembrolizumab 2 mg/kg and 10 mg/kg groups). Treatment-related grade 3 or 4 adverse events occurred in 11% of patients in the pembrolizumab 2-mg/

group being anemia (5%), fatigue (5%), neutropenia (4%), and leukopenia (4%). Treatment-related adverse events led to treatment interruption in 8%, 8%, and 18% of patients and treat-

chemotherapy in this setting is a welcome confirmation, it is not surprising in view of several previously published studies. In a phase I study of 173 patients, pembrolizumab previously demonstrated an overall response rate of 26% in ipilimumabrefractory melanoma, dramatically better than historical response rates to chemotherapy.6 A phase II study compared nivolumab with investigator’s choice chemotherapy and noted an improved overall response rate with nivolumab (31.7% vs 10.6% in ipilimumab-refractory melanoma).7 A phase III study compared nivolumab with dacarbazine in patients with untreated BRAF wild-type melanoma. This study reported improved overall survival at 1 year (72.9% vs 42.1%), median progression-free survival (5.1 vs 2.2 months), and overall response rate (40% vs 13.9%).8 Finally, two separate studies have demonstrated the superiority of both pembrolizumab and nivolumab compared with ipilimumab, the previous standard-ofcare immunotherapy.4,9 Even though similar results have been reported with in-class agents, this study provides several additional insights to the existing literature. First, this is the first study to report progression-free survival data for patients treated with anti–PD-1 in the ipilimcontinued on page 64

ment discontinuation in 3%, 7%, and 6%, respectively. The investigators concluded: “These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.” They noted that since available data do not indicate that one pembrolizumab dosing regimen is superior to another, the pembrolizumab dose of 2 mg/kg given every 3 weeks is recommended for further use. n

Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Ribas A, Puzanov I, Dummer R, et al: Pembrolizumab versus investigatorchoice chemotherapy for ipilimumabrefractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial. Lancet Oncol. June 23, 2015 (early release online).

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

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Important Safety Information Contraindications XTANDI is not indicated for women and

is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions

Seizure In Study 1, conducted in patients with metastatic castrationresistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience readministering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES

requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions

The most common adverse reactions (≥ 10%) reported from two combined clinical studies that occurred more commonly (≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. • Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Significantly improved radiographic progression-free survival†1

Significantly improved overall survival†‡§1 Updated overall survival analysis: • 23% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.77 [95% CI, 0.67-0.88])

• 83% reduction in risk of radiographic disease progression or death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001)

• Median overall survival was 35.3 months with XTANDI + GnRH therapy* (95% CI, 32.2-not reached) vs 31.3 months with placebo + GnRH therapy* (95% CI, 28.8-34.2)

• Median radiographic progression-free survival was not reached (95% CI, 13.8-not reached) for XTANDI + GnRH therapy* and was 3.7 months (95% CI, 3.6-4.6) for placebo + GnRH therapy*

‡At a prespecified interim analysis for overall survival (co-primary endpoint): HR = 0.71 (95% CI, 0.600.84); P < 0.00011

Significantly delayed the time to chemotherapy initiation†1 • Delayed time to chemotherapy initiation by a median of 28.0 months with XTANDI + GnRH therapy* vs 10.8 months with placebo + GnRH therapy* (HR = 0.35 [95% CI, 0.30-0.40]; P < 0.0001)

Oral, once-daily dosing with no required steroid coadministration1 • Dosage: XTANDI 160 mg (four 40 mg capsules) is administered orally, once daily • Steroids were allowed but not required||

patient lives 94% ofareinsured covered for XTANDI

¶3

¶As of February 2015. A product’s placement on a plan formulary involves a variety of factors known only to the plan and is subject to eligibility.

To learn more, please visit XtandiHCP.com

• Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. • Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas. • Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If coadministration cannot be avoided, reduce the dose of XTANDI. Avoid strong or moderate CYP3A4 or CYP2C8 inducers as they can alter the plasma exposure to XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. †As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,2 §Results from this analysis were consistent with those from the prespecified interim analysis. ||In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebo-controlled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1 References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al, for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433. 3. Data on file, Medivation, Inc.

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Perspective

Douglas B. Johnson, MD continued from page 61

umab-refractory setting. Although the median progression-free survival for pembrolizumab is not extremely impressive, the 24% to 36% of patients who are progression-free at 9 months (depending on whether progression

is investigator or centrally assessed) is dramatically better than the 8% to 10% of patients who receive chemotherapy. Second, this study includes patientreported outcomes and quality-of-life metrics (EORTC QLQ-C30 global health status and quality-of-life scores). As would be hoped for an agent with

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information. INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI [see Adverse Reactions (6.2)]. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XTANDI in patients who develop PRES. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the

less toxicity and more responses, quality-of-life score decrements were fewer in the pembrolizumab arms compared with chemotherapy.

Future Directions With the advent of durable responses induced by pembrolizumab XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in Study 1 XTANDI Placebo N = 800 N = 399 Grade Grade Grade Grade a 3-4 1-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 9.3 Conditionsb Peripheral 15.4 1.0 13.3 0.8 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 4.0 Arthralgia 20.5 2.5 17.3 1.8 Musculoskeletal 15.0 1.3 11.5 0.3 Pain Muscular 9.8 1.5 6.8 1.8 Weakness Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness Gastrointestinal Disorders Diarrhea 21.8 1.1 17.5 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 5.5 0.0 Dizzinessc 9.5 0.5 7.5 0.5 Spinal Cord Compression and Cauda 7.4 6.6 4.5 3.8 Equina Syndrome Paresthesia 6.6 0.0 4.5 0.0 Mental Impairment 4.3 0.3 1.8 0.0 Disordersd Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations Upper Respiratory 10.9 0.0 6.5 0.3 Tract Infectione Lower Respiratory 8.5 2.4 4.8 1.3 Tract And Lung Infectionf Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.5 Anxiety 6.5 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 4.5 1.0 Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 3.5 0.0 1.3 0.0

and other anti–PD-1 agents, assessing patient-reported quality-of-life outcomes and delayed toxicities in the long-term follow-up settings will also become increasingly important. This is particularly true as these agents are used in a variety of cancers and as they are tested in the adjuvant setting. Table 1. Adverse Reactions in Study 1 (cont.) Respiratory Disorders Epistaxis 3.3 0.1 1.3

0.3

a CTCAE v4 b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 2. Adverse Reactions in Study 2 Placebo XTANDI N = 844 N = 871 Grade Grade Grade Grade 1-4 3-4 3-4 1-4a (%) (%) (%) (%) General Disorders Asthenic 33.0 46.9 3.4 2.8 Conditionsb Peripheral 8.2 11.5 0.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders 22.4 Back Pain 28.6 2.5 3.0 16.1 Arthralgia 21.4 1.6 1.1 Gastrointestinal Disorders 17.3 Constipation 23.2 0.7 0.4 14.3 Diarrhea 16.8 0.3 0.4 Vascular Disorders 7.8 Hot Flush 18.0 0.1 0.0 4.1 Hypertension 14.2 7.2 2.3 Nervous System Disorders 7.1 11.3 0.3 0.0 Dizzinessc 7.0 Headache 11.0 0.2 0.4 3.7 Dysgeusia 7.6 0.1 0.0 Mental 1.3 5.7 0.0 0.1 Impairment Disordersd Restless Legs 0.4 2.1 0.1 0.0 Syndrome Respiratory Disorders 8.5 11.0 0.6 0.6 Dyspneae Infections And Infestations Upper 10.5 0.0 0.0 Respiratory Tract 16.4 Infectionf Lower Respiratory 4.7 7.9 1.5 1.1 Tract And Lung Infectiong Psychiatric Disorders 5.7 Insomnia 8.2 0.1 0.0 Renal And Urinary Disorders 5.8 Hematuria 8.8 1.3 1.3 Injury, Poisoning And Procedural Complications 5.3 Fall 12.7 1.6 0.7 Non-Pathological 3.0 8.8 2.1 1.1 Fracture Metabolism and Nutrition Disorders Decreased 16.4 18.9 0.3 0.7 Appetite Investigations Weight 8.5 12.4 0.8 0.2 Decreased Reproductive System and Breast Disorders 1.4 Gynecomastia 3.4 0.0 0.0

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Perspective

Our group evaluated a small cohort of patients with long-term (> 2 year) survival after being treated with ipilimumab.10 Although quality of life and overall functional status were generally excellent, several patients developed presumed delayed radiation toxicities, and several others had perTable 2. Adverse Reactions in Study 2 (cont.)

a CTCAE v4 b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized clinical trials, falls including fallrelated injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. Post-Marketing Experience The following additional adverse reactions have been identified during post approval use of XTANDI. Because these reactions were 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. Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Coadministration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended. Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Coadministration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma

Pembrolizumab was superior to cytotoxic chemotherapy among pa-

tients with advanced melanoma who previously failed to respond to ipilimumab and (if applicable) a BRAF inhibitor. A number of critical questions remain surrounding front-line therapy for patients with advanced melanoma, including the use of single-agent anti– PD-1 vs nivolumab and ipilimumab

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

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

USE IN SPECIFIC POPULATIONS

OVERDOSAGE

Pregnancy- Pregnancy Category X. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/ day (approximately 0.4 times the exposures in patients based on AUC). Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal

In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at ≤ 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

sistent endocrine deficits. Characterizing these endpoints in patients who receive anti–PD-1 alone or in combination will be a critical next step.

Conclusion

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: August 2015 14L082-XTA Rx Only © 2015 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

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in combination, the preference of targeted vs immune therapy in patients with BRAF V600-mutated melanoma, and the development of predictive biomarkers to discriminate between potential treatment options. In this treatment-refractory setting, however, the data are clear and unequivocal: pembrolizumab (and nivolumab) should be strongly preferred over cytotoxic chemotherapy. n Disclosure: Dr. Johnson serves on advisory boards for Bristol-Myers Squibb and Genoptix.

References 1. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012. 2. Hamid O, Robert C, Daud A, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134-144, 2013. 3. Wolchok JD: PD-1 blockers. Cell 162:937, 2015. 4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23-34, 2015. 5. Ribas A, Puzanov I, Dummer R, et al: Pembrolizumab versus investigatorchoice chemotherapy for ipilimumabrefractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial. Lancet Oncol 16:908-918, 2015. 6. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109-1117, 2014. 7. Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015. 8. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015. 9. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521-2532, 2015. 10. Johnson DB, Friedman DL, Berry E, et al: Survivorship in immune therapy: Assessing chronic immune toxicities, health outcomes, and functional status among long-term ipilimumab survivors at a single referral center. Cancer Immunol Res 3:464-469, 2015.

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Global Cancer Burden World Health Organization Region: The Americas Country: United States

Cancer: Increasing Awareness and Addressing This Lethal Disease on the Global Stage By Chandrakanth Are, MBBS, MBA, FRCS, FACS The ASCO Post is pleased to introduce this special focus on the worldwide cancer burden, beginning in this issue with a close look at the cancer incidence and mortality rates in the United States. The aim of this special feature is to highlight the global cancer burden for various countries of the world. For the convenience of the reader, each issue will focus on one country from one of the six regions of the world as defined by the World Health Organization (ie, Africa, the Americas, South-East Asia, Europe, Eastern Mediterranean, and Western Pacific). Each section will focus on the general aspects of the country followed the current and predicted rates of incidence and cancer-related mortality. It is hoped that through these issues, we can increase awareness and shift public policy and funds toward proactively addressing this lethal disease on the global stage. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

ancer is a leading cause of morbidity and mortality across the globe. Worldwide, there were 14.1 million new cancer cases, 8.2 million cancer-related deaths, and 32.6 million people alive with a cancer diagnosis in the year 2012. Overall the incidence of cancer tends to be almost 25% higher in men. The worldwide rates of incidence of new cancer cases and cancer-related mortality are expected to rise significantly over the next few decades. The overall incidence of new cancer cases worldwide is predicted to increase from 15.2 million in 2015 to 23.9 million in 2035. Similarly the incidence of cancer-related deaths worldwide is expected to rise significantly from 8.8 million to 14.6 million.

Burden of Cancer Greater in Less Developed Regions Although we will witness an alarming rise in the overall global cancer burden, the worldwide distribution of new cancer cases and cancerrelated mortality will be extremely uneven. In 2012, nearly 57% of the

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Focus: United States new cancer cases and 65% of the cancer-related deaths occurred in the less developed regions of the world. This differential increase in the incidence and cancerrelated mortality rates in the less developed regions of the world will be further accentuated due to various factors. These factors include increasing population, extended lifespan, adoption of western lifestyle habits, increasing rates of obesity, and better control of communicable diseases. Analysis of the cancer burden based on the regions as divided by the World Health Organization (WHO) reveals the marked differences (see Table on page 112). Although the cancer burden is shown to increase over the next 3 decades in all six of these regions (ie, Africa, the Americas, South-East Asia, Europe, Eastern Mediterranean, and Western Pacific), these differences are starkly higher for the African and Eastern Mediterranean regions when compared to the European region. While these data may change due to various factors over the next few decades, the general trends lead us to assume that cancer will become a major public health burden of global proportions. It is imperative that the public, health-care community, and the respective governments are made aware of this looming cancer burden that can inflict severe damage to large populations and thereby affect the financial and socieconomic fabric of various nations. n Disclosure: Dr. Are reported no potential conflicts of interest.

Table 1: General Facts Population

321 million (2015)

Median age

37.6 years

Population growth rate

0.7% (2015)

Birth rate per 1,000 population

12.49 (2015)

Death rate per 1,000 population

8.15 (2015)

Life expectancy at birth

79.68 years

Health expenditure as % of GDP

17.9% (2015)

Physicians per 1,000 population

2.45 (2011)

Hospital bed density per 1,000 population

2.9 beds (2011)

Obesity prevalence rate

35% (2014)

Mobile telephones

317 million (2014)

Land lines

129 million (2014)

180,000 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 0

250,000 200,000 150,000 100,000 50,000 0 Prostate

Breast

Lung

Colorectum Melanoma of skin

Bladder

Non-Hodgkin Lymphoma

Kidney

Thyroid

Corpus uteri

Fig. 1: Top 10 Cancers by Incidence—Current Rates in the United States.

Lung

Colorectum

Breast

Pancreas

Prostate

Leukemia

Liver

Non-Hodgkins Bladder Lymphoma

Oesophagus

2030

2035

Fig. 2: Top 10 Cancers by Mortality—Current Rates in the United States.

2,500,000

1,200,000

2,000,000

1,000,000 800,000

1,500,000

600,000

1,000,000

400,000

500,000

200,000 0

0 2015

2020

2015

2030

2035

2015

2020

2015

Fig. 3: Trends in the Incidence of New Cancer Cases in the United States: 2015–2035.

Fig. 4: Trends in Cancer-Related Mortality in the United States: 2015–2035.

References http://www.cia.gov/library/publications/the-world-factbook/ http://globocan.iarc.frDefault.aspx The Economist: Pocket World in Figures 2015

Note to Readers: If you are interested in participating in this continuing series on the global cancer burden and have an interesting perspective to share about a particular region of the world, contact Dr. Are at care@unmc.edu. For more in this issue on the global burden of cancer, see page 112.

GUEST EDITOR

D Chandrakanth Are, MBBS, MBA, FRCS, FACS

r. Are is Jerald L & Carolynn J. Varner Professor of Surgical Oncology & Global Health, Vice Chair of Education, Program Director, General Surgery Residency, University of Nebraska Medical Center, Omaha.

In MBC patients who have progressed on an anthracycline and a taxane

Consider IXEMPRA® (ixabepilone) and capecitabine combination therapy

Indication

Warning: Toxicity in hepatic impairment1

IXEMPRA® (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. ◗ Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting ◗ Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting

IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death

Please see Important Safety Information, including boxed WARNING regarding hepatic impairment, on next page.

Important Safety Information for IXEMPRA® (ixabepilone) Warning: Toxicity in hepatic impairment ◗ IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death ◗ In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater in patients with hepatic impairment ◗ Caution should be used when using IXEMPRA as monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended ◗ With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent in patients with hepatic impairment Contraindications ◗ IXEMPRA is contraindicated in patients: • with a known history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives such as polyoxyethylated castor oil • who have a baseline neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3 Peripheral neuropathy ◗ Peripheral neuropathy was common. Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain ◗ Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening peripheral neuropathy may require changes in the dose or discontinuation of IXEMPRA ◗ Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy Myelosuppression ◗ Myelosuppression is dose-dependent and primarily manifested as neutropenia. ◗ Patients should be monitored for myelosuppression; frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA ◗ Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced. Neutropeniarelated deaths occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. Neutropeniarelated death occurred in 0.4% of 240 patients with IXEMPRA as monotherapy

Hypersensitivity reaction ◗ Premedicate with an H1 and an H2 antagonist approximately 1 hour before IXEMPRA (ixabepilone) infusion and observe for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm) ◗ In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started ◗ Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered Pregnancy ◗ Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy or the patient becomes pregnant, the patient should be apprised of the potential hazard to the fetus Cardiac adverse reactions ◗ Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function due to reports of cardiovascular adverse reactions (eg, myocardial ischemia, supraventricular arrhythmia, and ventricular dysfunction). The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group Potential for cognitive impairment from excipients ◗ IXEMPRA contains dehydrated alcohol USP. Consideration should be given to the possibility of central nervous system and other effects of alcohol Adverse reactions ◗ The most common adverse reactions (≥20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional events occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. Drug-associated hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia Cremophor is a registered trademark of BASF AG. AST = aspartate aminotransferase ALT = alanine aminotransferase ULN = upper limit of normal CTC = common terminology criteria

Please see brief summary of Full Prescribing Information on adjacent pages. Reference: 1. IXEMPRA (ixabepilone) Prescribing Information; 2011. For additional information, please visit www.IXEMPRA.com.

IXEMPRA® Kit (ixabepilone) for Injection, for intravenous infusion only Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: TOXICITY IN HEPATIC IMPAIRMENT IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death [see Contraindications and Warnings and Precautions]. INDICATIONS AND USAGE IXEMPRA (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting. IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. CONTRAINDICATIONS IXEMPRA is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) [see Warnings and Precautions]. IXEMPRA is contraindicated in patients who have a neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3 [see Warnings and Precautions]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning and Warnings and Precautions]. WARNINGS AND PRECAUTIONS Peripheral Neuropathy Peripheral neuropathy was common (see Table 1). Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening symptoms may require a reduction or delay in the dose of IXEMPRA [see Dosage and Administration (2.2) in Full Prescribing Information]. In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and treatment discontinuation. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3/4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset. Table 1: Treatment-related Peripheral Neuropathy

Peripheral neuropathy (all grades)a,b Peripheral neuropathy (grades 3/4)a,b Discontinuation due to neuropathy Median number of cycles to onset of grade 3/4 neuropathy Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1 a b

IXEMPRA with capecitabine Study 046

IXEMPRA as monotherapy Study 081

67% 23% 21% 4

63% 14% 6% 4

6.0 weeks

4.6 weeks

Sensory and motor neuropathy combined. 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1).

A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy. Myelosuppression Myelosuppression is dose-dependent and primarily manifested as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm3) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as monotherapy, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN [see Boxed Warning, Contraindications, and Warnings and Precautions]. Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA monotherapy. IXEMPRA must not be administered to patients with a neutrophil count <1500 cells/mm3. To monitor for myelosuppression, frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA. Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced [see Dosage and Administration (2.2) in Full Prescribing Information]. Hepatic Impairment Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with IXEMPRA at 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater [see Warnings and Precautions]. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of IXEMPRA as monotherapy were evaluated in a dose escalation study in 56 patients with varying degrees of hepatic impairment. Exposure was increased in patients with elevated AST or bilirubin [see Use in Specific Populations]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death [see Boxed Warning, Contraindications, and Warnings and Precautions]. Patients who are treated with IXEMPRA as monotherapy should receive a reduced dose depending on the degree of hepatic impairment [see Dosage and Administration (2.2) in Full Prescribing Information]. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with AST or ALT >5 x ULN. Caution should be used when treating these patients [see Dosage and Administration (2.2) in Full Prescribing Information]. Hypersensitivity Reactions Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with IXEMPRA. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before IXEMPRA infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1%) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered [see Dosage and Administration (2.3) in Full Prescribing Information and Contraindications]. Pregnancy Pregnancy Category D. IXEMPRA may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with IXEMPRA in pregnant women. Women should be advised not to become pregnant when taking IXEMPRA. 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. Ixabepilone was studied for effects on embryo-fetal development in pregnant rats and rabbits given IV doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively. There were no teratogenic effects. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally

toxic dose of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately one-tenth the human clinical dose based on body surface area). No fetuses were available at this dose for evaluation. Cardiac Adverse Reactions The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA (ixabepilone) in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group. Supraventricular arrhythmias were observed in the combination arm (0.5%) and not in the capecitabine alone arm. Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function. Potential for Cognitive Impairment from Excipients Since IXEMPRA contains dehydrated alcohol USP, consideration should be given to the possibility of central nervous system and other effects of alcohol [see Description (11) in Full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections. • Peripheral neuropathy [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hypersensitivity reactions [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over 3 hours every 3 weeks. The most common adverse reactions (≥20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia. Table 2 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 3. Table 2:

Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA

System Organ Classa/ Preferred Term Infections and Infestations Upper respiratory tract infectionb Blood and Lymphatic System Disorders Febrile neutropenia Immune System Disorders Hypersensitivityb Metabolism and Nutrition Disorders Anorexiab Dehydrationb Psychiatric Disorders Insomniab Nervous System Disorders Peripheral neuropathy Sensory neuropathy b,e Motor neuropathyb Headache Taste disorderb Dizziness Eye Disorders Lacrimation increased Vascular Disorders Hot flushb Respiratory, Thoracic, and Mediastinal Disorders Dyspneab Coughb Gastrointestinal Disorders Nausea Vomitingb Stomatitis/mucositisb Diarrheab Constipation Abdominal painb Gastroesophageal reflux diseaseb Skin and Subcutaneous Tissue Disorders Alopeciab Skin rashb Nail disorderb Palmar-plantar erythrodysesthesia syndromeb,f Pruritus Skin exfoliationb Skin hyperpigmentationb Musculoskeletal, Connective Tissue, and Bone Disorders Myalgia/arthralgiab Musculoskeletal painb General Disorders and Administration Site Conditions Fatigue/astheniab Edemab Pyrexia Painb Chest painb

Study 046 IXEMPRA with Capecitabine capecitabine n=369 n=368 Total Grade 3/4 Total Grade 3/4 (%) (%) (%) (%)

Study 081 IXEMPRA monotherapy n=126 Total Grade 3/4 (%) (%)

34 5

3d 2

15 2

1d <1d

19 2

2d 1d

<1d

65 16 8 12 8

21 5d <1d 0 1d

16 <1 3 4 5

0 0 0 0 1d

62 10 11 6 7

14 1d 0 0 0

<1d

7 6

1 0

4 2

1 0

9 2

1d 0

53 39 31 44 22 24 7

3d 4d 4 6d 0 2d 1d

40 24 20 39 6 14 8

2d 2 3d 9 <1d 1d 0

42 29 29 22 16 13 6

2d 1d 6 1d 2d 2d 0

31 17 24 64

0 1d 2d 18d

3 7 10 63

0 0 <1d 17d

48 9 9 8

0 2d 0 2d

5 5 11

0 <1d 0

2 3 14

0 0 0

6 2 2

1d 0 0

39 23

8d 2d

5 5

<1d 0

49 20

8d 3d

60 8 10 9 4

16 0 1d 1d 1d

29 5 4 2 <1

4 <1d 0 0 0

56 9 8 8 5

13 1d 1d 3d 1d (Continued)

Table 2: (Continued)

Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA

System Organ Classa/ Preferred Term

Study 046 IXEMPRA with Capecitabine capecitabine n=369 n=368 Total Grade 3/4 Total Grade 3/4 (%) (%) (%) (%)

Study 081 IXEMPRA monotherapy n=126 Total Grade 3/4 (%) (%)

System organ class presented as outlined in Guidelines for Preparing Core Clinical Safety Information on Drugs by the Council for International Organizations of Medical Sciences (CIOMS). b A composite of multiple MedDRA Preferred Terms. c NCI CTC grading for febrile neutropenia ranges from Grade 3 to 5. Three patients (1%) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and Precautions]. d No grade 4 reports. e Peripheral sensory neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy. f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1-3 severity scale in Study 046. Table 3:

Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA

Hematology Parameter Neutropeniaa Leukopenia (WBC) Anemia (Hgb) Thrombocytopenia

Study 046 IXEMPRA with Capecitabine capecitabine n=369 n=368 Grade 3 Grade 4 Grade 3 Grade 4 (%) (%) (%) (%) 32 41 8 5

36 16 2 3

9 5 4 2

2 1 1 2

Study 081 IXEMPRA monotherapy n=126 Grade 3 Grade 4 (%) (%) 31 36 6 5

23 13 2 2

G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage colony stimulating factor) was used in 20% and 17% of patients who received IXEMPRA in Study 046 and Study 081, respectively.

The following serious adverse reactions were also reported in 1323 patients treated with IXEMPRA as monotherapy or in combination with other therapies in Phase 2 and 3 studies. Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection Blood and Lymphatic System Disorders: coagulopathy, lymphopenia Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage Hepatobiliary Disorders: acute hepatic failure, jaundice Skin and Subcutaneous Tissue Disorders: erythema multiforme Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus Renal and Urinary Disorders: nephrolithiasis, renal failure General Disorders and Administration Site Conditions: chills Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase Postmarketing Experience Radiation recall has been reported during postmarketing use of IXEMPRA. Because this reaction was 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. DRUG INTERACTIONS Effect of Other Drugs on Ixabepilone Drugs That May Increase Ixabepilone Plasma Concentrations CYP3A4 Inhibitors: Coadministration of ixabepilone with ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered. The effect of mild or moderate inhibitors (eg, erythromycin, fluconazole, or verapamil) on exposure to ixabepilone has not been studied. Therefore, caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment with IXEMPRA, and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during treatment with IXEMPRA should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood counts between cycles of IXEMPRA) [see Dosage and Administration (2.2) in Full Prescribing Information]. Drugs That May Decrease Ixabepilone Plasma Concentrations CYP3A4 Inducers: IXEMPRA is a CYP3A4 substrate. Coadministration of IXEMPRA with rifampin, a potent CYP3A4 inducer, decreased ixabepilone AUC by 43% compared to IXEMPRA treatment alone. Other strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifabutin, and phenobarbital) may also decrease ixabepilone concentrations leading to subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction potential should be considered for coadministration with IXEMPRA. St. John’s Wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided. If patients must be coadministrated a strong CYP3A4 inducer, a gradual dose adjustment may be considered [see Dosage and Administration (2.2) in Full Prescribing Information]. Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Capecitabine In patients with cancer who received ixabepilone (40 mg/m2) in combination with capecitabine (1000 mg/m2), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. Nursing Mothers It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue IXEMPRA taking into account the importance of the drug to the mother.

Pediatric Use The effectiveness of IXEMPRA (ixabepilone) in pediatric patients has not been established. IXEMPRA was evaluated in one Phase 1 and one Phase 2 trial. The pediatric patients had a safety profile consistent with that seen in adults, and no new safety signals were identified. In the Phase 1 open-label, dose-finding trial, the safety of IXEMPRA was evaluated in 19 pediatric patients with advanced or refractory solid tumors and 2 with acute leukemias. IXEMPRA was administered as a one-hour IV infusion daily for the first five days of a 21-day cycle at one of 5 dose levels, ranging from 3 to 10 mg/m2. Among the 21 patients, 12 ranged in age from 2 to 12 years and 9 ranged from 13 to 18 years. The maximum tolerated dose was 8 mg/m2 IV daily for 5 days every 21 days. No significant activity was observed. The pharmacokinetics of ixabepilone were characterized by population pharmacokinetic analysis of data for 16 patients from this trial, who were aged 2 to 18 years (median 12 years). The pharmacokinetic parameters of ixabepilone in these pediatric patients were compared to the corresponding parameters of 130 adult patients enrolled in clinical trials using the same dosing schedule. The median BSA normalized clearance of ixabepilone in pediatric patients (17 L/h/m2) was similar to that in adult patients (20 L/h/m2). In the Phase 2 trial of 59 patients with advanced or refractory solid tumors, 28 ranged in age from 3 to 12 years and 19 ranged in age from 13 to 18 years. Twelve additional patients over the age of 18 were treated in this trial. IXEMPRA was administered at a dose of 8 mg/m2 IV daily for 5 days every 21 days. This trial was terminated early due to lack of efficacy. Geriatric Use Clinical studies of IXEMPRA did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects. Forty-five of 431 patients treated with IXEMPRA in combination with capecitabine were ≥65 years of age and 3 patients were ≥75. Overall, the incidence of grade 3/4 adverse reactions was higher in patients ≥65 years of age versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients ≥65 years with normal baseline hepatic function or mild impairment. Thirty-two of 240 breast cancer patients treated with IXEMPRA as monotherapy were ≥65 years of age and 6 patients were ≥75. No overall differences in safety were observed in these patients compared to those <65 years of age. Hepatic Impairment IXEMPRA was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC0-infinity) of ixabepilone increased by: • 22% in patients with a) bilirubin >1 – 1.5 x ULN or b) AST >ULN but bilirubin <1.5 x ULN; • 30% in patients with bilirubin >1.5 – 3 x ULN and any AST level; and • 81% in patients with bilirubin >3 x ULN and any AST level. Doses of 10 and 20 mg/m2 as monotherapy were tolerated in 17 patients with severe hepatic impairment (bilirubin >3 x ULN). IXEMPRA in combination with capecitabine must not be given to patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning, Contraindications, and Warnings and Precautions]. Dose reduction is recommended when administering IXEMPRA as monotherapy to patients with hepatic impairment [see Dosage and Administration (2.3) in Full Prescribing Information]. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter. Renal Impairment Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with IXEMPRA in patients with renal impairment. IXEMPRA in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of <50 mL/min. IXEMPRA as monotherapy has not been evaluated in patients with creatinine >1.5 times ULN. In a population pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 mL/min) on the pharmacokinetics of ixabepilone. OVERDOSAGE Experience with overdose of IXEMPRA is limited to isolated cases. The adverse reactions reported in these cases included peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, stomatitis). The highest dose mistakenly received was 100 mg/m2 (total dose 185 mg). There is no known antidote for overdosage of IXEMPRA. In case of overdosage, the patient should be closely monitored and supportive treatment should be administered. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with ixabepilone have not been conducted. Ixabepilone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in an in vitro cytogenetic assay using primary human lymphocytes. Ixabepilone was clastogenic (induction of micronuclei) in the in vivo rat micronucleus assay at doses ≥0.625 mg/kg/day. There were no effects on male or female rat mating or fertility at doses up to 0.2 mg/kg/day in both males and females (approximately one-fifteenth the expected human clinical exposure based on AUC). The effect of ixabepilone on human fertility is unknown. However, when rats were given an IV infusion of ixabepilone during breeding and through the first 7 days of gestation, a significant increase in resorptions and pre- and post-implantation loss and a decrease in the number of corpora lutea was observed at 0.2 mg/kg/day. Testicular atrophy or degeneration was observed in 6-month rat and 9-month dog studies when ixabepilone was given every 21 days at intravenous doses of 6.7 mg/kg (40 mg/m2) in rats (approximately 2.1 times the expected clinical exposure based on AUC) and 0.5 and 0.75 mg/kg (10 and 15 mg/m2) in dogs (approximately 0.2 and 0.4 times the expected clinical exposure based on AUC). Animal Toxicology Overdose In rats, single intravenous doses of ixabepilone from 60 to 180 mg/m2 (mean AUC values ≥8156 ng•h/mL) were associated with mortality occurring between 5 and 14 days after dosing, and toxicity was principally manifested in the gastrointestinal, hematopoietic (bone-marrow), lymphatic, peripheral-nervous, and male-reproductive systems. In dogs, a single intravenous dose of 100 mg/m2 (mean AUC value of 6925 ng•h/mL) was markedly toxic, inducing severe gastrointestinal toxicity and death 3 days after dosing. PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in Full Prescribing Information] Peripheral Neuropathy Patients should be advised to report to their physician any numbness and tingling of the hands or feet [see Warnings and Precautions]. Fever/Neutropenia Patients should be instructed to call their physician if a fever of 100.5° F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination develops [see Warnings and Precautions]. Hypersensitivity Reactions Patients should be advised to call their physician if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness or other hypersensitivity-related symptoms following an infusion of IXEMPRA [see Warnings and Precautions]. Pregnancy Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid nursing during treatment with IXEMPRA [see Warnings and Precautions and Use in Specific Populations]. Cardiac Adverse Reactions Patients should be advised to report to their physician chest pain, difficulty breathing, palpitations or unusual weight gain [see Warnings and Precautions]. IXEMPRA® (ixabepilone) for injection Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany DILUENT for IXEMPRA Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany Distributed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

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Palliative Care in Oncology The Need for a Multidisciplinary Approach to Combating Cancer-Related Pain Four specialists discuss the challenges of achieving effective pain relief in patients with cancer and how to overcome them. By Jo Cavallo

he statistics are staggering. Despite the development of novel analgesics and the increasing awareness of the importance of adequately controlling pain from cancer or its treatment, up to 50% of patients undergoing treatment and between 70% and 90% of patients with advanced disease experience some degree of pain.1 What’s more, the World Health Organization (WHO) estimates that 25% of all patients with cancer die with unrelieved pain.2

tium (cancerpainresearchconsortium. org). Dr. Rosenberg, a neurosurgeon, launched the consortium 2 years ago to improve the management of cancerrelated pain through interdisciplinary collaboration in research, best practice guidelines, and patient and physician education. To better understand the relationship among the various disciplines involved in treating the physical aspects of cancer-related pain and the barriers that can often circumvent physicians’

efforts, The ASCO Post held a roundtable discussion with Dr. Rosenberg; Elizabeth Rickerson, MD, Instructor in Anesthesia at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston; Candice A. Johnstone, MD, MPH, Associate Professor of Radiation Oncology at the Medical College of Wisconsin and Medical Director of Froedtert and the Medical College of Wisconsin Cancer Network in Milwaukee; and Richard Boortz-Marx, MD, Chief of Interventional Pain Medicine

at the Center for Neuromodulation and Associate Professor in the Department of Anesthesiology, Division of Pain Medicine at Duke University in Durham, North Carolina.

Beyond the Pain Relief Ladder Dr. Rosenberg, please explain the multidisciplinary approach to cancer-related pain and how it works. Dr. Rosenberg: We are still trying to figure it all out. Part of the problem continued on page 73

Improving Management of Cancer-Related Pain By Jamie H. Von Roenn, MD

William S. Rosenberg, MD, FAANS

Although pain from cancer can usually be sufficiently controlled for most patients, the problem remains undertreated due to several factors. They include professional-related barriers, such as poor pain management education during medical training; underutilization of opioids; unavailability of analgesics from pharmacies; inadequate pain assessment; and patient-related barriers, such as adherence to analgesic regimens and cultural differences in response to pain. Compounding these factors is the multidimensional nature of cancer pain, which can include physical, psychosocial, emotional, and spiritual components. Thus, cancer pain requires multidisciplinary interventions from a team of experts in the diverse fields of medical oncology, radiation oncology, anesthesia, neurosurgery, palliative care, and physiatry, as well as from psychiatry, psychology, social work, nutrition, and chaplaincy. Without a formal method in place to coordinate the number of disciplines needed to achieve cancer-related pain control, care is often haphazard, uneven, and fragmented, according to William S. Rosenberg, MD, FAANS, Medical Director of the Center for the Relief of Pain, a service of the Midwest Neuroscience Institute at Research Medical Center in Kansas City, Missouri, and President and Founder of the Cancer Pain Research Consor-

espite multiple guidelines from national and international organizations,1,2 the quality of current cancer pain management remains inadequate. The World Health Organization’s three-step analgesic dosing ladder forms the foundation of these guidelines.3 Yet, as noted by William S. Rosenberg, MD, FAANS, Medical Director of the Center for the Relief of Pain, the effectiveness of the analgesic ladder has not been rigorously evaluated. Clinical observations and consensus support the use of the analgesic ladder for a selection of pharmacologic treatment for cancer pain based on pain severity. For mild pain (rated

agement of cancer pain requires delivery of the appropriate drug, in the right dose, by the best route of administration, with consideration for a “rescue medication” for breakthrough pain and prevention and treatment of analgesic side effects. Unfortunately, multiple studies demonstrate the inadequacy of our pharmacologic treatment for cancer pain. A recent review assessing the adequacy of analgesic therapy reported that about one-third of patients still do not receive pain medication proportional to their pain intensity.4 However, when analgesics appropriate to the pain intensity are pre-

The experience of pain, the suffering that is pain, arises from all of the domains of distress—physical, psychological, social, emotional, and spiritual. —Jamie H. Von Roenn, MD

1–3 on a 0–10 scale), non-opioid analgesics are recommended; for more intense pain (rated as 4 or greater), the ladder approach recommends different opioids, such as codeine and tramadol, for moderate pain; and for severe pain, the ladder recommends morphine, for example.

The Analgesic Ladder as a First Step The analgesic ladder is a first step—effective pharmacologic man-

scribed, there is now some evidence that pain management outcomes improve.5 As highlighted by the roundtable discussion reported in this issue of The ASCO Post, control of cancer pain may require more than pharmacologic interventions. Radiation therapy is an exceedingly effective intervention for pain related to bone metastases, celiac plexus blocks have demonstrated benefit for patients with abdominal pain from pancre-

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.

atic cancer, and a radiosurgical hypophysectomy may be an effective option for patients with pain due to advanced widespread bone metastases. But, these interventions are generally a step after optimization of pharmacologic management for treatment of the physical domain of cancer pain.

More Than Just Physical The experience of pain, however, is more than physical. Dame Cicely Saunders, who established the discicontinued on page 73

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Palliative Care in Oncology Cancer-Related Pain continued from page 72

is we are in the beginning of having the conversation on what is the best approach to providing multidisciplinary care to alleviate patients’ pain. Clearly, what it is not is the three-step pain relief ladder developed by WHO, which calls for prescribing nonopioids first and then mild opioids, such as codeine, followed by strong opioids, such as morphine, until the patient is free of pain.3 Although there is some clinical evidence that WHO’s recommendation manages pain, it has not been subjected to the rigors of a modern, evidence-based approach to clinical data. At my facility, we have weekly pain conferences with physicians from all disciplines to discuss what each specialty has to offer and to determine a rational plan for coordinating care.

Strategies for Overcoming Barriers From each of your perspectives, what are the barriers to controlling pain from cancer or its treatment, and how can they be overcome? Dr. Rosenberg: From my perspective as a neurosurgeon, the biggest barrier is having access to patients. The staff involved in patients’ front line of care— the medical oncologists, radiation oncologists, and nurse practitioners—is usually unaware of what I do or has misconceptions of when and how neurosurgery might be incorporated into patients’ care. As a result, I often don’t see patients, except through serendipity or when it’s too late for my treatment to have a meaningful impact on their cancer journey. Dr. Johnstone: The main barrier is that the patient’s experience of pain is unique, and not everyone responds to the same algorithm of interventions. Sometimes it’s unclear whether the problem is the type of medication being used or dosing. Controlling pain in the setting of

Jamie H. Von Roenn, MD continued from page 72

pline and principles of palliative care, articulated the concept of “total pain” to emphasize the multidimensional nature of pain. The experience of pain, the suffering that is pain, arises from all of the domains of distress— physical, psychological, social, emotional, and spiritual. So, absolutely, as the roundtable discussion noted,

opioid intolerance is exceedingly difficult. Obviously, there are a number of interventions in addition to medication we can use, but they may not be as fast acting. For example, radiation therapy takes time to be effective for most people, and patients need to have adequate pain control so they can lie on the table to have their radiation planning and treatment completed. Even after radiation treatment is completed, it can take several weeks for its full effect to be realized. So physicians need to have an interim plan for pain control until the radiation has time to work.

However, pain is now the fifth vital sign in assessing health status, and physicians should ask about the level of a patient’s pain as well as other symptoms at every visit.

Medical Oncologists: The Portal of Entry for Care Who evaluates patients for pain and coordinates their care? Is it the medical oncologist? Dr. Rosenberg: The medical oncologist is the primary care provider for a patient with active cancer and ultimately is the person who should be assessing pain and coordinating care.

Controlling pain in the setting of opioid intolerance is exceedingly difficult. There are a number of interventions in addition to medication we can use, but they may not be as fast acting. Physicians need to have an interim plan for pain control. —Candice A. Johnstone, MD, MPH

Dr. Boortz-Marx: Overcoming the barriers to effectively treating cancer pain takes education and communication between the patient and the people who treat cancer pain. Understanding that there are effective options available to help oncologists help their patients is critical. Dr. Rickerson: The biggest barriers are diagnosing the pain and getting patients to the specialty care they need. There is no central recording system for pain symptoms, and reporting pain is not mandatory. Also, the degree of pain patients score on a scale of 0 to 10 does not always reflect the degree of pain they are experiencing. As Dr. Boortz-Marx said, educating both our patients and our practitioners is step one. Many times, patients think pain is just part of having cancer and they have to live with it. we need multidisciplinary care in the broadest sense to manage cancer pain effectively. n Disclosure: Dr. Von Roenn reported no potential conflicts of interest.

References 1. Ripamonti CI, Bandieri E, Roila F: Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol 22(suppl 6):vi69-vi77, 2011.

Assessing pain is complicated, however, and an oncologist only has about 15 minutes to discuss myriad issues with a patient. I think a simple triage system should be developed. For example, if a patient has a pain rating of 4 or greater, he should be prescribed an opioid like hydrocodone, and persistent pain should trigger a pain consult with the appropriate specialist. Dr. Rickerson: I agree that the medical oncologist is the first layer in the evaluation and coordination of care. Because there is a shortage of palliative care physicians, medical oncologists and primary care physicians should have “primary palliative care skills,” which include basic symptom management skills, communication skills, and coordination of care skills. Then if patients don’t do well, they should be referred to an interventional pain physi2. Swarm R, Abernethy AP, Anghelescu DL, et al: Adult cancer pain. J Natl Compr Canc Netw 8:1046-1086, 2010. 3. World Health Organization: World Health Organization’s Cancer Pain Ladder for Adults. Available at who.int/cancer/palliative/painladder/ en/. Accessed September 22, 2015. 4. Greco MT, Roberto A, Corli O, et al: Quality of cancer pain management:

cian, such as an anesthesiologist and/or a palliative care specialist. Dr. Johnstone: Ideally, every person who interacts with patients should assess their pain and try to do something about it. Every physician should have some fundamental basic training in pain management and know who to send the patient to if interventions cannot control the pain. Some patients need the services of pain management specialists or palliative care professionals who have advanced training in pain management, but coordinating care should be a collaborative process. A physician should never say to a patient, “I don’t assess pain, you need to see someone else.” A physician may, however, determine that a single person should manage a patient’s pain medications, so there aren’t too many people making changes at the same time and a single person is in charge. Dr. Boortz-Marx: The medical oncologist is the portal of entry for care. However, ultimately, a pain medicine specialist should evaluate a patient’s pain level.

Different Perspectives, Different Tools From each of your perspectives, how is your specialty involved in controlling cancer pain? Dr. Rosenberg: We have a number of procedures in neurosurgery to manage pain. For instance, cordotomy is a percutaneous outpatient procedure performed under local anesthesia in which we put a tiny electrode into the spinal cord and disrupt the pain fibers. Patients will often have immediate and total relief of pain following the procedure. For widespread metastatic bone disease, we use radiosurgical hypophysectomy to deliver high-dose radiation to the pituitary gland, which also results in immediate and total pain relief. Dr. Johnstone: As a radiation oncologist, I can deal with both localized continued on page 74

An update of a systematic review of undertreatment of patients with cancer. J Clin Oncol 32:4149-4154, 2014. 5. Mearis M, Shega JW, Knoebel RW: Does adherence to National Comprehensive Cancer Network guidelines improve pain-related outcomes? An evaluation of inpatient cancer pain management at an academic medical center. J Pain Symptom Manage 48:451458, 2014.

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Palliative Care in Oncology Cancer-Related Pain continued from page 73

and widespread pain, but my primary role is in alleviating localized pain. Radiation is exceptionally good at taking care of cancer pain caused by bone metastases. According to the literature, 80% of patients will have pain relief with radiation. Radiopharmaceuticals—radiolabeled chemicals that go throughout the body and localize to bone—are another tool in our toolbox for widespread bone metastasis; however, they are more complicated to use because they can lower blood counts and make the use of chemotherapy more challenging. Dr. Boortz-Marx: Anesthesiologists bring a unique perspective to relieving cancer-related pain. Although our lives are built around pharmacology-based therapies—it is what we use in the operating room—we also use interventional types of procedures. Peripheral nerve blocks, spinal cord stimulation, targeted drug delivery, and alcohol phenol injections are all part of our armamentarium. Dr. Rickerson: I’m trained in anesthesia and do palliative care and interventional pain management. All of our specialties bring different perspectives to patient care and different tools. I can place needles in different parts of the body and block nerves or do small surgeries to implant intrathecal pumps in the area around the spinal cord to prevent pain signals from being perceived by the brain. The key to working with other specialists is to know who should be first to manage the patient’s pain. Is it the surgical oncologist who removes the tumor; the radiation oncologist who radiates the lesion; or should I be first to control the pain, so the other specialists can do their jobs? There is no right answer for every single patient.

Patients in Need of Multidisciplinary Care Multidisciplinary pain management is not necessary for every patient. What are the situations or types of patients who require this type of care the most? Dr. Rosenberg: If we are truly going to be practicing patient-centered care, there has to be a major paradigm

shift in organized medicine, and I think the work we’ve done so far in the Cancer Pain Research Consortium reflects that. We have to organize around patients’ symptoms and diseases and be agnostic to specific disciplines. Any patient who is suffering and not achieving relief is the right patient to receive our care and should get our attention. Dr. Johnstone: Usually the patients with the most complicated health status are the ones who require multidisciplinary care. They may need to see a surgeon for part of their treatment, and if they have intractable pain, they may need to see someone else. My basic tool is radiation; I have a basic knowledge of pain medications, but if after I’ve radiated a lesion the patient is still in pain, I might transfer the patient to a palliative care specialist, a pain management physician, or an anesthesiologist for additional care. Dr. Boortz-Marx: Any patient with physical as well as emotional distress should see an appropriate member of the multidisciplinary care team

The WHO ladder is only a pharmacologic ladder. It does not mention multidisciplinary care interventions for pain. So I think as a profession, we need to develop much more rigorous standards. —Elizabeth Rickerson, MD

about their pain. These patients often have difficult-to-control pain and usually need specialty-level pain care.

Standards of Care Are there standards of care for cancerrelated pain? Dr. Rosenberg: The National Comprehensive Cancer Network (NCCN) has developed guidelines for adult cancer-related pain,4 but if you read them critically from a multidisciplinary perspective, then the answer is no. In my field of neurosurgery, we have a lot to offer patients for pain, but in the NCCN guidelines, my profession is reduced to one sentence: “A neurosurgeon can cut

Pain is now the fifth vital sign in assessing health status, and physicians should ask about the level of a patient’s pain as well as other symptoms at every visit. —Richard Boortz-Marx, MD

for help. This includes psychosocial care for those whose lives have been turned upside down after their cancer diagnosis or for those having a difficult time accepting their diagnosis. Dr. Rickerson: I agree. There is a wide range of patients who fall into this category. They include patients with tumors in difficult places and patients with severe neuropathic pain, which is very difficult to control. Patients who had chronic pain before their cancer diagnosis are at higher risk for experiencing cancer-related pain, because they have already experienced a lot of pain and may be tolerant to pain medications and have a great deal of anxiety

some nerves.” Who is going to sign up for that? Dr. Boortz-Marx: The NCCN Guidelines for pain cover two parts. One covers the assessment of cancerrelated pain, and one deals with pain management. However, medical oncologists as well as other specialists need to develop a core of like-minded individuals who are interested in patient care and patient outcomes and develop standards of pain management. Dr. Rickerson: I agree. As Dr. Rosenberg mentioned, WHO developed the three-step ladder for cancer pain relief in adults, but the evidence that it is effective is limited. There

is good evidence showing that many patients who get put on the protocol in the pain ladder have much of their pain controlled. However, there are also good data showing that there are a significant number of patients who go through the three steps and don’t have good pain control. And the WHO ladder is only a pharmacologic ladder. It does not mention multidisciplinary care interventions for pain. So I think as a profession, we need to develop much more rigorous standards. n

Disclosure: Drs. Rosenberg and Rickerson reported no potential conflicts of interest.

References 1. American Cancer Society: Cancer facts and figures 2007. Available at http:// www.cancer.org/acs/groups/content/@ nho/documents/document/caff2007pwsecuredpdf.pdf. Accessed September 4, 2015. 2. World Health Organization: Cancer Pain Relief, 1st ed. Geneva, Switzerland, World Health Organization, 1986. 3. World Health Organization: WHO’s cancer pain ladder for adults. Available at www.who.int/cancer/palliative/painladder/en/. Accessed September 4, 2015. 4. National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Adult Cancer Pain, version 2.2015. Available at http://www.nccn.org/ professionals/physician_gls/pdf/pain.pdf. Accessed September 4, 2015.

Editor’s Note: The ASCO Post is planning a roundtable discussion on the psychosocial, emotional, and spiritual components of cancer-related pain, which will be published in a future Palliative Care in Oncology column.

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Through the Lens of Oncology History

A Century of Progress The text and photographs on this page are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD, FACS. The photos below are from the volume titled “The Anesthesia Era: 1916–1945.” To view additional photos from this series of books, visit burnsarchive.com.

THE Anesthesia Era: 1916–1945 ‘Modern’ Surgical Scene, Circa 1945

The operating room was

a sterile environment, even hermetically sealed off from the audience, and the audience had changed from physicians to nurses.

he performance and professionalism of surgery dramatically changed between 1845 and 1945. Each advance in medicine created changes in the personnel of the operating room and its observers. At the beginning of this era, surgery was a public event; anyone who could tolerate watching was permitted entrance, and, in the preanesthesia era, some were even enlisted to help restrain the patient. Women were only allowed in the operating room as patients until the 1870s, when female nurses were granted access, but only to assist the patient. It wasn’t until the end of the century that nurses began to help prepare the operating rooms and assist physicians in some institutions. By the 1920s, the role of the female nurse had been extended to include passing instruments and administering anesthesia. Until then, the least senior man of the operating team normally performed these responsibilities. Only major hospital centers had dedicated anesthesiologists. At the turn of the century, the surgeon assumed center stage as the hero of emerging surgical specialties, and the audience now was comprised of only physicians and medical students. They were usually seated in a hierarchical assemblage; the most revered, senior members in the front rows and the students in the top rows. With each passing decade, starting in the 1870s, the medical community gained increased awareness of the critical nature of sterile protocols in the operating room. The operating dress of the physician graduated from a black “Prince Albert” long coat and street clothes, to sterile operating garb from head to foot. However, it was the sterility concerns in the operating area that experienced the most dramatic alterations. In the 1840s, most operations, especially those of the wealthy and middle class, were performed in the home using the kitchen table as the operating arena. Hospitals were certainly not viewed as “the heart of healing,” but as the last resort, a place to die. By 1905, the emphasis of medical photography had turned its focus to the physician’s ability to conquer disease, and photographs of operating rooms decorated the walls of hospitals and physicians’ offices to reflect the “professionalization” of an institution. When this photograph was taken, in the mid-1940s, hospitals had acquired a new image as a sacred place to save lives. The operating room was a sterile environment, even hermetically sealed off from the audience, and the audience had changed from physicians to nurses. The style and format of this photograph was popularized in the 1940s to convey the sterile conditions of the operating room and the education of nurses. As medicine continues to advance, nurses and ancillary personnel continue to undertake more positions and procedures, which, a generation earlier, were the sole sacred domain of physicians. n

Excerpted from Oncology: Tumors & Treatment, A Photographic History, The Anesthesia Era: 1916–1945, by Stanley B. Burns, MD, FACS. Photographs courtesy of Stanley B. Burns, MD, and The Burns Archive.

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Expert’s Corner Community Oncology

A Cancer Care Model for Rural Areas A Conversation With Laurence J. Heifetz, MD By Ronald Piana become a ski bum and a cowboy. I tried my hand in the business of electronic medical records and promptly fell on my face. But it wasn’t a total loss because I learned a lot about the business world for about a year and a half.

A Location in Need of Cancer Services

Laurence J. Heifetz, MD

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How was the working relationship with UC Davis? What made the relationship real were the virtual tumor boards, which

Virtual Tumor Board

So we built a small conference room designed to integrate multiple doctors into a communal tumor board using basic flat screen and video technology. Each physician’s image and voice can be viewed along with the diagnostic imaging studies, pathology, and PowerPoint presentation. The high-definition images and sound are transmitted through encrypted Web-based technology, ensuring both security and quality. Each site created a dedicated virtual conference room with two monitors and a video camera. One monitor is for the audiovisual transmission and can be divided so the participating members can see and speak with each other. The other monitor is for the presentation outline as well as radiology and pathology images viewed through a Web-conferencing interface.

centers in our region: the University of California (UC) Davis, UC San Francisco, and Stanford. As it happened, UC Davis has cutting-edge technology where they have been pushing telemedicine to patients in the foothills of the Sierra Nevada mountains. So we partnered with them and created a program called the UC Davis Cancer Care Network, with four satellite facilities in addition to our Tahoe Forest Cancer Center; they include Rideout Cancer Center (Marysville), Mercy Cancer Center (Merced), and AIS Cancer Center (Bakersfield).

ROUND: 1 Last Saved: 6-19-2015 7:06 PM

What initiated the idea to develop a rural cancer center? At that time, there were no cancer services in Lake Tahoe; it was a blank slate. Here I was, an oncologist in town who didn’t want to work. However, after a while, the hospital and I sort of recruited each other to design an ideal rural oncology program. And since we didn’t have any legacy systems to work around, it allowed me to build it from the ground up. I insisted that it be hospital owned, as there was no way in this

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began about 6 years ago. Since about 80% of malignancies comprise four cancers—lung, breast, prostate, and colorectal—if I’m going to start a program up in the middle of nowhere, it needs to have an infrastructure that knows how to treat those four cancers; then all the other clinical issues follow suit. At UC Davis, every Monday is the gastroenterology tumor board, Tuesday is genitourinary, Wednesday is thoracic, and Thursday is breast. I had 80% of the cancers I’d be treating discussed every day at UC Davis. All we needed to do was use technology to make the communication functional.

Utilizing a high-quality secure telemedicine video connection allows patients who either cannot afford to or do not feel well enough to travel long distances the ability to stay close to home and still receive the best available care.

DATE: 6-19-2015 7:06 PM CW: L Gibbons INK Spec: 4C

Please tell the readers a bit about your career prior to the Tahoe Forest Cancer Center. I finished my training at MD Anderson in 1979. After that, I was in clinical practice at Cedars-Sinai Medical Center in Los Angeles up until 2003. While at Cedars-Sinai, I had been a founding partner in Tower Hematology Oncology Medical Group, a wonderful ninedoctor partnership. When I left Cedars-Sinai, I was in my mid-fifties and decided to shake things up a bit, so I moved up to Lake Tahoe to

What were some of the early challenges? I’d never been in a solo-practitioner setting, and I needed partners from the academic oncology world as a backup. So I reached out to the three National Cancer Institute–designated cancer

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Telemedicine as a Backup

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ural cancer patients have long had to adjust to difficult geographic and financial barriers to access highquality cancer care. These problems are exacerbated by today’s fiscal challenges, which have disrupted many of the small community practices that once served rural communities. In 2006, the Tahoe Forest Cancer Center in Truckee, California, which is a remote mountain resort town, opened its doors, with the goal of focusing on patient and family fears that are common among all patients with cancer but more frightening and challenging in the rural settings. The ASCO Post recently spoke with Laurence J. Heifetz, MD, the Center’s Founder and Director.

Please describe the hospital setting where you initiated the cancer care program. Tahoe Forest Hospital is a 25-bed critical access facility that serves a community of approximately 50,000 people living in an area of more than 4,000 square miles in the Lake Tahoe region of the Sierra Nevada mountains. The town of Truckee has a population of about 15,000, which swells considerably during high-volume tourist seasons. The hospital also has a six-bed intensive care unit, four operating rooms, an outpatient surgery center, busy labor and delivery room, and an active emergency room. The hospital is located about 30 miles from Reno, Nevada, and 100 miles from Sacramento, California. Those distances are misleading, as the weather from November through April is harsh and snowy, causing significant traffic and safety issues.

environment that I was going to open a private practice. After we designed the program, we rented a small place, figuring that we would see very few patients. However, we doubled our expectations within the first 6 months and found that the hospital staff and the surrounding community valued the service.

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Expert’s Corner

Aside from the obvious clinical benefits of a virtual tumor board, did this collegial virtual gathering have any other perks? Yes. The sort of closed-door attitude that exists in many academic centers opened up because we were in the inside. We were able to operate in an academic environment, so, in effect, our community patients were also UC Davis patients. And the virtual tumor board became a vital element of our rural practice. Within a few years, we were up to four doctors: three medical oncologists and a radiation oncologist. The community built us a beautiful state-of-the-art facility, and about 40% of patients are coming from outside our catchment area. We have become a very solid program, and one reason for that is our doctors eat lunch together in the virtual tumor board conference room. We block out time together for the tumor board, even if we’re not presenting a case. It has made us feel better about the care we deliver, which in turn results in better care for our patients. Did your positive experience with the virtual tumor boards lead to other helpful technologies that might help serve a rural community? Yes. We’re at the top of Lake Tahoe, and we are hours away from the academic centers in our network. We also have patients living in the Sierra crest, and they would have to drive close to 2 hours to see us for follow-ups after treatment. And we’d follow these patients for years. Since we’d become comfortable with technology ourselves, we decided to open up our own telemedicine clinics to serve our patients in their rural communities. We now operate four of these remote telemedicine clinics. Utilizing a high-quality secure telemedicine video connection allows patients who either cannot afford to or do not feel well enough to travel long distances the ability to stay close to home and still receive the best available care.

Fiscal Health In these challenging times, has your fiscal health been an issue? Money is always an issue, but the finances of a hospital-based cancer facility are different from those of a community practice. For one, our ability to generate revenue from our infusion therapy services is far greater than that from a community practice.

Plus, we have a very solid insurance mix: about 55% commercial, 29% Medicare, 12% Medicaid, and 4% self-pay. Our program is able to make a fairly seamless transition to an accountable care organization, whatever that may look like. We believe that we have all the elements for sustainability and growth.

The Affordable Care Act How does your model of care fit in with the new era of oncology practice and the changes brought about by the Affordable Care Act? Our model needs an investment from health systems. It cannot be replicated in private practice. My sense is B:8.75” that there is a global T:7.75” shift from small practices into much S:6.875” more organized

practices like ours. And for us in the rural community, the Affordable Care Act has been a profound benefit to us as oncologists. Before its enactment, there were a tremendous amount of cancer patients without insurance. Now we can see all of our rural patients. n Disclosure: Dr. Heifetz reported no potential conflicts of interest.

STRENGTHEN HER DEFENSE

Treatment guidelines recommend PERJETA-based therapy as the preferred first-line option • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA) + trastuzumab (Herceptin) + docetaxel as a (category 1) preferred option for the first-line treatment of patients with HER2+ MBC1 • ASCO® Clinical Oncology Practice Guidelines recommend pertuzumab + trastuzumab + docetaxel as first-line therapy for advanced HER2+ breast cancer 2 NCCN®=National Comprehensive Cancer Network®; HER2=human epidermal growth factor receptor 2; ASCO®=American Society of Clinical Oncology®.

Indication

PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Boxed WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity • PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for eﬀective contraception. Please see additional select Important Safety Information throughout, and the Brief Summary of full Prescribing Information including Boxed WARNINGS on the following pages.

Announcements

Children’s Hospital of Philadelphia Is a Founding Member of the New Pediatric Preclinical Testing Consortium

ddressing the relatively small number of new cancer drugs for children, a selective group of leading research centers is joining a new federally funded research consortium

aimed at bringing scientific rigor and a concentrated effort to identifying new drug candidates for pediatric clinical trials. The Children’s Hospital of Phila-

delphia (CHOP) and four other highprofile oncology research programs, plus a coordinating center, together S:6.875” form the Pediatric Preclinical Testing Consortium (PPTC) newly launched

by the National Cancer Institute. CHOP is building on its decadeslong investigations in the biology and treatment of neuroblastoma. The other centers in the PPTC, selected

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly extended progression-free survival (PFS) in first-line HER2+ metastatic breast cancer Combining PERJETA with Herceptin + docetaxel added 6 months median PFS3

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6.1-month improvement in median PFS by independent review (primary endpoint)3

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PERJETA + Herceptin + docetaxel

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Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction (LVEF) assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

Important Safety Information

Additional Important Safety Information

• PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and for 7 months after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months prior to conception to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Left Ventricular Dysfunction (LVD)

Boxed WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity

ej 1

• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel3

HR=hazard ratio; CI=confidence interval. Median PFS was reached at the first interim analysis.3 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.3

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PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. • In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel • Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions

• PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

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like CHOP after a highly competitive process, focus on leukemia, brain tumors, osteosarcoma, sarcoma, and renal tumors. “The primary rationale for this consortium is the fact that there are very few new drugs for pediatric cancer, and many of those drugs that have been introduced have been dependent on the

results of clinical trials in adults,” said pediatric oncologist John M. Maris, MD, who leads CHOP’s research program within the PPTC. Dr. Maris will collaborate on this project with CHOP coinvestigators Edward Attiyeh, MD; Lori Hart, PhD; and Matthew Tang. “Before testing a drug in children, we need a scientific basis for using it,

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John M. Maris, MD

based on deep understanding of the biology involved and supported by promising results in cell and animal models,” Dr. Maris added. “These preclinical findings will provide stronger evidence for us to engage proactively with drug companies who could partner in developing these continued on page 82

Overall survival (OS) data PERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis3

15.7-month improvement in median OS in the final analysis (secondary endpoint)3 PERJETA + Herceptin + docetaxel

100

Placebo + Herceptin + docetaxel

HR=0.68 95% CI: 0.56-0.84 P=0.0002

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median line

• The final OS analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group3 • The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 3

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• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI-CTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

PER/100114/0010(2)

Printed in USA.

06/15

Most Common Adverse Reactions • In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555. For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp. Please see additional select Important Safety Information throughout, and the Brief Summary of full Prescribing Information including Boxed WARNINGS on the following pages. References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.2.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed April 23, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(19):2078-2099. 3. PERJETA Prescribing Information. Genentech, Inc. 2015. 4. Data on file. Genentech, Inc. 5. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

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Hypersensitivity Reactions/Anaphylaxis

• Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized

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• Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

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• PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup4,5 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.11 [95% CI: 0.66-1.85])3

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Announcements New Pediatric Preclinical Testing Consortium continued from page 81

drugs.” Dr. Maris also envisions that preclinical research will lead to rational drug combination strategies for more effective treatments, rather than a reliance on single agents. Dr. Maris published an edito-

rial commentary this month in The Journal of the American Medical Association1 in which he praises the great potential of genetic analysis for improving pediatric cancer treatment but calls for major efforts to mount rigorous preclinical testing of candidate drugs in the most appropriate cell and animal models. PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012

WARNING: LEFT VENTRICULAR DYSFUNCTION and EMBRYO-FETAL TOXICITY Left Ventricular Dysfunction PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.1, 6.1) Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.2, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in eventfree survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)]. Limitations of Use: • The safety of PERJETA as part of a doxorubicincontaining regimen has not been established. • The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established. 4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. 5 WARNINGS AND PRECAUTIONS 5.1 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxeltreated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with

About the PPTC The PPTC is a program to systematically evaluate novel agents against pediatric solid tumor and leukemia models. The primary goal of the PPTC is to develop high-quality preclinical data to help pediatric oncology researchers identify new agents that will show significant activity when clinitrastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients. In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m 2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.2 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug or within 7 months following the last dose of PERJETA in combination with trastuzumab, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency

Cosmos Communications K

cally evaluated against selected childhood cancers. By supporting a more reliable agent prioritization process, the PPTC can contribute to the goal of identifying more effective treatments for children with cancer. The PPTC builds upon 10 years of experience with the Pediatric Preclinical Testing Program, which collaborated with of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxeltreated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grade 3 – 4. Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)]. 5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Left Ventricular Dysfunction [see Warnings and Precautions (5.1)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)]

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more than 50 pharmaceutical companies to test novel agents against the program’s pediatric preclinical models. The PPTC is supported through NCI cooperative agreement research grants to the PPTC Coordinating Center at Research Triangle Institute International (Primary Investigator, Diana Severynse-Stevens, PhD) and to five 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. Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional 2.75 years of follow-up (median total follow-up of 50 months) in Study 1. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 Placebo PERJETA + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades Grades, % 3–4, %

All Grades, %

Grades 3–4, %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8

research programs responsible for the evaluation of agents against pediatric cancer preclinical models. The research programs are led by: • Peter Houghton, PhD, Sarcoma and renal tumors, Greehey Children’s Cancer Institute • John Maris, MD, Neuroblastoma, Children’s Hospital of Philadelphia Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA‑treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebotreated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebotreated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (>30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2. Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

PERJETA PERJETA PERJETA + trastuzumab Trastuzumab + docetaxel + trastuzumab + docetaxel + docetaxel n=108 n=108 n=107 n=107 Frequency rate Frequency rate Frequency rate Frequency rate % % % % Grades All Grades All Grades All Grades All Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue Asthenia Edema peripheral Mucosal inflammation Pyrexia

27.1 0.0 26.2 0.9 12.0 17.8 0.0 20.6 1.9 2.8

0.0 25.5 1.1 0.0 16.0 2.1

10.3 0.0

2.8

0.0

0.9

0.0

5.3

0.0

21.5 0.0 26.2 1.9 10.3 0.0 16.8 0.0

2.8 8.3

0.0 25.5 0.0 0.0 8.5 0.0

66.4 0.0 65.4 0.0 2.8 21.5 1.9 26.2 0.9 11.1

0.0 67.0 0.0 0.0 28.7 1.1

Skin and subcutaneous tissue disorders Alopecia Rash

Cosmos Communications K

• Richard Lock, PhD, Leukemia, Children’s Cancer Institute, Sydney, Australia • Xiao-Nan Li, MD, PhD, Brain tumors, Texas Children’s Hospital • Richard Gorlick, MD, Osteosarcoma, Albert Einstein College of Medicine More information about the Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 Peripheral Sensory Neuropathy 12.1 0.9 8.4 0.9 1.9 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 Metabolism and nutrition disorders Decreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0

54.3 36.2 16.0 9.6

4.3 1.1 2.1 0.0

64.9 57.4 13.8 8.5 12.8 0.0 7.4 0.0 10.6 0.0 21.3 0.0 9.6 0.0 14.9 0.0 8.5

0.0

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA‑treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T +D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+ T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (>30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (>2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (>30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (>2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3.

PPTC is available at its website: www.ncipptc.org. n Reference 1. Schnepp RW, Bosse KR, Maris JM: Improving patient outcomes with cancer genomics: unique opportunities and challenges in pediatric oncology. JAMA 9:881883, 2015.

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Announcements

NIH Awards Nearly $35 Million to Research Natural Products

ive research centers will focus on the safety of natural products, how they work within the body, and the development of cutting-edge research technologies. The centers, jointly funded by the National Institutes of Health’s Office of Dietary SuppleTable 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab by PERJETA + docetaxel + trastuzumab following FEC PERJETA + TCH + docetaxel n=75 n=76 n=72 Frequency rate, % Frequency rate, % Frequency rate, % Grades All Grades All Grades All 3–4 Grades 3–4 Grades 3–4 Grades % % % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 Asthenia 9.7 0.0 14.7 1.3 13.2 Edema peripheral 11.1 0.0 4.0 0.0 9.2 Mucosal 23.6 0.0 20.0 0.0 17.1 inflammation Pyrexia 16.7 0.0 9.3 0.0 15.8 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 Rash 19.4 0.0 10.7 0.0 21.1 Dry skin 5.6 0.0 9.3 0.0 10.5 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 Dyspepsia 25.0 1.4 8 0.0 22.4 Nausea 52.8 0.0 53.3 2.7 44.7 Vomiting 40.3 0.0 36.0 2.7 39.5 Constipation 18.1 0.0 22.7 0.0 15.8 Stomatitis 13.9 0.0 17.3 0.0 11.8 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 Anemia 19.4 1.4 9.3 4.0 38.2 Leukopenia 22.2 19.4 16.0 12.0 17.1 Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 Nervous system disorders Neuropathy 5.6 0.0 1.3 0.0 10.5 peripheral Headache 22.2 0.0 14.7 0.0 17.1 Dysgeusia 11.1 0.0 13.3 0.0 21.1 Dizziness 8.3 0.0 8.0 1.3 15.8 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 Arthralgia 11.1 0.0 12.0 0.0 6.6 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 Dyspnea 12.5 0.0 8.0 2.7 10.5 Epistaxis 11.1 0.0 10.7 0.0 15.8 Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 Metabolism and nutrition disorders Decreased appetite 20.8 0.0 10.7 0.0 21.1 Eye disorders Lacrimation 12.5 0.0 5.3 0.0 7.9 increased Psychiatric disorders Insomnia 11.1 0.0 13.3 0.0 21.1 Investigations ALT increased 6.9 0.0 2.7 0.0 10.5

3.9 1.3 0.0 1.3 0.0 0.0 1.3 0.0 0.0 11.8 0.0 0.0 5.3 0.0 0.0 46.1 17.1 11.8 17.1 11.8 2.6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.3 1.3 0.0 0.0 0.0 0.0 3.9

FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/ Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm) Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm) Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms)

ments (ODS) and the National Center for Complementary and Integrative Health (NCCIH), include three Botanical Dietary Supplements Research Centers and two Centers for Advancing Natural Products Innovation and Technology.

Natural products include a wide variety of substances produced by plants, bacteria, fungi, and animals that have historically been used in traditional medicine and other complementary and integrative health practices.

6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA.

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

Patients in Study 1 were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development.

8.5 Geriatric Use Of 402 patients who received PERJETA in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryofetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 7 months following the last dose of PERJETA in combination with trastuzumab. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)].

Many of the botanical supplements proposed for study by these centers—such as black cohosh, bitter melon, chasteberry, fenugreek, grape seed extract, hops, maca, milk thistle, resveratrol, licorice, and valerian—are among the top 100 supplements consumed in the United States based on sales data. Nearly one in five American adults use botanical supplements and other nonvitamin, nonmineral dietary supplements, such as fish oil/omega-3 fatty acids and probiotics, according to the 2012 National Health Interview Survey.

Competitive Awards The three Botanical Dietary Supplements Research Centers will receive competitive awards of approximately $2 million per year for 5 years, pending available funds. These three interdisciplinary and collaborative centers will advance understanding of the mechanisms through which complex botanical dietary supplements may affect human health and resilience.

8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date. 17 PATIENT COUNSELING INFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.1)] • Advise pregnant women and females of reproductive potential that PERJETA exposure can result in fetal harm, including embryo-fetal death or birth defects [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)] • Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 7 months following the last dose of PERJETA in combination with trastuzumab [see Warnings and Precautions (5.2) and Use in Special Populations (8.6)] • Advise nursing mothers treated with PERJETA to discontinue nursing or discontinue PERJETA, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.3)] • If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who are exposed to PERJETA during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.6)]

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

Paul M. Coates, PhD

The two Centers for Advancing Natural Products Innovation and Technology have a combined budget of approximately $1.25 million per year for 5 years, pending available funds. These centers are expected to develop new research approaches and technologies that will have significant impact on the chemical and biologic investigation of natural products. They will also provide leadership in coordinating scientific discourse and disseminating innovative methodology and good research practices to the research community on natural products. “Our Botanical Research Centers Program has been a unique driver of research on natural products for 16 years,” said Paul M. Coates, PhD, ODS Director. “The two new Centers for Advancing Natural Products Innovation and Technology will develop pioneering methods and techcontinued on page 86

Cosmos Communications K

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2015-2016 Oncology Meetings October

ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org/Meetings-andEvents/2015-Annual-Meeting/Index. aspx 2015 International Cancer Education Conference October 21-23 • Tucson, Arizona For more information: http://2015.attendicec.org ACCC 32nd National Oncology Conference October 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/ calendar.asp Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies October 22-24 • New York, New York For more information: http://www.imedex.com/lymphomamyeloma-conference/index.asp Cutaneous Oncology Symposium 2015 October 23-24 • Fernandina Beach, Florida For more information: https:// ce.mayo.edu/hematology-andoncology/node/3306 4th Annual New Therapeutics in Oncology: The Road to Personalized Medicine October 23-25 • Los Angeles, CA For more information: https:// www.regonline.com/builder/ site/?eventid=1727722 13th Annual West Coast Colorectal Cancer Symposium October 23 • Seattle, Washington For more information: http:// www.swedish.org/for-healthprofessionals/cme/conferences/ colorectal-cancer-symposium

2015-2016

53rd Annual Meeting of the Japan Society of Clinical Oncology (JSCO) October 24-26 • Kyoto, Japan For more information: www.jsco. or.jp/english/index/page/id/73

2015 Oncofertility Conference November 3-5 • Chicago, Illinois For more information: https:// oncofertility.northwestern.edu/2015Conference

ESGO 2015-International Meeting of the European Society of Gynaecological Oncology October 24-27 • Nice, France For more information: http://esgo2015.esgo.org

33rd Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® November 4-6 • New York, New York For more information: http://www.chemotherapyfoundationsymposium.org/CMS/

AACI/CCAF Annual Meeting October 25-27 • Washington, DC For more information: http://www. aaci-cancer.org/annual_meeting/ Modern Management of Urologic Cancers: A Multidisciplinary Approach (Memorial Sloan Kettering) October 29-31 • New York, New York For more information: http://www. themerzgroup.com/mskcc/mskccurologic-conference/

Lynn Sage Breast Cancer Symposium October 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org Caring for the Caregivers X October 30 • Waltham, MA For more information: http://www.massmed.org Continuing-Education-and-Events/ Event-Information/?code=CFC2015

November NRCI Cancer Conference November 1-4 • Liverpool, UK For more information: http://conference.ncri.org.uk 3rd International Conference on Hematology & Blood Disorders November 2-4 • Atlanta, Georgia For more information: http:// hematology.conferenceseries.com

14th International Kidney Cancer Symposium November 6-7 • Miami, Florida For more information: http://registeruo.niu.edu/ iebms/wbe/wbe_p1_main. aspx?oc=40&cc=WBE4014167 ESMO Summit Americas 2015 Oncology Updates: From Evidence to Practice November 6-8 • Miami, Florida For more information: www.esmo.org/Conferences/ESMOSummit-Americas-2015

Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.sitcancer.org/2015 JADPRO Live at APSHO for Advanced Practitioners in Oncology November 5-8, 2015 • Phoenix, Arizona JW Marriott Desert Ridge For more information: jadprolive.com City of Hope Presents: Multidisciplinary Approaches to Cancer Symposium November 5-8 • Las Vegas, Nevada For more information: https://cme.cityofhope.org/ eventinfo_5980.html Advanced Breast Cancer Third International Consensus Conference November 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org 13th Annual School of Breast Oncology November 5-7 • Atlanta, Georgia For more information: http://www.gotoper.com/ conferences/sobo/meetings/13thAnnual-School-of-Breast-Oncology AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics November 5-9 • Boston, Massachusetts For more information: http:// www.aacr.org/Meetings/Pages/ MeetingDetail

10th Annual New York Lung Cancer Symposium November 7 • New York, New York For more information: http://www.gotoper.com/ conferences/nyl/meetings/10thAnnual-New-York-Lung-CancerSymposium 17th Annual Brain Tumor Update and 6th Annual International Symposium on Long-Term Control of Metastases to the Brain and Spine November 7-8 • Las Vegas, Nevada For more information: http://www. clevelandclinicmeded.com/live/ courses/2015/brainmets15/.aspx?Ev entItemID=52&DetailItemID=196#. VSZlr_msXpU Best of ASTRO November 13-14 • San Diego, CA For more information: www.astro.org/Meetings-andEvents/2015-Best-of-ASTRO/Index.aspx 2015 Oncologic Emergency Medicine Conference November 13-14 • Houston, Texas For more information: http://www.mdanderson.org/ education-and-research/educationand-training/schools-and-programs/ cme-conference-management/ conferences/d114243-2015oncologic-emergency-medicineconference.html continued on page 88

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Announcements Natural Products continued from page 84

niques to catalyze research on these products.” “Natural products have a long and impressive history as sources of medicine and as important biologic research

John MacMillan, PhD, Roger Linington, PhD, and Michael White, PhD • Institutions: The University of Texas Southwestern Medical Center; Simon Fraser University; University of California, Santa Cruz

The UIC Natural Products Technology Center • Principal Investigator: Guido Pauli, PhD • Institution: University of Illinois at Chicago The Office of Dietary Supplements initiated the Botanical Research Centers Program in partner-

ship with the National Center for Complementary and Integrative Health in 1999, in response to a Congressional mandate. To learn more about the Botanical Research Centers Program, visit http://ods.od.nih.gov/Research/ Dietar y_Supplement_Research_ Centers.aspx. n

Josephine Briggs, MD

tools,” said Josephine Briggs, MD, NCCIH Director. “These centers will seek not only to understand potential mechanisms by which natural products may affect health, but also to address persistent technologic challenges for this field by taking full advantage of innovative advances in biologic and chemical methodology.”

Dietary Botanicals in the Preservation of Cognitive and Psychological Resilience • Principal Investigators: Giulio Pasinetti, MD, PhD, and Richard Dixon, PhD • Institution: Icahn School of Medicine at Mount Sinai • Partner Institutions: Purdue University; Rutgers, The State University of New Jersey; University of North Texas

Inactivated T Cell

PD-1 Receptor

Activated T Cell

Botanicals and Metabolic Resiliency • Principal Investigator: William Cefalu, MD • Institution: Pennington Biomedical Research Center, Louisiana State University • Partner Institutions: North Carolina State University, Kannapolis; Rutgers, The State University of New Jersey; University of Illinois at Chicago

PD-L2 PD-1 Receptor

Tumor

PD-L1

Botanical Dietary Supplements for Women’s Health • Principal Investigator: Richard van Breemen, PhD • Institution: University of Illinois at Chicago

The Center for High-Throughput Functional Annotation of Natural Products • Principal Investigators:

Artist’s interpretation based on scanning electron microscopy.

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Announcements

Recent Johns Hopkins Oncology Faculty Appointments

ina Wagner-Johnston, MD, has been appointed Associate Professor of Oncology in the Hematologic Malignancies Division, and will lead the Lymphoma Drug Development Program. At the Siteman Cancer Center at the Washington University in St. Louis,

Dr. Wagner-Johnston made several important contributions relevant to the diagnosis and treatment of lymphoma and chronic lymphocytic leukemia. She also brings expertise in neuropathic pain, particularly related to chemotherapy. Stacy Cooper, MD, has been

appointed Instructor in Oncology and Pediatrics. Dr. Cooper’s interests are in improving outcomes for children with hematologic malignancies and the role of transcription factors in leukemogenesis. During her fellowship, Dr. Cooper worked in the laboratory of Alan Friedman, MD, Nina Wagner-Johnston, MD

Discover PD-1: an immune checkpoint pathway1 Stacy Cooper, MD

Some tumor cells can evade the body’s immune response, which may result in disease progression2,3 • One function of the body’s immune response is to detect and destroy tumor cells through activated T cells and other mechanisms; tumor cells express multiple antigens that are not expressed in normal tissue.1—3 • However, some tumor cells may evade the body’s immune response by exploiting the PD-1 checkpoint pathway through expression of the dual PD-1 ligands, PD-L1 and PD-L2.1,2,4—6 • PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumor cells to evade the immune response.1,2,7

PD-L1, an immune checkpoint ligand, is a potential predictive biomarker expressed on tumor cells in many different types of cancer8 Merck is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway and PD-L1 as a potential predictive biomarker.

To discover more about the PD-1 pathway and to register for updates, visit discoverthePD1pathway.com.

PD-1=programmed death receptor-1; PD-L1=programmed death receptor-1 ligand 1; PD-L2=programmed death receptor-1 ligand 2. References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. 2. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. 3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 4. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477. 5. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862. 6. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157. 7. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–268. 8. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):OF1–OF10.

Catherine Albert, MD

studying novel therapeutic pathways for the treatment of leukemia. Dr. Cooper will manage the Pediatric Hematology/ Oncology Fellowship, and she has a strong interest in phase I clinical trials for pediatric oncology and in resident and fellow education. Catherine Albert, MD, has been appointed Instructor in Oncology and Pediatrics. She will focus on translational research to benefit children with cancer. During Dr. Albert’s fellowship, she focused on molecular pathways in pediatric rhabdomyosarcoma in the laboratory of David Loeb, MD, PhD. She recently received grants from the Stetler Foundation and Bear Necessities Pediatric Cancer Foundation. n

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

The ASCO Post | OCTOBER 10, 2015

PAGE 88

2015-2016 Oncology Meetings Meetings Calendar continued from page 85

8th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved November 13-16 • Atlanta, Georgia For more information: http:// www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=68#.Vba1EqTbJjq

Joint Conference: Acupuncture, Oncology and Fascia November 14 • Boston, Massachusetts For more information: http:// oshercenter.org/joint-conferenceacupuncture-oncology-fascia/ Society for Integrative Oncology 12th International Conference November 14-16 • Boston, Massachusetts For more information: http://www.integrativeonc.org/ conference 4th Cancer Epigenetics Conference November 16-17 • San Francisco, California For more information: www.gtcbio.com/conferences Advances in Cancer ImmunotherapyTM November 18 • San Francisco, California For more information: www.sitcancer.org/sitc-meetings/ aci2015/casf

11th Annual Personalized Medicine Conference November 18-19 • Boston, Massachusetts For more information: http://personalizedmedicine. partners.org/Education/ Personalized-Medicine-Conference/ Program.aspx 12th International Congress of the Society for Melanoma Research November 18-21 • San Francisco, California For more information: www.melanomacongress.com/ 20th Annual Scientific Meeting of the Society for Neuro-Oncology November 19-22 • San Antonio, Texas For more information: www.soc-neuro-onc.org ESMO Symposium on Immuno-Oncology November 20-21 • Lausanne, Switzerland For more information: www.esmo.org/Conferences/ Immuno-Oncology-2015

December 9th European Colorectal Congress (ECC) December 1-4 • St. Gallen, Switzerland For more information: www.colorectalsurgery.eu Advances in Cancer ImmunotherapyTM December 4 • New Orleans, Louisiana For more information: www.sitcancer.org/sitc-meetings/ aci2015/la

2015-2016

10th Annual Practical Course in Dermoscopy & Update on Malignant Melanoma 2015 December 4-6 • Scottsdale, Arizona For more information: https://ce.mayo.edu/dermatology/ node/2463 57th Annual ASH Meeting & Exposition December 5-8 • Orlando, Florida For more information: www.hematology.org/

Genitourinary Cancers Symposium January 7-9 • San Francisco, California For more information: http://gucasym.org Cancer Survivorship Symposium: Primary Care and Oncology Collaboration January 15-16 • San Francisco, California For more information: www.survivorsym.org/

San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org

Gastrointestinal Cancers Symposium January 21-23 • San Francisco, California For more information: http://gicasym.org American Society for Cell Biology Annual Meeting December 12-16 • San Diego, Callifornia For more information: http://ascb.org/2015meeting/ European Society for Medical Oncology Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ESMOAsia-2015-Congress

January 2016 4th AACR-IASLC International Joint Conference: Lung Cancer Translational Science January 4-7 • San Diego, California For more information: http:// www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=74#.VbbijqTbJjo

8th Immunotherapeutics & Immunomonitoring Conference January 25-26 • San Diego, California For more information: https:// www.gtcbio.com/conferences/ immunotherapeuticsimmunomonitoring-overview

February Multidisciplinary Head and Neck Cancer Symposium February 18-20 • Scottsdale, Arizona For more information: www.headandnecksymposium.org 25th Conference of the Asian Pacific Association for the Study of the Liver February 20-24 • Tokyo, Japan http://www.apasl2016.org

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Announcements

Todd Demmy, MD, FACS, FCCP, Joins Rutgers Cancer Institute of New Jersey

utgers Cancer Institute of New Jersey has named Todd Demmy, MD, FACS, FCCP, as its new Chief of Thoracic Oncology and Associate Chief of the Division of Surgical Oncology. Dr. Demmy, who is leading Rutgers Cancer Institute’s Thoracic Oncology Program, is an international leader in minimally invasive thoracic surgery and one of the pioneers of video-assisted thoracoscopic surgery (VATS). Dr. Demmy was most recently at Roswell Park Cancer Institute, where he served as Clinical Chair of Thoracic Surgery and Professor of Oncology.

cal School, performs many laparoscopic and thoracoscopic operations for benign esophageal diseases like repair of large hiatal hernias. Dr. Demmy received his medical degree from Jefferson Medical College. He completed a general surgery

internship at Baylor College of Medicine, followed by a residency and research fellowship in cardiothoracic and cardiovascular surgery at Allegheny General Hospital-West Campus, Medical College of Pennsylvania. Prior to his extensive work at

Roswell Park Cancer Institute, Dr. Demmy served as Chief of Thoracic Oncology, Codirector of Cardiac Transplantation, and Associate Professor of Surgery at University of Missouri Hospital and Clinics and Ellis Fischel Cancer Center. n

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 CASES OF PROGRESSION WITH FIRSTGENERATION EGFR TKIs ARE RELATED TO THE T790M MUTATION1,2 Lung cancer is the leading cause of cancer-related deaths both in the US and worldwide.3,4 For NSCLC EGFRm+ patients, the recommended frst-line treatment is EGFR tyrosine kinase inhibitors (TKIs).5

The majority of tumors will acquire EGFR TKI–resistance mutations Todd Demmy, MD, FACS, FCCP

Dr. Demmy has been recognized internationally for advanced VATS operations, including chest wall resections, the first United States VATS extrapleural pneumonectomy, and the world’s largest series of thoracoscopic pneumonectomies. While lung disease has been a major component of his scholarly work, Dr. Demmy also maintained a busy clinical practice in foregut surgery by founding the first minimally invasive esophagectomy program in Buffalo, New York, more than 10 years ago. Dr. Demmy, who also was appointed Professor in the Department of Surgery and Chief, Section of Thoracic Surgery, within the Division of Cardiothoracic Surgery at Rutgers Robert Wood Johnson Medi-

Despite initial high response rates with frst-generation EGFR TKIs, many tumors will develop new mutations and become resistant.6,7 A major barrier to disease control is resistance to treatment. Resistance to frst-generation therapy will develop in most patients with EGFRm+ advanced NSCLC on a currently approved EGFR TKI.7 After disease progression, clinical guidelines recommend subsequent treatments including either continuing with an EGFR TKI therapy or beginning platinum-based chemotherapy.5

Nearly 2 out of 3 cases of progression with ﬁrst-generation EGFR TKIs are related to the T790M mutation In patients with NSCLC who are EGFRm+, T790M is an acquired mutation and has been identifed as the most common mechanism of acquired resistance in nearly 2 out of 3 patients.1,2 Development of T790M mutation may confer resistance through several potential mechanisms, which may include8,9: - Steric hindrance, which reduces receptor binding of reversible EGFR TKIs - Increased binding affnity of EGFR for ATP, resulting in reduced TKI potency

T790M Is the Most Common Mechanism of Acquired Resistance to First-Generation EGFR TKI Therapy1

63%

T790M (98/155)

CI, (9555 –70 ) %

MET amplifcation (4/75)

5% (95% CI, 1%–13%)

HER2 amplifcation (3/24)

NEARLY 2 OUT OF 3

13% (95% CI, 3%–32%)

10% 20% 30% 40% 50% 60% 70%

Study of 155 patients with radiographic progression following a response or durable stable disease with frst-generation EGFR TKI therapy.

CASES ARE RELATED TO T790M

Other rare mechanisms of acquired resistance may include BRAF, FGFR, and PIK3CA mutations, and transformation to small-cell histology.10,11

Discovering the cause of resistance

The ASCO Post Follow us on

Patients should be monitored for radiologic or clinical progression. Tumors can also be assessed for molecular progression to uncover additional acquired mutations.1,12-16 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).5

AstraZeneca is a leader in lung cancer research AstraZeneca is conducting ongoing research to understand the science of the T790M mutation as a driver of resistance.

Find out more at EGFRevolution.com.

@ASCOPost

References: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 2. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. American Cancer Society. Cancer Facts & Figures 2015. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed March 17, 2015. 4. GLOBOCAN 2012. http://globocan.iarc.fr. Accessed February 9, 2015. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 7. Sequist LV, Yang JCH, 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;31:3327-3334. 8. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to geftinib. N Engl J Med. 2005;352:786-792. 9. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affnity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070-2075. 10. Cheng L, Alexander RE, MacLennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347-369. 11. Ware KE, Marshall ME, Heasley LY, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One. 2010;5:e14117. doi:10.1371/journal.pone.0014117.12. Johnson KR, Ringland C, Stokes BJ, et al. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet. 2006;7:741-746. 13. Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specifc microRNAs. PLoS One. 2012;7:e50141. doi:10.1371/journal.pone.0050141. 14. Jackman DM, Miller VA, Cioffredi, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non–small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009;15:5267-5273. 15. Noronha V, Joshi A, Gokarn A, et al. The importance of brain metastasis in EGFR mutation positive NSCLC patients. Chemother Res Pract. doi:10.1155/2014/856156. 16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. ©2015 AstraZeneca. All rights reserved. 3140404 6/15

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In the News Breast Cancer

Varied Reactions to Study Finding That Preventing Ipsilateral Recurrence Did Not Prevent Death From Breast Cancer By Charlotte Bath

omen diagnosed with ductal carcinoma in situ have a low risk of dying of breast cancer, according to an observational study looking at data from 108,196 women diagnosed with ductal carcinoma in situ between 1988 and 2011.1 The breast cancer–specific mortality rate for these women was 1.1% at 10 years and 3.3% at 20 years. Mortality rates were higher for black women and women diagnosed before the age of 35. “The risk of death increases after a diagnosis of ipsilateral second primary invasive breast cancer, but prevention of these recurrences by radiotherapy does not diminish breast cancer mortality at 10 years,” the authors concluded in JAMA Oncology.1 This study garnered national media coverage, including The New York Times, The Washington Post, USA Today, TIME magazine, National Public Radio, and the PBS NewsHour. That coverage included varied reactions to the study and its implications for the treatment of women diagnosed with ductal carcinoma in situ. “The finding of greatest clinical importance was that prevention of ipsilateral invasive recurrence did not prevent death from breast cancer,” the authors stated in their report and lead author Steven A. Narod, MD, confirmed in an interview with The ASCO Post. Dr. Narod is Senior Scientist and Director of the Familial Breast Cancer Research Unit at Women’s College Research Institute, Toronto, Ontario, Canada. The investigators also found that after adjusting for tumor size, grade, and other factors, “the difference in survival for mastectomy vs lumpectomy was not significant.”

Practice-Changing or Not? The authors of the study did not deem their finding practice-changing. Some news reports, however, suggest the finding that breast cancer–specific mortality for women diagnosed with ductal carcinoma in situ was similar no matter what the treatment—and just 1.8 times higher than for women in the general population—indicating it does not need to be treated. The New York Times headlined its article on the study “Early-Stage Breast Condition May Not Require Treatment”2 and listed the following as one of the “provocative questions” raised by the study: “Is there any

reason for most patients with the diagnosis to receive brutal therapies?” “Let me emphatically say that I do not understand how an observational study of patients for whom we don’t have complete characterization of their ductal carcinoma in situ, who were treated in different ways, and who were not randomly assigned could possibly be a practice-changing study,” stated Monica Morrow, MD, Chief, Breast Service, Memorial Sloan Kettering Cancer Center, New York, in an interview with The ASCO Post. “That is not how we change practice.” Dr. Morrow added that she considers calls for additional trials to be appropriate. “But telling people they should change practice on the basis of this is

needle biopsy will actually be found to have invasive cancer when you remove the entire area.”3

Study Details Information about study patients’ age at diagnosis, race/ethnicity, pathologic features, date of second primary breast cancer, cause of death, and survival data was abstracted from the most recent Surveillance, Epidemiology, and End Results (SEER) 18 registries database. According to the study authors, “the SEER18 database covers approximately 28% of the U.S. population (based on the 2010 census).” The mean age of the patients at diagnosis was 53.8 (range, 15–69) years, and the mean duration of fol-

The ductal carcinoma in situ is the cancer, and the recurrence is the recurrence. Just like invasive cancer. And if you prevent that invasive cancer recurrence, it doesn’t prevent death. —Steven A. Narod, MD

a mistake. I think the most important message of this study is that when you treat ductal carcinoma in situ, the risk of breast cancer deaths is incredibly low. What we don’t know is whether or not the risk of breast cancer deaths will be equally low if we don’t treat ductal carcinoma in situ. That is a giant extrapolation of the data, saying the outcome of data is good and therefore we don’t have to treat. Those are not the same things. But that is what some people are saying.” Commenting on the study for the PBS NewsHour, Dr. Morrow said that she thinks what the study “does tell us is that, to date, physicians have been pretty good at selecting low-risk ductal carcinoma in situ, which can be treated minimally with lumpectomy alone. I think it says we should think hard about expanding the indications for minimal treatment. But I think it’s also important for women to be aware that we can only say there is nothing there but ductal carcinoma in situ after we have removed the entire area. Twenty percent of women who are diagnosed as having ductal carcinoma in situ on a

low-up was 7.5 (range, 0–23.9) years. At 20 years, the overall breast cancer–specific mortality for women diagnosed with ductal carcinoma in situ was 3.3% (95% confidence interval [CI], 3.0%–3.6%) but higher for women diagnosed before age 35, 7.8% vs 3.2% for older women (hazard ratio [HR] = 2.58 [95% CI, 1.85–3.60]; P < .001), and for blacks, 7.0% vs 3.0% for non-Hispanic whites (HR = 2.55 [95% CI, 2.17–3.01]; P < .001). The risk of dying of breast cancer was higher among women who experienced an ipsilateral invasive breast cancer (HR = 18.1 [95% CI, 14.0–23.6]; P < .001). The use of radiotherapy with lumpectomy reduced the risk of developing an ipsilateral invasive recurrence from 4.9% to 2.5% for lumpectomy alone “but did not reduce breast cancer–specific mortality at 10 years (0.9% vs 0.8%),” the authors noted. After adjusting for tumor size, grade, and other factors, the difference in survival was not significant for patients who underwent mastectomy vs lumpectomy (HR = 1.20 [95% CI, 0.96–1.50]; P = .11).

Risk Factors for Mortality Only 1.2% of women in the study were diagnosed with ductal carcinoma in situ before age 35, “but for them, mortality was approximately 17 times greater than expected in the 9 years following diagnosis,” the authors reported. Dr. Narod explained that this is the relative risk compared with the baseline risk for the general population. “Very few 35 year olds die of breast cancer,” he said, so even 17 times that number is “is not very big. If the same risk was seen in a 50-year-old woman, it would be much different than in a 35-year-old woman.” Dr. Morrow noted that older women who have screening mammographies often present with microscopic areas of calcium deposits, but that “is not what these young women present with. They present with lumps or nipple discharge, and the bigger the area of the ductal carcinoma in situ, the bigger the chance of sampling error with core needle biopsy as well as in the surgical specimen. The greater the possibility that there may be undiagnosed cancer, number 1. And number 2, we know from clinical trials that have been done in the past that young women who are treated with lumpectomy alone without radiation tend to have a higher rate of local recurrence.” The breast cancer–specific mortality rate was also higher for black women than non-Hispanic white women. “The proportion of black and white women treated with mastectomy and radiotherapy was similar,” the authors wrote. “It is improbable that black women had inferior survival because of less-frequent screening or inadequate treatment.” “Other important risk factors for mortality following ductal carcinoma in situ included estrogen receptor status, high grade, tumor size, and comedonecrosis,” the researchers reported. “In the first 10 years after diagnosis, the mortality rate for women with estrogen receptor–negative cancers exceeded that for estrogen receptor–positive cancers, but at 20 years, the mortality rates had reversed. Among the deaths from estrogen receptor–negative ductal carcinoma in situ, 13.4% occurred in years 10 to 19. In contrast, among the deaths of patients with estrogen receptor–positive ductal carcinoma in situ, 26.8% occurred in years 10 to 19.”

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In the News Clinical Course Similarities “It is well known that estrogen receptor–negative cancers do badly but only transiently,” Dr. Narod noted. “The estrogen receptor–positive ones tend to lie dormant, and then they can wake up to kill you after 15 years.” This relationship between estrogen receptor status and mortality risk “is one of several similarities between the clinical course of women with ductal carcinoma in situ and that of women with small invasive cancers,” the investigators reported. “That is really important,” Dr. Narod stated. “Ductal carcinoma in situ resembles cancer in almost every way. The estrogen receptor pattern is the same, the age pattern is the same, the black women pattern is the same, and most important, preventing recurrence does not prevent death. It has been known for years, since NSABP trials compared lumpectomy

and mastectomy, that preventing breast cancer recurrence didn’t prevent death from invasive cancer. Now we show exactly the same thing for ductal carcinoma in situ, and people don’t get it. They still think that ductal carcinoma in situ is the precursor, and the recurrence is the cancer. No: The ductal carcinoma in situ is the cancer, and the recurrence is the recurrence. Just like invasive cancer. And if you prevent that invasive cancer recurrence, it doesn’t prevent death,” Dr. Narod asserted.

In-Breast Recurrence Among the 3% of women in the study who died of breast cancer, 54% of them did not experience an in-breast recurrence (ipsilateral or contralateral). “That leads me to think that when ductal carcinoma in situ was removed by the surgeon, it had already spread

around the breast, and it took years, up to 20 years, for those cells that had spread to flourish and to be metastatic and to ultimately cause the breast cancer death,” Dr. Narod said on the PBS NewsHour.3 The other 46% will “experience an in-breast ipsilateral recurrence or contralateral breast cancer,” Dr. Narod told The ASCO Post. “It’s not to say that that killed them.” The risk of contralateral invasive recurrence was higher than the risk of ipsilateral invasive recurrence, 6.2% vs 5.9%, at 20 years for all women in the study. “The ipsilateral [recurrence rate] was reduced by radiotherapy. Had there been no radiotherapy, the ipsilateral [recurrence rate] would have been higher than the contralateral [recurrence rate],” Dr. Narod explained. “But certainly, ductal carcinoma in situ

predisposes to contralateral. We need to explore why that it is. Contralateral breast cancer is increased about twice as much as we would expect in an average woman,” he added. “The risk of contralateral breast cancer following ductal carcinoma in situ is identical to the risk of contralateral breast cancer following stage I breast cancer. So it is another reason to say that ductal carcinoma in situ is an early form of breast cancer, not precancer,” Dr. Narod said. He and his coauthors acknowledged, “although it is accepted that, for women with invasive breast cancer, prevention of in-breast recurrence does not prevent death for women with small invasive breast cancers, this has not been widely accepted for women with ductal carcinoma in situ.” Dr. Narod told The ASCO Post continued on page 92

Expect Questions About Treatment for Ductal Carcinoma in Situ By Charlotte Bath

he recent study findings that women diagnosed with ductal carcinoma in situ had a low breast cancer–specific mortality and that preventing ipsilateral recurrences did not prevent breast cancer mortality1 might lead some women diagnosed with ductal carcinoma in situ to question the need for treatment aimed at preventing recurrences. However, it does not mean that most women will choose to opt out of that treatment. “Surgeons are more likely, believe it or not, to recommend less surgery, lumpectomy, and patients are more likely to want more surgery, bilateral mastectomy,” Monica Morrow, MD, Chief, Breast Service, Memorial Sloan Kettering Cancer Center, New York, told The ASCO Post. “The approach to that conflict is to help patients understand what will and won’t prolong their survival. But even when you have that conversation, it is just an idea that is hard to get rid of—that bigger surgery doesn’t cure more cancer,” Dr. Morrow. Commenting on the study on the PBS NewsHour, Dr. Morrow said, “A critical finding of this study is how good the prognosis for ductal carcinoma in situ is, and women should be reassured, because we know that women with ductal carcinoma in situ estimate their risk of dying of breast cancer to be as high as 30%. And this study says that’s just simply not true.”2

A Conversation With the Patient “The way we determine whether anyone is a candidate for lumpectomy with radiotherapy or mastectomy is based on the amount of ductal carcinoma in situ in the breasts relative to the size of the breasts. So can you do a lumpectomy, remove all the ductal

tion? Most people can receive radiation. If you’ve had prior radiation to the breast area, you can’t. If you have some uncommon diseases like active lupus or scleroderma, we generally don’t give radiation. But other than that, most people other than pregnant women can get radiation,” Dr. Morrow explained. “So then it boils

Surgeons are more likely, believe it or not, to recommend less surgery, lumpectomy, and patients are more likely to want more surgery, bilateral mastectomy. The approach to that conflict is to help patients understand what will and won’t prolong their survival. —Monica Morrow, MD

carcinoma in situ with a margin of normal tissue around it, and still leave a breast that looks relatively normal? If the answer to that question is yes, that is pretty much the only thing that determines candidacy for lumpectomy,” Dr. Morrow said. “Then if there are patients who based on the characteristics of the ductal carcinoma in situ and age are going to need radiation, is there any reason that they can’t receive radia-

down to a conversation with the patient about what the risks and benefits of the two treatments are and which one better meets her needs if she is eligible for both.”

Recurrence Can Be Psychologically Devastating Recurrence in the breast, even if it is not associated with death, can be “a psychologically devastating complication” for many women, Dr. Morrow

noted. “They want to avoid experiencing breast cancer again, and so they are willing to do radiotherapy. Now, do I think all women with ductal carcinoma in situ need radiotherapy? No. I think there are many women with small, lowgrade ductal carcinoma in situ, particularly postmenopausal women, where the risk of recurrence is extremely low with radiation, and that should be explained to them. But we also have new clinical trials showing that even in those very low-risk women, the risk of cancer recurrence in the breast is further reduced with radiation.” Women who have ductal carcinoma in situ are at increased risk of developing contralateral breast cancer. “That risk can be reduced with tamoxifen in premenopausal women and in postmenopausal women with tamoxifen, or raloxifene [Evista], or aromatase inhibitors,” Dr. Morrow noted. Currently, however, “the use of endocrine therapy is quite low in women with ductal carcinoma in situ.” n

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

The ASCO Post | OCTOBER 10, 2015

PAGE 92

In the News Ipsilateral Recurrence continued from page 91

that although he had thought the publication of the study would increase that acceptance, “it turns out not to be the case” or at least “not as much as I had hoped.”

Monitoring vs Surgery Dr. Morrow noted that an ongoing trial, the LORIS (low-risk) ductal carcinoma in situ study, is comparing active monitoring with surgery for women with non–high-grade ductal carcinoma in situ. According to trial information posted online by the trial sponsor, the University of Birmingham, the target patient population is women aged ≥ 46 years with histologically confirmed non–high-grade ductal carcinoma in situ. The anticipated recruitment end date is 2020.4,5 The primary outcome measure is ipsilateral invasive breast cancer–free survival time, but investigators are also looking at psychological issues related to active monitoring or surgery. “Although some treating cancer doctors, particularly many epidemiologists, are going on about overtreatment of ductal carcinoma in situ,” Dr. Morrow said, “research that we have done shows that the driving force behind mastectomies in ductal carcinoma in situ is not surgeons; it’s patient desire.” That research involves work with a group called CANSORT at the University of Michigan, which studies decision-making and breast cancer. Dr. Morrow explained: “In one of our first studies, we asked women with ductal carcinoma in situ and early-stage breast cancer, ‘Who made the decision about

what surgery you should have: you, your doctor, or you and your doctor as a shared decision?’ If the doctor made the decision, the mastectomy rate was 5%. If the decision was shared, it went up to about 16%, and if the patient made the decision, the mastectomy rate went up to about 28%.” Dr. Morrow concluded: “So it is a patient-driven decision, even though most patients will tell you that they have been told that there is no difference in breast cancer survival between lumpectomy and radiation and mastectomy. Patients opt for more treatment.”

or might be candidates for risk-reducing endocrine therapy.2 In an editorial accompanying the study in JAMA Oncology,6 Laura Esserman, MD, MBA, and Christina Yau, PhD, of the University of California, San Francisco, stated: “The analysis

Disclosure: Drs. Narod and Morrow reported no potential conflicts of interest.

Laura Esserman, MD, MBA

Otis W. Brawley, MD

Call for Additional Studies The study authors noted that “potential treatments that affect mortality are deserving of study,” and other individuals have cited the need for additional ductal carcinoma in situ trials. The article in The New York Times reported that Otis W. Brawley, MD, Chief Medical Officer of the American Cancer Society, said that before changing treatment approaches to ductal carcinoma in situ, a large clinical trial is needed to define which patients would most benefit from treatment for ductal carcinoma in situ and which might forgo active treatment

and Yau. “Adverse effects of endocrine risk-reducing agents can be a problem. Different doses and schedules should be investigated to mitigate adverse effects, improve tolerability, and avoid serious complications.” Drs. Esserman and Dr. Yau concluded that they are initiating studies to determine whether they can activate the immune system to reverse high-risk ductal carcinoma in situ “with a more targeted approach to address the specific mortality risk.” n

of Narod et al fuels a growing concern that we should rethink our strategy for the detection and the treatment of ductal carcinoma in situ.” Ductal carcinoma in situ “may best represent an opportunity to alter the environment of the breast. For the lowest-risk lesions, observation and prevention interventions alone should be tested either in trials or as part of a registry . Diet, exercise, moderate alcohol intake, and avoidance of postmenopausal hormone therapy with progesterone-containing regimens should be the starting point for prevention,” the editorial continued. “For premenopausal women, tamoxifen therapy is a good choice for hormone-positive low-grade, low-risk ductal carcinoma in situ. For postmenopausal women, aromatase inhibitor therapy has been shown to have a bigger impact on risk reduction. Raloxifene hydrochloride [Evista] is a better-tolerated prevention alternative,” continued Drs. Esserman

References 1. Narod SA, Iqbal J, Giannakeas V, et al: Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. August 20, 2015 (early release online). 2. Kolata G: Early-stage breast condition may not require cancer treatment. The New York Times, August 20, 2015. 3. Study raises questions about treatment for early breast cancer. PBS NewsHour, August 20, 2015. 4. Sussex Health Outcomes Research & Education in Cancer (SHORE-C): A phase III trial of surgery versus active monitoring for LOw RISk DCIS (LORIS). Available at http://shore-c/sussex.ac.uk/loris.htm. Accessed September 8, 2015. 5. LORIS: A phase III trial of surgery versus active monitoring for low risk ductal carcinoma in situ (DCIS). Available at http://www.birmingham.ac.uk/loris. Accessed September 8, 2015. 6. Esserman L, Yau C: Rethinking the standard for ductal carcinoma in situ treatment. JAMA Oncol. August 20, 2015 (early release online).

Don’t Miss These Important Reports in This Issue of The ASCO Post Roy Herbst, MD, PhD, and Fred R. Hirsch, MD, PhD, on EGFR as a Biomarker for Antibody Treatment in NSCLC see page 1

Eric Lim, MD, on Lung Cancer Rates in Nonsmokers see page 5

Karen Reckamp, MD, on Nivolumab in Lung Cancer see page 9

Visit The ASCO Post online at ASCOPost.com

Tetsuya Mitsudomi, MD, PhD, on AZD9291 in Treatment-Resistant NSCLC see page 3

Arif Kamal, MD, MHS, on Patient and Survivor Care Studies see page 14

Change your perspective on whatâ&#x20AC;&#x2122;s possible for your patients with multiple myeloma

153

High-dose dex

6 9 Months (ITT population)

Hazard ratio (2-sided 95% CI) 0.45 (0.35, 0.59) Log-rank P-value=<0.001 (2-sided) Data cutoff: September 7, 2012

POMALYST + low-dose dexamethasone (dex) High-dose dex

Progression-free survival

Progression-free survival (PFS) based on the assessment by the Independent Review Adjudication Committee (IRAC) review at the final PFS analysis.

107

302

Number of patients at risk:

POMALYST + low-dose dex

0.0

0.2

0.4

0.6

0.8

1.0

Kaplan-Meier median: POMALYST + low-dose dex=3.6 [3.0, 4.6] Kaplan-Meier median: high-dose dex=1.8 [1.6, 2.1] Events: POMALYST + low-dose dex=164/302; high-dose dex=103/153

See where survival may lead

POMALYST + low-dose dex is the only approved therapy that delivered a survival benefit in patients who failed lenalidomide and bortezomib

POMALYST is only available through a restricted distribution program, POMALYST REMS速.

POMALYST速 (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Proportion of patients

Hazard ratio 0.45 (95% CI: 0.35, 0.59; P <0.001)

Patients >75 years of age started treatment with 20 mg dex using the same schedule.

Learn more about the survival beneﬁt of POMALYST at www.mmperspective.com

Study Design: Phase 3 multicenter, randomized, open-label study, where POMALYST + low-dose dex was compared with high-dose dex in patients with relapsed and refractory multiple myeloma, who had received at least 2 prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy (N=455). Patients with creatinine clearance ≥45 mL/min qualified for the trial. Patients in the POMALYST + low-dose dex arm (n=302) were administered 4 mg POMALYST orally on Days 1-21 of each 28-day cycle. Low-dose dex (40 mga) was administered once per day on Days 1, 8, 15, and 22 of a 28-day cycle. For the high-dose dex arm (n=153), dex (40 mga) was administered once per day on Days 1-4, 9-12, and 17-20 of a 28-day cycle. Treatment continued until patients had disease progression.

VENOUS AND ARTERIAL THROMBOEMBOLISM • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Antithrombotic prophylaxis is recommended.

POMALYST is available only through a restricted program called POMALYST REMS®.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, and Important Safety Information on the following pages.

• POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST 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

CONTRAINDICATIONS: Pregnancy

• For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of 2 reliable methods of contraception.

EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects.

See full prescribing information for complete boxed warning

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Median OS for POMALYST + low-dose dex was 12.4 months (95% CI: 10.4, 15.3) vs 8.0 months (95% CI: 6.9, 9.0) for high-dose dex

Hazard ratio 0.70 (95% CI: 0.54, 0.92; P =0.009)

The difference in OS between the POMALYST + low-dose dex vs high-dose dex was statistically signiﬁcant, with a 30% reduced risk of death

POMALYST + low-dose dex signiﬁcantly prolonged overall survival (OS)

reduced risk of progression or death

55%

POMALYST + low-dose dex delivered signiﬁcantly longer progression-free survival vs high-dose dex

POMALYST® (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment.

POMALYST is only available through a restricted distribution program called POMALYST REMS®.

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST 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 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST POMALYST REMS® Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS®.” Prescribers and pharmacies must be certified with the program; patients must sign an agreement form and

comply with the requirements. Further information about the POMALYST REMS® program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboembolic events (ATE) (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST and low-dose dexamethasone (Low-dose Dex) vs 3.3% treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with POMALYST and Low-dose Dex vs 1.3% treated with highdose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with POMALYST and Low-dose Dex vs 1.3% treated with high-dose dexamethasone. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Hematologic Toxicity: In Trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor

Venous and Arterial Thromboembolism • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

WARNINGS AND PRECAUTIONS (continued) liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Hypersensitivity Reactions: Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy. Dizziness and Confusional State: In Trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 14% experienced dizziness and 7% a confusional state; 1% of patients experienced Grade 3 or 4 dizziness and 3% experienced a Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice. Neuropathy: In Trials 1 and 2, patients who received POMALYST + Low-dose Dex experienced neuropathy (18%) and peripheral neuropathy (~12%). In Trial 2, 2% of patients experienced Grade 3 neuropathy. Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) may occur in patients treated with POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Avoid the use of strong CYP1A2 inhibitors. If medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients >65 years of age were more likely than patients ≤65 years of age to experience pneumonia. Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

ADVERSE REACTIONS Nearly all patients treated with POMALYST + Low-dose Dex experienced at least one adverse reaction (99%). In Trial 2, the most common adverse reactions included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), Please see brief summary of full Prescribing back pain (19.7%), cough (20%), pneumonia (19.3%), Information, including Boxed WARNINGS, edema peripheral (17.3%), peripheral neuropathy (17.3%), on following pages. bone pain (18%), nausea (15%), and muscle spasms (15.3%). Grade 3 or 4 adverse reactions included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%). DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). POMALYST is only available through a restricted distribution program, POMALYST REMS®.

The ASCO Post | OCTOBER 10, 2015

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Announcements

Lisa Kachnic, MD, Named Chair of Radiation Oncology at Vanderbilt

isa Kachnic, MD, former Professor and Chair of Radiation Oncology and Associate Director of Multidisciplinary Cancer Research at Boston University School of Medicine, and Chief of Radiation Oncology at Boston Medical Center, has been named

Professor and Chair of the Vanderbilt University Medical Center Department of Radiation Oncology. She joined the faculty on September 21. Dr. Kachnic, who also served on the Radiation Oncology faculty at Massachusetts General Hospital and is a fellow

of the American Society for Radiation Oncology (ASTRO), succeeds Arnold Malcolm, MD, MBA, who retired from the position in December 2014. As the new Chair, Dr. Kachnic will be responsible for overseeing a department delivering oncologyT:7”services at Vander-

bilt-Ingram Cancer Center, focused on scientific discovery and educating leaders. The program also includes a thriving residency program that trains academic clinicians and physician scientists, as well as the nation’s first accredited medical physics professional doctorate program.

POMALYST® (pomalidomide) capsules, for oral use

2.2 Dose Adjustments for Toxicities

The following is a Brief Summary; refer to full Prescribing Information for complete product information.

Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities

Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles, or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS® [see Warnings and Precautions (5.2)]. Venous and Arterial Thromboembolism • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors [see Warnings and Precautions (5.3)].

2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST should be given in combination with dexamethasone. POMALYST may be taken with water. Inform patients not to break, chew, or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

Dose Modification • Interrupt POMALYST treatment, follow CBC weekly • Resume POMALYST treatment at 3 mg daily

• For each subsequent • Interrupt POMALYST drop <500 per mcL treatment • Return to more than or • Resume POMALYST equal to 500 per mcL treatment at 1 mg less than the previous dose Thrombocytopenia • Platelets <25,000 per mcL • Platelets return to >50,000 per mcL

• Interrupt POMALYST treatment, follow CBC weekly • Resume POMALYST treatment at 3 mg daily

• For each subsequent • Interrupt POMALYST drop <25,000 per mcL treatment • Resume POMALYST • Return to more than or equal to 50,000 per treatment at 1 mg less than previous dose mcL ANC, absolute neutrophil count To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL and the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. Permanently discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reaction [see Warnings and Precautions (5.6)]. For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. 2.3 Dose Adjustment for Strong CYP1A2 Inhibitors in the Presence of Strong CYP3A4 and P-gp Inhibitors Avoid co-administration of strong inhibitors of CYP1A2. If necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. No clinical efficacy or safety data exist [see Drug Interactions (7.1))]. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].

5.2 POMALYST REMS Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST, and comply with REMS requirements. Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. 5.3 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST and low dose-dexamethasone (Low-dose Dex), and 3.3% of patients treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with POMALYST and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with POMALYST and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone.

T:10”

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST, in combination with dexamethasone, is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Toxicity Neutropenia • ANC <500 per mcL or febrile neutropenia (fever more than or equal to 38.5°C and ANC <1,000 per mcL) • ANC return to more than or equal to 500 per mcL

ASCOPost.com | OCTOBER 10, 2015

PAGE 99

Announcements History of Leadership

Lisa Kachnic, MD

Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors. 5.4 Hematologic Toxicity In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 51% of patients in both trials. The rate of Grade 3/4 neutropenia was 46%. The rate of febrile neutropenia was 8%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes and evaluate. After return to baseline values, treatment at a lower dose may be considered. 5.6 Hypersensitivity Reactions Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy [see Dosage and Administration (2.2)].

5.8 Neuropathy In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 18% of patients experienced neuropathy, with approximately 12% of the patients experiencing peripheral neuropathy. Two percent of patients experienced Grade 3 neuropathy in trial 2. There were no cases of Grade 4 neuropathy adverse reactions reported in either trial. 5.9 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 5.10 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous and Arterial Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hepatotoxicity [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions [see Warnings and Precautions (5.6)] • Dizziness and Confusional State [see Warnings and Precautions (5.7)] • Neuropathy [see Warnings and Precautions (5.8)]

• Risk of Second Primary Malignancies [see Warnings and Precautions (5.9)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dex (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty-seven percent of patients in the study had a dose interruption of either drug due to adverse reactions. Forty-two percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to adverse reactions was 11%. In Trial 2, data were evaluated from 450 patients (safety population) who received treatment with POMALYST + Low-dose Dex (300 patients) or Highdose Dexamethasone (High-dose Dex) (150 patients). The median number of treatment cycles for the POMALYST + Low-dose Dex arm was 5. In the POMALYST + Low-dose Dex arm, 67% of patients had a dose interruption of POMALYST, the median time to the first dose interruption of POMALYST was 4.1 weeks. Twenty-seven percent of patients had a dose reduction of POMALYST, the median time to the first dose reduction of POMALYST was 4.5 weeks. Eight percent of patients discontinued POMALYST due to adverse reactions. Tables 2 and 3 summarize the adverse reactions reported in Trials 1 and 2, respectively. In Trial 1 of 219 patients who received POMALYST alonea (N=107) or POMALYST + Low-dose Dex (N=112), all patients had at least one adverse reaction.* Adverse reactions ≥10% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (53%, 49%), Anemiab (38%, 42%), Thrombocytopeniab (26%, 23%), Leukopenia (13%, 20%), Febrile neutropeniab (<10%, <10%), Lymphopenia (4%, 15%); General disorders and administration site conditions: Fatigue and astheniab (58%, 63%), Edema peripheral (25%, 17%), Pyrexiab (23%, 32%), Chills (10%, 13%); Gastrointestinal disorders: Nauseab (36%, 24%), Constipationb (36%, 37%), Diarrhea (35%, 36%), Vomitingb (14%, 14%); Musculoskeletal and connective tissue disorders: Back painb (35%, 32%), Musculoskeletal chest pain (23%, 20%), Muscle spasms (22%, 20%), Arthralgia (17%, 15%), Muscular weakness (14%, 13%), Bone pain (12%, 7%), Musculoskeletal pain (12%, 17%), Pain in extremity (8%, 14%); Infections and infestations: Upper respiratory tract infection (37%, 29%), Pneumoniab (28%, 34%), Urinary tract infectionb (10%, 17%), Sepsisb (<10%, <10%); Metabolism and nutrition disorders: Decreased appetite (23%, 19%), Hypercalcemiab (22%, 12%), Hypokalemia (12%, 12%), Hyperglycemia (11%, 15%), Hyponatremia (11%, 13%), Dehydrationb (<10%, <10%), Hypocalcemia (6%, 12%); Respiratory, thoracic and mediastinal disorders: Dyspneab (36%, 45%), Cough (17%, 22%), Epistaxis (17%, 11%), Productive cough (9%, 13%), Oropharyngeal pain (6%, 11%); Nervous system disorders: Dizziness (22%, 18%), Peripheral neuropathy (22%, 18%), Headache (15%, 13%), Tremor (10%, 13%); Skin and subcutaneous tissue disorders: Rash (21%, 16%), Pruritus (15%, 9%), Dry skin (9%, 11%), Hyperhidrosis (8%, 16%), Night sweats (5%, 13%); Investigations: Blood creatinine increasedb (19%, 10%), Weight decreased (15%, 9%), Weight increased (1%, 11%); Psychiatric disorders: Anxiety (13%, 7%), Confusional stateb (12%, 13%), Insomnia (7%, 16%); Renal and urinary disorders: Renal failureb (15%, 10%).

In Trial 1, Grade 3/4 at least one adverse reaction reported in 92% of patients treated with POMALYSTa alone (N=107) and 91% with POMALYST + Low-dose Dex (N=112).* Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (48%, 41%), Anemiab (23%, 21%), Thrombocytopeniab (22%, 19%), Leukopenia (7%, 10%), Febrile neutropeniab (6%, 3%), Lymphopenia (2%, 7%); General disorders and administration site conditions: Fatigue and astheniab (12%, 17%), Edema peripheral (0%, 0%), Pyrexiab (<5%, <5%), Chills (0%, 0%); Gastrointestinal disorders: Nauseab (<5%, <5%), Constipationb (<5%, <5%), Diarrhea (<5%, <5%), Vomitingb (<5%, 0%); Musculoskeletal and connective tissue disorders: Back painb (14%, 10%), Musculoskeletal chest pain (<5%, 0%), Muscle spasms (<5%, <5%), Arthralgia (<5%, <5%), Muscular weakness (6%, 4%), Bone pain (<5%, <5%), Musculoskeletal pain (<5%, <5%), Pain in extremity (0%, <5%); Infections and infestations: Upper respiratory tract infection (<5%, <5%), Pneumoniab (20%, 29%), Urinary tract infectionb (2%, 9%), Sepsisb (6%, 5%); Metabolism and nutrition disorders: Decreased appetite (<5%, 0%), Hypercalcemiab (10%, 1%), Hypokalemia (<5%, <5%), Hyperglycemia (<5%, <5%), Hyponatremia (<5%, <5%) Dehydrationb (5%, 5%), Hypocalcemia (0%, <5%); Respiratory, thoracic and mediastinal disorders: Dyspneab (8%, 13%), Cough (0%, 0%), Epistaxis (<5%, 0%), Productive cough (0%, 0%), Oropharyngeal pain (0%, 0%); Nervous system disorders: Dizziness (<5%, <5%), Peripheral neuropathy (0%, 0%), Headache (0%, <5%), Tremor (0%, 0%); Skin and subcutaneous tissue disorders: Rash (0%, <5%), Pruritus (0%, 0%), Dry skin (0%, 0%), Hyperhidrosis (0%, 0%), Night sweats (0%, 0%); Investigations: Blood creatinine increasedb (6%, 3%), Weight decreased (0%, 0%), Weight increased (0%, 0%); Psychiatric disorders: Anxiety (0%, 0%), Confusional stateb (6%, 3%), Insomnia (0%, 0%); Renal and urinary disorders: Renal failureb (8%, 7%). * Regardless of attribution of relatedness to POMALYST. a POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. b Serious adverse reactions were reported in at least 2 patients in any POMALYST treatment arm. Data cutoff: 01 March 2013 In Trial 2 of 450 patients who received POMALYST + Low-dose Dex (N=300) or High-dose-Dex (N=150), at least one adverse reaction was reported in 99% of patients. All Adverse Reactions ≥5% in POMALYST + Lowdose Dex arm, and at least 2% point higher than the High-dose-Dex arm included: Blood and lymphatic system disorders: Neutropeniab (51%, 21%), Thrombocytopenia (30%, 29%)a, Leukopenia (13%, 5%), Febrile neutropeniab (9%, 0%); General disorders and administration site conditions: Fatigue and asthenia (47%, 43%), Pyrexiab (27%, 23%), Edema peripheral (17%, 11%), Pain (4%, 2%)a; Infections and infestations: Upper respiratory tract infectionb (31%, 13%), Pneumoniab (19%, 13%), Neutropenic sepsisb (1%, 0%)a; Gastrointestinal disorders: Diarrhea (22%, 19%), Constipation (22%, 15%), Nausea (15%, 11%), Vomiting (8%, 4%); Musculoskeletal and connective tissue disorders: Back painb (20%, 16%), Bone Painb (18%, 14%), Muscle spasms (15%, 7%), Arthralgia (9%, 5%), Pain in extremity (7%, 6%)a; Respiratory, thoracic and mediastinal disorders: Dyspneab (25%, 17%), Cough (20%, 10%), Chronic obstructive pulmonary diseaseb (2%, 0%)a; Nervous system disorders: Peripheral neuropathy (17%, 12%), Dizziness (12%, 9%), Headache (8%, 5%), Tremor (6%, 1%), Depressed level of consciousness (2%, 0%)a; Metabolism and nutrition disorders: Decreased appetite (13%, 8%), Hypokalemia (9%, 8%)a, Hypocalcemia (4%, 6%)a;

Committee Vice-Chair and Editor of ASTRO’s newsletter, Dr. Kachnic chaired ASCO’s 2014 Gastrointestinal Cancer Symposium, is a member of the Annual Meeting’s Scientific Program Committee, and serves on the editorial boards of the Journal of the National Cancer Institute and Gastrointestinal Cancer Research. n

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5.7 Dizziness and Confusional State In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 14% of patients experienced dizziness and 7% of patients experienced a confusional state; 1% of patients experienced Grade 3 or 4 dizziness, and 3% of patients experienced Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.

Dr. Kachnic is internationally recognized for her clinical trial leadership positions in the National Cancer Institute (NCI) and its cooperative group research bases. She is actively involved in the NRG Oncology Gastrointestinal and Patient-Reported Outcome Strategic Committees, T:7” and is the Co-Chair

of their NCI Community Oncology Research Program in Cancer Control and Prevention. She is Vice Chair of the NCI Anorectal Cancer Taskforce, and Co-Chair of the Anorectal Committee for the Southwest Oncology Group, where she also serves as their Multimodality Executive Officer. In addition to serving as Scientific

The ASCO Post | OCTOBER 10, 2015

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Announcements

Melanoma Research Alliance Appoints President and CEO-Elect

he Melanoma Research Alliance (MRA) announced the appointment of Robin L. Davisson, PhD, as President and CEO-Elect, effective October 1, 2015. Dr. Davisson, The Andrew Dickson White Professor of Molecular Physiology at Cornell University, brings to

Robin L. Davisson, PhD

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Cardiac disorders: Myocardial infarction, Atrial fibrillation, Angina pectoris, Cardiac failure congestive Ear and labyrinth disorders: Vertigo Gastrointestinal disorders: Abdominal pain General disorders and administration site conditions: General physical health deterioration, Non-cardiac chest pain, Multi-organ failure Hepatobiliary disorders: Hyperbilirubinemia Infections and infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis, Bacteremia, Pneumonia respiratory syncytial viral, Cellulitis, Urosepsis, Septic shock, Clostridium difficile colitis, Pneumonia streptococcal, Lobar pneumonia, Viral infection, Lung infection Investigations: Alanine aminotransferase increased, Hemoglobin decreased

lence in cardiovascular research from the American Heart Association. She was recently elected a Fellow of the American Association for the Advancement of Science. In addition, she plays active leadership roles at various local and national nonprofit organizations. n

Injury, poisoning and procedural complications: Fall, Compression fracture, Spinal compression fracture Metabolism and nutritional disorders: Hyperkalemia, Failure to thrive Nervous System disorders: Depressed level of consciousness, Syncope Psychiatric disorders: Mental status change Renal and urinary disorders: Urinary retention, Hyponatremia Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, Pulmonary embolism, Respiratory failure, Bronchospasm Vascular disorders: Hypotension

Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/ or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption.

6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide postmarketing experience with POMALYST: Pancytopenia, tumor lysis syndrome, allergic reactions (e.g., angioedema, urticaria), elevated liver enzymes, hepatic failure (including fatal cases). 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. 7 DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP1A2 inhibitors: Pomalidomide exposure is increased when POMALYST is co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in the presence of a strong CYP3A4/5 and P-gp inhibitor (ketoconazole). Ketoconazole in the absence of a CYP1A2 inhibitor does not increase pomalidomide exposure. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine) [see Dosage and Administration (2.3)]. If it is medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, POMALYST dose should be reduced by 50%. The effect of a CYP1A2 inhibitor in the absence of a co-administered CYP3A4 and P-gp inhibitor has not been studied. Monitor for toxicities if CYP1A2 inhibitors are to be co-administered in the absence of a co-administered CYP3A4 and P-gp inhibitor, and reduce dose if needed. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. CYP1A2 inducers: Co-administration of POMALYST with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants.

8.3 Nursing Mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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 effectiveness of POMALYST in patients below the age of 18 years have not been established. 8.5 Geriatric Use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 44% were aged older than 65 years, while 10% were aged older than 75 years. No overall differences in effectiveness were observed between these patients and younger patients. In these studies, patients older than 65 years were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy.

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Skin and subcutaneous tissue disorders: Rash (8%, 1%), Pruritus (7%, 3%), Hyperhidrosis (5%, 1%); Investigations: Neutrophil count decreased (5%, 1%), Platelet count decreased (3%, 2%)a, White blood cell count decreased (3%, 1%)a, Alanine aminotransferase increased (2%, 1%)a, Aspartate aminotransferase increased (1%, 1%)a, Lymphocyte count decreased (1%, 1%)a; Renal and urinary disorders: Renal failure (10%, 12%)a; Injury, poisoning and procedural complications: Femur fractureb (2%, 1%)a; Reproductive system and breast disorders: Pelvic pain (2%, 2%)a. In Trial 2, Grade 3/4 at least one adverse reaction was reported in 86% of patients treated with POMALYST + Low-dose Dex (N=300) and 85% with High-dose Dex (N=150). Grade 3/4 Adverse Reactions ≥1% in POMALYST + Low-dose Dex arm, and at least 1% point higher than the High-dose-Dex arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (48%, 16%), Thrombocytopenia (22%, 26%)a, Leukopenia (9%, 3%), Febrile neutropeniab (9%, 0%); General disorders and administration site conditions: Fatigue and asthenia (9%, 12%)a, Pyrexiab (3%, 5%)a, Edema peripheral (1%, 2%)a, Pain (2%, 1%); Infections and infestations: Upper respiratory tract infectionb (3%, 1%), Pneumoniab (16%, 10%), Neutropenic sepsisb (1%, 0%); Gastrointestinal disorders: Diarrhea (1%, 1%)a, Constipation (2%, 0%), Nausea (1%, 1%)a, Vomiting (1%, 0%); Musculoskeletal and connective tissue disorders: Back painb (5%, 4%), Bone painb (7%, 5%), Muscle spasms (0%, 1%)a, Arthralgia (1%, 1%)a, Pain in extremity (2%, 0%); Respiratory, thoracic and mediastinal disorders: Dyspneab (6%, 5%), Cough (1%, 1%)a, Chronic obstructive pulmonary diseaseb (1%, 0%); Nervous system disorders: Peripheral neuropathy (2%, 1%)a, Dizziness (1%, 1%)a, Headache (0%, 0%)a, Tremor (1%, 0%)a, Depressed level of consciousness (1%, 0%); Metabolism and nutrition disorders: Decreased appetite (1%, 1%)a, Hypokalemia (4%, 3%), Hypocalcemia (2%, 1%); Skin and subcutaneous tissue disorders: Rash (1%, 0%), Pruritus (0%, 0%)a, Hyperhidrosis (0%, 0%)a; Investigations: Neutrophil count decreased (5%, 1%), Platelet count decreased (3%, 1%), White blood cell count decreased (3%, 0%), Alanine aminotransferase increased (2%, 0%), Aspartate aminotransferase increased (1%, 0%), Lymphocyte count decreased (1%, 0%); Renal and urinary disorders: Renal failure (6%, 5%); Injury, poisoning and procedural complications: Femur fractureb (2%, 1%); Reproductive system and breast disorders: Pelvic pain (1%, 0%). a Percentage did not meet the criteria to be considered as an adverse reaction for POMALYST for that category of event (i.e., all adverse events or Grade 3 or 4 adverse events). b Serious adverse reactions were reported in at least 3 patients in the POM + Low-dose Dex arm, AND at least 1% higher than the High-dose-Dex arm percentage. Data cutoff: 01 March 2013

MRA more than 25 years of internationally recognized scientific research and deep engagement in graduate student and postdoctoral education and mentoring. She has received numerous research awards in her field, including the Arthur T:7” Award for excelC. Corcoran Memorial

ASCOPost.com | OCTOBER 10, 2015

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Book Review

Measuring Global Health Issues, Seven Billion Times By Ronald Piana

ealth measures are essential tools in assessing public health and safety. Collecting large amounts of data is a laborious task, requiring a certain kind of relentless stamina and sense of

8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.

gain a truer understanding of how humans across the globe live and die. This monumental undertaking is described in lively prose by journalist Jeremy N. Smith in his new book, Epic Measures:

In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.

with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS. Provide patients with the telephone number and Web site for information on how to obtain the product. Venous and Arterial Thromboembolism Inform patients of the risk of developing DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warnings and Warnings and Precautions (5.3)]. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia, and anemia and the need to report signs and symptoms associated with these events to their healthcare provider for further evaluation [see Warnings and Precautions (5.4)]. Hepatotoxicity Inform patients on the risks of developing hepatotoxicity, including hepatic failure and death, and to report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.5)]. Hypersensitivity Inform patients of the risk for angioedema and severe skin reactions and to report any signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.6)]. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusional state with the drug, to avoid situations where dizziness or confusional state may be a problem, and not to take other medications that may cause dizziness or confusional state without adequate medical advice [see Warnings and Precautions (5.7)]. Neuropathy Inform patients of the risk of neuropathy and to report the signs and symptoms associated with these events to their healthcare provider for further evaluation [see Warnings and Precautions (5.8)]. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown [see Warnings and Precautions (5.9)]. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10)]. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day. • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID®, THALOMID®, and POMALYST REMS® are registered trademarks of Celgene Corporation. Pat. http://www.celgene.com/therapies © 2005-2015 Celgene Corporation All rights reserved. POM HCP Bsv.004 04/15

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindications (4)]. POMALYST is a thalidomide analogue and may cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during POMALYST therapy, during therapy interruption, and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program called POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Physician Agreement Form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements, and participate in monthly telephone surveys. Males must comply

One Doctor. Seven Billion Patients. The book is based primarily on a dozen reporting trips and more than 100 interviews. As the author explains, “Everyone wants the world to move in a healthier direction. But what we need is a map. And if no accurate, sufficiently extensive map exists, someone needs to create one.” Enter Dr. Murray, whose central argument is that until we can accurately measure global health issues, we cannot understand what makes humans sick or do much to improve the conditions that cause disease. From his early days at Harvard University, Dr. Murray was a save-the-world crusader. Now, he’s a trained physician who no longer practices medicine but is trying to treat the world’s 7 billion inhabitants. His life’s work, the Global Burden of Disease project, is a concept, a quantity, an ongoing project, and its numbers can be broken down personby-person by place, ailment, and consequence—what kills us, what makes us sick, and what shortens our pain-free years of life. According to the author, after all of these metadata are collected, “the question then becomes not what stops us from living better, but how far and how fast are we willing to improve?”

Informative Journey What kind of person devotes his career to dissecting the health outcomes of 7 billion people? The author writes, “Murray himself was fascinating: blunt, often abrasive, hyper-energetic, supremely confident, yet fiercely collaborative…. [He] likes to argue, and he seemed to operate on the assumption that scientific progress relies on picking fights.” No doubt, Dr. Murray has a big personality, which one would expect for anyone undertaking a project of this dimension, and following Dr. Murray through the ups and downs of the Global Burden of Disease project is, at times, a thrilling and informative journey. It took Mr. Smith 3 years to write his book. He introduces the main character, Dr. Murray, by returning to his childhood, which by all accounts was enthralling. His parents had wanderlust, and he and his siblings saw much of the world. But these family jaunts to far-flung places were not of the Disneyworld variety; they were adventurous learning trips that became the foundation of Dr. Murray’s later work in global health care. T:10”

Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

purpose. Christopher Murray, MD, who is also an economist, began one of the largest scientific data-collection undertakings in history when he initiated the Global BurdenT:7” of Disease study to

continued on page 102

The ASCO Post | OCTOBER 10, 2015

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Book Review Epic Measures continued from page 101

Mr. Smith begins the book, “March 1973. The Sahara. There was no road, and certainly no GPS. Forward motion meant following a dusty track. Occasionally, through the haze, the family had seen a lone gazelle or a few people on camels. Every now and then they had discovered a village. For the last three days, however, they had encountered no one but themselves.” This makes for good adventurous travel writing, but the book is ostensibly about a game-changing public health project, and the author takes four chapters introducing Dr. Murray, which is a tad too much. It feels, at times, as if he needed filler to make his publisher’s word count.

Setting Things Right Chapter 5, called “The Big Picture,” begins, “Everyone on Earth should have the chance to live a long life in full health. But statistics we [use] to measure progress toward that goal [have been] not only inaccurate, but also irrelevant.” According to Dr. Murray, the World Health Organization (WHO), the United Nations, the Centers for Disease Control and Prevention, and others have botched the business of collecting health outcomes, and he’s here to set things right. To that end, he does have some weighty supporters, such as Bill Gates, who kicked in $100 million for the project. While some of the global health-care content is informative enough to rate as an interesting read, the author still needs to develop a compelling storyline to keep readers engaged. Health policy books generally don’t achieve best-seller status often because most people, with the exception of policy wonks, find discussions of data points and health measure met-

rics tiresome. So Mr. Smith juices up the narrative, for example, with anecdotal snapshots about how Dr. Murray reinvented the program midstream and how Dr. Murray met Bill Gates. A tangential homage to Bill Gates’ father is particularly long-winded. Collecting data for data’s sake, no matter how well crafted the project might be, is sort of like building the Great Pyramid of Giza. Yes, it was an incredible feat that took tens of thousands of laborers decades to construct; to boot, it is one of the Seven Wonders of the Ancient World. But what purpose does it serve other than being a colossal tomb in the desert for the pharaoh who commissioned it? Therein lies the danger of the potentially fruitless grandiosity that Dr. Murray’s Global Burden of Disease project faces.

Politics and Sacrifices When Dr. Murray finally released the first installment of reports stemming from his work, he was broadsided by global

Bookmark Title: Epic Measures: One Doctor. Seven Billion Patients Author: Jeremy N. Smith Publisher: Harper Wave Publication date: April 7, 2015 Price: $26.99; hardcover, 352 pages start squabbling over who is on the right side of an issue, it gets nasty. Moreover, like many save-theworld dreamers, Dr. Murray was more concerned with kids in the developing world than his own. “Those who couldn’t stand his intense style left, or became very estranged, especially if they were family. Following fifteen

Dr. Murray and his associates say that we need a single measure of what particular diseases cost us in quantity and quality of life. Such a single measure might prove to be a ‘useful policy tool,’ but it does not address the key issue underlying Dr. Murray’s data: the impact of poverty. health agencies such as WHO, claiming that his “complex statistical models and computer analyses were a ‘black box step’ other researchers would find very hard to reproduce.” The reader gets an up-close and personal view of the politics involved in the huge world of nonprofit, nongovernmental organizations. And when these supersized egos and billionaires

years of litigation, Murray had lost all visitation rights to his three children from his first marriage.” That’s quite a sacrifice. Was it worth it? Can this massive collection of healthcare data be used to increase health standards across the globe, enough to justify its cost and scope, or is it another pyramid—a glorious but useless

monument to its creator? Time will tell. However, if the afterword detailing the suggested solutions that Dr. Murray derived from his work is any indication, he hasn’t yet offered enough to move the needle on these issues.

Key Issue Among Dr. Murray’s findings: If you were a male born in Sierra Leone, you could expect to live for about 39 years, whereas if you were born in Japan, you could expect to live for about 84 years. People living in countries with stable governments, high literacy rates, high per capita income, and good healthcare systems live much longer, diseasefree lives than those in poor countries with dysfunctional governments. Dr. Murray and his associates say that we need a single measure of what particular diseases cost us in quantity and quality of life. Such a single measure might prove to be a “useful policy tool,” but it does not address the key issue underlying Dr. Murray’s data: the impact of poverty. His work, well intentioned as it is, does not offer a solution to that. n

Extraordinary Medical Advances and the Conundrum They Pose By Ronald Piana

edicine has changed radically over the past 15 years. Who doesn’t welcome the availability of cholesterollowing drugs, joint replacements and arthroscopic surgery, and the antiretroviral drugs that have made AIDS a chronic, manageable disease? In oncology, advances in therapeutic options have greatly improved the 5-year survival rates and the quality of life of patients with cancer. However, medical advances also prove problematic, in that they sometimes have unintended consequences that create ethical dilemmas. For instance, trauma care has reached a point of technical skill

that saves lives that just a decade or so ago would have been lost. The most dramatic examples of these medical advances are seen on the battlefield, where soldiers survive breathtaking physical trauma. Moreover, sometimes the quality of life after surviving catastrophic brain trauma, for instance, can raise ethical questions, such as Where do we draw the line and factor in a person’s quality of life as a survivor before initiating heroic medical efforts? Or is that a question doctors should not have to answer? Is it the profession’s charter to save lives at any cost? This is the thorny and in-

tellectually fertile terrain that author Sharon R. Kaufman tackles in her fine new book Ordinary Medicine: Extraordinary Treatments, Longer Lives, and Where to Draw the Line.

The Line Between Enough and Too Much Ms. Kaufman, a medical anthropologist at the University of California, San Francisco, is also the author of the wellreceived book And a Time to Die: How American Hospitals Shape the End of Life. In this new book, Ms. Kaufman builds on the basic theme that most humans

want medical advances that extend their lives, contending that the line between life-giving therapies and too much treatment is difficult to see, as it is often obscured by a perfect storm created by the pharmaceutical and biomedical industries, along with insurance companies. Even deeper, the author investigates what drives that “perfect storm,” laying much of the blame on our country’s more-is-better approach to medicine; in her view, this approach has created a chain of social, economic, and bureaucratic forces that has ultimately made oncecontinued on page 103

ASCOPost.com | OCTOBER 10, 2015

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Book Review Extraordinary Advances continued from page 102

extraordinary medical treatments seem ordinary, necessary, and desirable. In the preface, Ms. Kaufman states that since 2002, she has listened to “hundreds of older patients, their physicians, and family members express their hopes, fears, and reasoning as they faced the line between enough and too much intervention.” This is a well-researched book about vital public policy, which much of the lay public will have little interest in. In style, it blends compelling narrative with wonky policy issues. Although slightly dry, given the multitude of permutations in health care, from reimbursement to arguments over “death panels,” Ordinary Medicine is a worthwhile book for The ASCO Post readership.

bursed by insurance companies, to what is considered standard and necessary and why, to what patients and doctors ultimately talk about and decide to do. As Ms. Kaufman writes, this discussion, although always of value, isn’t new. “In 1980, Arnold Relman, MD, then editor of The New England Journal of Medicine, coined the phrase ‘medi-

Centered on the intersection of medicine, our aging society, and the concerns raised by today’s treatment options, the book is about the structure and culture of the entire biomedical health-care enterprise, from research funding for treatments, to what is reim-

work of private corporations engaged in the business of supplying health-care services to patients for a profit.’” The worries Dr. Relman articulated in 1980 were about the corporatization of health care, the rise of the medical marketplace, and the demise of medicine as a social good. No one continued on page 104

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‘Medical Industrial Complex’

cal industrial complex’ to describe the ways science, medicine, profits, and politics were becoming entangled and were beginning to have a growing impact on health care. Inspired by President Eisenhower’s earlier coinage of the term military industrial complex, Dr. Relman defined that new health-care complex as ‘a large and growing net-

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Book Review

A Practical Guide to Surviving Breast Cancer and Its Treatments By Ronald Piana

here are a plethora of books written by breast cancer survivors, and there are sure to be many more penned about women’s most feared disease and the difficult issues of dealing with the side effects of chemotherapy and breast surgery. Unfortunately, there’s a huge audience for these books.

Well-Written Gem of a Guide “Labor Day weekend 2009. The beginning of the rest of my life. The weekend I crossed the street from normal girl to Cancer Girl…and then, thankfully, to survivor,” writes Ms. Hutton at the start of her neat little, well-written gem of a guide for

It turns out that the doctors start counting your healthy days from the day of diagnosis…. So you become a survivor from the day your life fell apart. Cherish it. —Andrea Hutton

Despite breakthrough advances in detection and treatment options, breast cancer is the second leading cause of death in women, exceeded only by lung cancer. This year, more than 40,000 American women will die of the disease. Currently, there are close to 3 million breast cancer survivors in America. One such survivor is Andrea Hutton, the author of the recently published book Bald Is Better With Earrings: A Survivor’s Guide to Getting Through Breast Cancer.

women with breast cancer. She opens with a compelling description of the mammogram that detected a lump and a needle biopsy that confirmed it as breast cancer. At the time, she was 41 years old, healthy, with no family history of the disease. Her writing style is friendly and, at the proper times, humorous. After telling her story of diagnosis and the emotions that swirl around after hearing a woman’s most feared words, “You have breast cancer,” Ms. Hutton’s chapters

Extraordinary Advances

does a credible and unsentimental job describing the disparities that exist in the haves and have-nots in our country. No matter what side of the political fence one might be, it becomes clear that the Affordable Care Act, at least for patients with cancer, is a good thing. The ASCO Post readers will em-

continued from page 103

could argue that medicine has changed dramatically, but its demise as a social good will certainly raise eyebrows. To her credit, Ms. Kaufman puts a face on the medical complex that she casts as a villain. The reader meets

Hundreds of older patients, their physicians, and family members expressed their hopes, fears, and reasoning as they faced the line between enough and too much intervention. —Sharon R. Kaufman

patients with cancer and people with kidney failure, all trying to survive and navigate their way through the complexities of our $3 trillion system. During the sections dealing with the Affordable Care Act, Ms. Kaufman

pathize with patients with cancer who struggle with large, financially crippling co-pays. Although drug pricing is a contentious issue in the oncology community, Ms. Kaufman only scrapes the surface of this complicated issue.

Bookmark Title: Bald Is Better With Earrings: A Survivor’s Guide to Getting Through Breast Cancer Author: Andrea Hutton Publisher: Harper Collins Publication date: July 7, 2015 Price: $17.99; paperback, 224 pages go step by step from Tests to End of Treatment. A linear treatment without well-placed diversions can sometimes turn into a slog of a read. Not so here. The chapters create an enjoyable rhythm, and she closes each one with a five-tip section, which, for the most part, will prove very helpful to a harried cancer patient. Books about breast cancer abound, but Ms. Hutton’s book boils the self-help breast cancer survivorship genre into an accessible and useful guide for the terrified women and their loved ones facing a diagnosis of breast cancer. Without being pedan-

tic or smarmy, the author celebrates, as she should, the incredible advances that the oncologist has made in cancer detection and treatment. And Ms. Hutton celebrates being one of our nation’s nearly 3 million cancer survivors. “Right after my treatment had ended, I got seven months of my life back. It turns out that the doctors start counting your healthy days from the day of diagnosis…so when you’ve had your second scan in 6 months, after 6 months of treatment, you’re really a year out! That was the day I found out I was a 2-year

Policy Discussions and Organ Transplantation

ploying new and aggressive therapies, giving a first-rate discussion on the pros and cons of organ transplantation. Here, we see incredible advances in medical technology that save lives and the ethical challenges surrounding those advances. For instance, in endstage kidney disease, she writes, “Greater scarcity of kidneys contributes to the tyranny of putting additional pressure of time on potential living donors and their families…. Living kidney donation poses an age-old question: What are our obligations across generations?” Criticism of American health care is at an all time high and is coming from every imaginable source, including Ms. Kaufman’s book. Her very good book is about the health-care system and the patients who are victimized by a moreis-better ethos and by those who profit from that ethos. However, she has inexplicably omitted one crucial part of the story: the incredibly talented and dedicated doctors on the front line of care. Despite that flaw, this is a worthwhile book for readers of The ASCO Post. n

It is the policy discussions to which The ASCO Post readers will be drawn. For instance, Ms. Kaufman contends that private industry largely determines which therapies will be investigated in clinical trials and other studies and which patient-consumer markets will be exploited. “As a consequence, its role in shaping what doctors recommend and what patients ask for has increased dramatically in the past several decades, and it continues to increase,” she writes. This is a bold accusation that reverberates through the medical community, especially the oncology community. In short, Ms. Kaufman is weaving a conspiracy among industry and doctors that influences prescribing habits. And she does so without embedded references. Careful readers, and those with skin in the game, may take issue with her on that critical omission, one that her publisher should have insisted on. Ms. Kaufman is at her best when assessing where to draw the line on em-

continued on page 105

ASCOPost.com | OCTOBER 10, 2015

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Book Review Surviving Breast Cancer continued from page 104

cancer-free survivor. So you become a survivor from the day your life fell apart. Cherish it.”

Many Positive Reviews The best way to review this book is to scroll down the multitude of lay-

Contact

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Editorial Correspondence

person reviewers on Amazon, many of whom are breast cancer survivors. For instance: “This is the book I was looking for 12 years ago when I began my rollercoaster ride through cancer land. Andrea Hutton has written a comprehensive, funny (yes there is laughter while going through this ordeal) guide to help anyone who has

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Andrea’s book, that light shines even brighter. If you know anyone who has been recently diagnosed, please give them this book. It will be a gift they will treasure.” Bald Is Better With Earrings may not be a suggested read for oncologists, but it certainly is for their patients with breast cancer. n

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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

been diagnosed with cancer.” This review continues: “The structure of the book is wonderful. She covers everything from diagnosis, surgery, treatment, recovery, and many subjects that are often not discussed during an appointment with the oncologist. I promise that there is light at the end of the “treatment tunnel,” and with

The ASCO Post | OCTOBER 10, 2015

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Reflections

Scotty’s Gift By Emil J Freireich, MD

The following essay by Emil J Freireich, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.

learned two lessons early in my career as an oncologist. The first is that conventional wisdom should not impede an investigator from pursuing innovative approaches to desperate problems. Second, patients who are well informed are prepared to participate in clinical research studies to take risks and reap potential benefits; their parents, relaDr. Freireich holds the Ruth Harriet Ainsworth Chair in Developmental Therapeutics at The University of Texas MD Anderson Cancer Center in Houston.

tives, and friends are an important part of the team moving to improve cancer therapy. After completing my training in internal medicine and hematology, I was drafted into the army and assigned to serve as a research physician at the newly opened clinical center of the National Cancer Institute. There I was assigned to care for children with acute leukemia. In 1955, the disease was 100% fatal, with a median survival of 8 weeks and more than 90% mortality at 1 year following diagnosis. It was the horror of a disease that killed children in less than a year, but what was also horrible was the way they died: of extensive bleeding from

was added. This seemed to suggest that it might be possible to stem our young patients’ terrible bleeding. I went directly to investigate this possibility in my patients. I found that the intensity of bleeding was directly related to a decrease in platelets in a patient’s blood. In my laboratory, I demonstrated that adding normal platelets to patients’ blood corrected all the clotting problems.

The Courage of Clinical Volunteers I had a patient named Scotty, a 10-year-old boy whose father was a minister. I had the idea that we could correct Scotty’s persistent hemorrhage by

Patients who are well informed are prepared to participate in clinical research studies to take risks and reap potential benefits; their parents, relatives, and friends are an important part of the team moving to improve cancer therapy. —Emil J Freireich, MD

every orifice in their bodies. For these children, bleeding was the worst part of their illness. The conventional wisdom was that the bleeding was a result of the circulating anticoagulant. However, it was demonstrated that experimental animals depleted totally of platelets would not bleed unless anticoagulant

replacing both his platelets and blood serum. One way to accomplish that was to conduct an “exchange transfusion.” I approached Scotty’s father and asked whether he could deliver from his congregation 20 volunteers who would sit with me for hours to exchange—in 50 ccl units—Scotty’s blood with their

blood. To achieve 50% replacement required replacing Scotty’s entire blood volume, approximately 1 L. The results of this study were dramatic. Scotty’s bleeding stopped immediately. After the transfusions were completed, his platelet count was approximately 50% of normal. We observed his platelet counts over the next 10 days, and they began to drop precipitously. When the platelet count got below 10,000, Scotty’s bleeding resumed. Scotty would subsequently die of progressive leukemia, but his contribution to research, which would help other patients, has stayed in my memory all these years. Relatively speaking, his death—terrible as it was—was not nearly as horrible as it would have been had he died of hemorrhage.

Advancing Cancer Treatment Scotty’s parents, the donors, and everyone involved were very grateful for this respite. This experience led to the development of effective methods for collecting and storing platelets, for defining the limits of donation by normal volunteer donors, for defining the dosage necessary to control hemorrhage, for defining the level of platelets in which hemorrhage is likely, and for developing prophylactic platelet transfusion. In a period of a few years, hemorrhage as a cause of morbidity and mortality was largely eliminated—thanks to the volunteer efforts of Scotty’s father and his church members who participated in this investigation. n

The ASCO Post Wants to Hear From You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Diagnosis of Additional Small Cancers Suggests Screening Mammography Leads to Overdiagnosis A study of screening mammography across U.S. counties found that “the clearest result of mammography screening is the diagnosis of additional small cancers” but without a “concomitant decline in the detection of larger cancers, which might explain the absence of any significant difference in the overall rate of death from the disease. Together, these findings suggest widespread overdiagnosis,” the study investigators wrote in JAMA Internal Medicine. The investigators included lead author Charles Harding, AB, in private practice in Seattle; corresponding author Richard Wilson, DPhil, Department of Physics, Harvard University, Cambridge; and H. Gilbert Welch, MD, MPH, Department of Medicine, Dartmouth Institute for Health Policy and Clinical Practice, Hanover, New Hampshire. Dr. Welch has previously been interviewed by The ASCO Post concerning cancer screening and is coauthor of the book Overdiagnosed: Making People Sick in the Pursuit of Health.

Key Data The researchers analyzed data on 6 million women 40 years or older who resided in 547 counties reporting to the Surveillance, Epidemiology, and End Results (SEER) cancer registries during the year 2000. “Of these wom-

en, 53,207 were diagnosed with breast cancer that year and followed up for the next 10 years,” the researchers reported. The extent of screening in each county was assessed as the percentage of included women who reported receiving a screening mammogram in the prior 2 years. The incidence of breast cancer, including ductal carcinoma in situ, in 2000 and incidencebased breast cancer mortality during the 10-year follow-up were calculated for each county and age adjusted to the U.S. population. “Across [the United States], there was a positive correlation between the extent of screening and breast cancer incidence (weighted r = 0.54; P < .001) but not with breast cancer mortality (weighted r = 0.00; P = .98). An absolute increase of 10 percentage points in the extent of screening was accompanied by 16% more breast cancer diagnoses (relative rate [RR], 1.16; 95% confidence interval [CI], 1.13–1.19) but no significant change in breast cancer deaths (RR, 1.01; 95% CI, 0.96–1.06),” the researchers reported. “In an analysis stratified by tumor size, we found that more screening was strongly associated with an increased incidence of small breast cancers (≤ 2 cm) but not with a decreased incidence of larger breast cancers (≥ 2 cm). An increase of 10 percentage points in screening was associated with a 25% increase in the incidence of small breast cancers (RR, 1.25; 95% CI, 1.18–1.32) and a 7% increase in the incidence of larger breast cancers

(RR, 1.07; 95% CI, 1.02–1.12),” the authors added. “The simplest explanation” of the observed data “is widespread overdiagnosis, which increased the incidence of small cancers without changing mortality, and therefore matches every feature of the observed data,” the investigators stated.

A Closer Look at Ecologic Studies “Clinicians are correct to be wary of ecological studies because of the ecological fallacy,” referring to making inferences about individuals from group data in statistical analyses, the authors acknowledged. “Ecological studies use an intuitively appealing research design that relates the frequency with which some exposure or intervention (eg, cancer screening) and some outcome of interest (eg, cancer diagnosis or mortality) occur in the same geographic area or care setting,” noted an accompanying editorial. The authors of that editorial are Joann G. Elmore, MD, MPH, University of Washington School of Medicine, and Ruth Etzioni, PhD, Fred Hutchinson Cancer Research Center, Seattle. The authors noted that ecological studies have been helpful throughout the years in identifying associations between smoking and subsequent lung cancer and Pap tests and cervical cancer. “However, much has also been written about the caution needed when interpreting ecological analyses,” the editorialists added. “It is well known, for example, that ecological studies provide no information as to whether the people who were actually exposed to the intervention were the same people who developed the disease, whether the exposure or the onset of disease came first, or whether there are other explanations for the observed association. Ecological analyses also may not properly reflect group-level associations because of area-level variations in confounding factors or other practices affecting the outcome.” The editorialists pointed out that the ecological study design used merged two large data sources, the SEER incidence and mortality data, and the “county-level estimates of mammography, based on national surveys of women who recount prior mammography examinations.” They also noted that

“prior ecological studies of mammography conducted at the larger state level with a wider range of mammography frequencies showed a decline in breast cancer mortality associated with more screening.”

Communicating About Uncertainty With no definitive answers about the percentages of overdiagnosis among women receiving screening mammography and which women are diagnosed with ductal carcinoma in situ or invasive cancers, “we need clear communication and better tools to help women make informed decisions regarding breast cancer screening mammography,” Drs. Elmore and Etzioni wrote. “Perhaps most important, we need to learn how to communicate with our patients about uncertainty and the limits of our scientific knowledge. In the end, we all need to become comfortable with informing women that we do not know the actual magnitude of overdiagnosis with precision. Part of informed decision making is providing all the information, even our uncertainty.”

Harding C, et al: JAMA Intern Med 175:1483-1489, 2015. Elmore JG, Etzioni R: JAMA Intern Med 175:1490-1491, 2015.

PROSTATE CANCER Decreased Mortality in Men With Unfavorable-Risk Prostate Cancer and Moderate or Severe Comorbidities Treated With Radiotherapy Alone Men with unfavorable-risk prostate cancer and moderate or severe comorbidities had significantly decreased overall and cardiac mortality when treated with radiotherapy alone vs radiotherapy and androgen-deprivation therapy, according to a study described in a research letter in The Journal of the American Medical Association (JAMA). In the letter, Anthony V. D’Amico, MD, PhD, of Brigham and Women’s Hospital, Boston, and colleagues presented long-term follow-up to their randomized trial, reported in JAMA in 2008, which showed that 6 months of androgendeprivation therapy and radiotherapy vs radiotherapy alone “prolongs survival and is the standard treatment for unfavorable-risk prostate cancer.”

ASCOPost.com | OCTOBER 10, 2015

PAGE 109

In the Literature

The new study builds on a “postrandomization hypothesis-generating analysis suggesting that men with moderate or severe comorbidity had no survival from combined therapy,” the researchers noted. “Using updated data from our randomized trial, we compared overall survival and mortality from prostate cancer, cardiac, or other causes in all men and those within comorbidity subgroups by randomized treatment group,” the authors explained. Information collected before randomization was used to assign a comorbidity score. A total of 206 men with unfavorable-risk prostate cancer were randomized to receive radiotherapy alone or radiotherapy and 6 months of androgen-deprivation therapy at three academic and three community-based centers in Massachusetts between December 1, 1995, and April 15, 2001, At a median follow-up of 16.62 years, 156 men had died (76%); 29 died of prostate cancer (19%), 39 died of cardiac causes (25%), and 88 died of other causes (56%). Among men with moderate or severe comorbidity, 46 of 49 patients had died (94%), compared with 110 of 157 (70%) men with no or minimal comorbidity. “Survival did not differ in the radiotherapy-alone group vs the radiotherapy and androgen-deprivation therapy group, but opposite effects of treatment on survival were observed in the comorbidity subgroups,” the authors reported. In multivariable analyses, radiotherapy alone vs radiotherapy and androgen-deprivation therapy in men with none or minimal comorbidity was associated with significantly increased overall mortality (hazard ratio [HR], 1.51 [95% confidence interval (CI), 1.03– 2.21]; P = .04) and prostate cancer mortality (HR, 4.30 [95% CI, 1.60–11.50]; P = .004), no difference in cardiac mortality (HR, 1.72 [95% CI, 0.64–4.58]; P = .28), and decreased other-cause mortality (HR, 0.60 [95% CI, 0.36–0.99]; P = .04),” the authors reported. “Conversely, in men with moderate or severe comorbidity, radiotherapy alone vs radiotherapy and androgendeprivation therapy was associated with significantly decreased overall mortality (HR, 0.36 [95% CI, 0.19– 0.67]; P = .001) and cardiac mortality (HR, 0.17 [95% CI, 0.06–0.46]; P < .001),” the researchers wrote. This finding is in contrast to no association with overall mortality at a median follow-up of 7.6 years (HR, 0.54 [95%

CI, 0.27–1.10]; P = .08), as previously reported. In addition, among men with moderate or severe comorbidity, radiotherapy alone vs radiotherapy and androgendeprivation therapy was associated with no difference in prostate cancer mortality (HR, 2.41 [95% CI, 0.23–25.21]; P = .46) and increased other-cause mor-

tality (HR, 2.79 [95% CI, 1.02–7.60]; P = .05). “Limitations include that the results from postrandomization analyses are hypothesis-generating and in some cases based on low event rates and therefore require validation,” the authors pointed out. “Nevertheless, the association of treatment with radiother-

apy alone with decreased cardiac and overall mortality in men with moderate or severe comorbidity suggests that administering androgen-deprivation therapy to treat unfavorable-risk prostate cancer in these men should be carefully considered.” n

D’Amico AV, et al: JAMA 314:12911293, 2015.

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PAGE 110

In Memoriam

Sidney Mirvish, PhD, Carcinogenesis Researcher, Dies at 86

Sidney Mirvish, PhD

idney Mirvish, PhD, Professor Emeritus in the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center (UNMC), whose pioneering research into nitrosamines and carcinogenesis led to changes in the way lunch

meats, hot dogs, and sausages were made, died August 23 due to complications following emergency surgery. He was 86. Ken Cowan, MD, PhD, Director of the Fred & Pamela Buffett Cancer Center, called Dr. Mirvish “an internationally recognized leader in nitrosamines and carcinogenesis who helped build the scientific reputation of UNMC and the Eppley Institute.” “Sidney was a remarkable individual and scientist,” Dr. Cowan said. “His continued passion for science and the Eppley Institute was truly inspirational. He will be dearly missed.” Samuel Cohen, MD, PhD, HavlikWall Professor of Oncology, Pathology, and Microbiology, knew Dr. Mirvish for 45 years—first at Wisconsin, then at UNMC.

“He was an outstanding scientist, known for his seminal research on carcinogenic N-nitrosamines,” Dr. Cohen said. “He was the first to show their formation from nitrites in food and the inhibition of this formation by vitamin C. This led to changes in the way lunch meats, hot dogs, and sausages were made.” Dr. Mirvish completed his doctorate degree in organic chemistry at Cambridge University in England and received his bachelor’s and master’s degrees at the University of Cape Town in South Africa. After working in South Africa at the University of Witwatersrand, he joined the Weizmann Institute of Science in Israel, where he developed his interest in carcinogenesis. After working briefly at the McArdle Laboratory for Cancer Research at the

University of Wisconsin, he was recruited as an Associate Professor to the Eppley Institute in 1969. He was promoted to Professor in 1977, served as Interim Director and Associate Director of the Institute from 1981–1986, and received the Outstanding Research and Creativity Award (ORCA) from the University of Nebraska in 1986. He was a faculty member at the Eppley Institute for 46 years. Dr. Mirvish had 155 publications, and his laboratory was funded by the National Cancer Institute through 2013 (as Professor Emeritus). He was still working on grant applications and research manuscripts and continued to come regularly to institute seminars and meetings. His wife, Lynda; two children; daughter-in-law; three grandchildren; and sister survive Dr. Mirvish. n

Thomas A. Stamey, MD, Noted Urologist and Prostate Cancer Expert, Dies at 87 A True Pioneer in the Field

Thomas A. Stamey, MD

homas A. Stamey, MD, Professor Emeritus of Urology at the Stanford University School of Medicine and a leader in the study and treatment of prostate cancer, died of Alzheimer’s disease September 4. He was 87.

Dr. Stamey helped lay the groundwork for the prostate-specific antigen (PSA) blood test for prostate cancer and helped transform the scope of research in urology and surgery. In 1989, he became the first urologist ever elected to the Institute of Medicine and was also named an honorary fellow of the Royal College of Surgeons Edinburgh. “Tom Stamey was the founding father of the Stanford Department of Urology and led it for more than 25 years. He was truly one of the giants in academic urology, with his biggest impact in the area of prostate cancer,” said Eila Skinner, MD, present Chair of Urology at Stanford and the Thomas A. Stamey Research Professor in Urology at the Stanford Univer-

sity School of Medicine. “His research collaborations…formed the basis of much of what we know about prostate cancer today. He trained over 100 residents and fellows, many of whom went on to be leaders in urology in their own right. His influence on the department will go on for many years to come, and I feel privileged to have known him.” Dr. Stamey earned his medical degree from Johns Hopkins University, where he also completed his internship and a residency. He was appointed as Associate Professor of Surgery and Chair of the Division of Urology at Stanford Medical School in 1961. In 1990, he was appointed Founding Chair of the newly created Department of Urology and worked to develop it into one of the top programs in the nation.

 In Memoriam

Sidney Mirvish, PhD 1929 – 2015

Thomas A. Stamey, MD 1928 – 2015

PSA Expertise He was an expert in PSA testing for over 15 years. In the late 1980s, he pioneered the development of the PSA blood test for prostate cancer, which allowed physicians to estimate the risk that a male patient had the disease. In 2004, he published a study showing that the PSA test predicted the size of the patient’s prostate but not necessarily the severity of cancer. Dr. Stamey wrote then, “Our job now is to stop removing every man’s prostate who has prostate cancer. We originally thought we were doing the right thing, but we are now figuring out how we went wrong. Some men need prostate treatment, but certainly not all of them.” In addition to his wife, Kathryn, Dr. Stamey is survived by his five children and five grandchildren. n

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The ASCO Post | OCTOBER 10, 2015

PAGE 112

Global Oncology

Cancer Incidence and Mortality Rates Worldwide

s discussed in the new series “Global Oncology Burden” (see pages 66–67 in this issue), analysis of the cancer burden based on the regions as divided by the World Health Organization (WHO) (ie, Africa, the Americas, South-East Asia, Europe, Eastern Mediterranean, and Western Pacific), reveals the marked differences (see Table 1). Although the cancer burden is shown to increase over the next 3 decades in all six of these regions, these differences are starkly higher for the African and Eastern Mediterranean regions when compared to the European regions.

The World Health Organization identifies six world regions as follows below and as shown in the table at right: • WHO-AFRO: Africa region • WHO-PAHO: Americas region • WHO-SEARO: South-East Asia region • WHO-EURO: European region • WHO-EMRO: Eastern Mediterranean region • WHO-WPRO: Western Pacific region n Reference http://globocan.iarc.fr/Default.aspx

Table 1: Predicted Incidence and Mortality Rates for Various Regions of the World.* Incidence

Mortality

2015

2035

2015

2035

WHO-AFRO

699,442

1,290,428

491,603

916,268

WHO-PAHO

3,132,937

4,955,305

1,410,277

2,414,698

WHO-SEARO

1,858,652

3,015,257

1,265,268

2,139,308

WHO-EURO

3,877,124

4,862,210

2,026,026

2,652,639

WHO-EMRO

599,105

1,118,608

396,619

770,354

WHO-WPRO

5,017,117

7,928,973

3,311,800

5,605,079

*Includes data for all cancers excluding nonmelanoma skin cancer. European Cancer Congress

Over Three-Quarters of People With Cancer Worldwide Have No Access to Safe Surgery

ver 80% of the 15 million people diagnosed with cancer worldwide in 2015 will need surgery, but less than one-quarter of them will have access to proper, safe, affordable surgical care when they need it, according to a major new Commission examining the state of global cancer surgery. The

national cancer plans and are allocated few resources. As a result, access to safe, affordable cancer surgical services is dismal. Our new estimates suggest that less than one in 20 (5%) patients in low-income countries and only roughly one in five patients (22%) in middle-income countries can access even the most basic cancer surgery.”

The evidence outlined by the Commission … leaves no doubt of the dire situation we are facing. It is imperative that surgery is at the heart of global and national cancer plans. —Richard Sullivan, MD, PhD

Commission’s findings were published by Sullivan et al in The Lancet Oncology1 and presented at the 2015 European Cancer Congress in Vienna, Austria.2 The Commission revealed that access is worst in low-income countries, where as many as 95% of people with cancer do not receive basic cancer surgery. Yet despite this worldwide shortfall in access to cancer surgery, the international community does not see surgical care as an essential component of global cancer control. Lead Commissioner Richard Sullivan, MD, PhD, of the Institute of Cancer Policy, King’s Health Partners Comprehensive Cancer Centre, King’s College London, said, “With many competing health priorities and substantial financial constraints in many low- and middle-income countries, surgical services for cancer are given low priority within

Poor access to basic cancer surgery and good quality cancer care is not just confined to the world’s poorer countries. Survival data across Europe show that many of the poorer European Union member states are not delivering high-quality cancer surgery to their populations.

Economic Losses Without urgent investment in surgical services for cancer care, global economic losses from cancers that could have been treated by surgery will reach a staggering USD $12 trillion by 2030, equivalent to 1% to 1.5% of economic output in highincome countries, and 0.5% to 1% in lowand middle-income countries every year. Furthermore, the lack of effective action to train more cancer surgeons and improve cancer surgical systems could cost the global economy more than USD $6 tril-

lion between now and 2030, said coauthor John Meara, MD, DMD, MBA, Director of the Program in Global Surgery and Social Change at Harvard Medical School. The demand for cancer surgery is growing as many of the worst affected countries face rising cancer rates. By 2030, of the almost 22 million new cancer patients, over 17 million will need operations, 10 million of them in low- and middle-income countries. “The global community can no longer ignore this problem,” said coauthor C. S. Pramesh, MS, FRCS, Head of Thoracic Surgery at Tata Memorial Hospital. The Commission also revealed that one-third of people with cancer in lowand middle-income countries who have a surgical procedure will incur financial catastrophe. Another quarter will stop treatment because they cannot afford it.

Training and Funding With a serious shortfall of cancer surgeons in over 82% of countries, radical action is needed to train general surgeons to deliver basic cancer surgery; produce more gynecologic and surgical oncologists; and create more high-quality surgical training programs, said the authors. Other solutions to improve access to surgery include better-regulated public systems; growing international partnerships between institutions and surgical societies; and a firm commitment to universal health coverage. Educating policymakers, patients, and the public about the key issues in delivering safe, affordable, timely surgical care is also essential, said the authors. “Policy makers at all levels still have little aware-

ness of the central importance of surgery to cancer control. Even recent studies of capacity building for cancer systems in Africa barely acknowledged the importance of surgery, focusing mainly on chemotherapy instead,” said coauthor Riccardo Audisio, MD, President of the European Society for Surgical Oncology. According to the Commission, funding for research in cancer surgery is dire and needs urgent investment. Despite its huge impact on patient outcomes, just 1.3% of the annual global cancer research and development budget goes toward surgery. “This Commission clearly outlines the enormous scale of the problem posed by the global shortfall in access to cancer surgery and current deficiencies in pathology and imaging,” Dr. Sullivan said. “The evidence outlined by the Commission, contributed by some of the world’s leading experts in the field, leaves no doubt of the dire situation we are facing. It is imperative that surgery is at the heart of global and national cancer plans. A powerful political commitment is needed in all countries to increase investment and training in publicly funded systems of cancer surgery.” n

Disclosure: For full disclosures of the study authors, visit press.thelancet.com/ GlobalCancerSurgeryCommission.pdf

References 1. Sullivan R, Alatise OI, Anderson BO, et al: Global cancer surgery: Delivering safe, affordable, and timely cancer surgery. Lancet Oncol 16:1193-1224, 2015. 2. Sullivan R, Olusegun IA, Anderson BO, et al: Delivering safe and affordable cancer surgery to all. 2015 European Cancer Congress. Abstract 9LBA. Presented September 28, 2015.

ASCOPost.com | OCTOBER 10, 2015

PAGE 113

Perspective Charles L. Bennett, MD, PhD, and William S. Shimp, MD continued from page 1

care management, regardless of their point of entry into the care system. In large measure, NCCN has been a stunning success, having now grown to 26 member institutions. Its published guidelines, compendium, and educational offerings have indeed become a national treasure. Further, its international reach is apparent from the large number of guideline inquiries that come from beyond U.S. borders. Just as physicians have looked to NCCN for authoritative guidance in patient care, agencies such as the Center for Medicare & Medicaid Services (CMS) and numerous commercial payers couple insurance coverage with NCCN Guidelines, which are designated as one of the three approved compendia for reimbursement. At one point several years ago, Medicare even offered additional payment for office visits where documented care was in compliance with NCCN Guidelines. Veterans Affairs clinician notes today generally include a statement indicating that patients were informed of NCCN Guidelines for their particular diagnosis. In effect, NCCN’s profound influence on oncology care has come to define a national standard for reimbursement in many instances and for determination of quality of care in other settings. Reimbursement and quality have always been important, but more so now that the term “unsustainable” is frequently and legitimately used to describe new (and sometimes old) oncology drug costs, which often exceed $10,000 per month.

The Way Forward Going forward, there are shortcomings in medical oncology practice that NCCN can help address. To begin, physician compliance with clinical guidelines is far from universal. Physician requests for oncology drugs are often “custom-crafted” and not supported by consensus-based scientific guidelines such as those developed by NCCN or other evidence-based guidelines such as those developed by ASCO, Cancer Care Ontario, or other guideline organizations. Some-

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times this is because the physician is unfamiliar with treatment algorithms for a given disease or is requesting a “promising but unproven” therapy, in advance of U.S. Food and Drug Administration (FDA) approval or support from an NCCN Guideline that is directly linked to reimbursement. In many cases involving Medicare,

Medicaid, or private health insurers, it is the responsibility of preauthorization utilization review to weed out oncology drug requests that are not compliant with a guideline from an organization such as NCCN or other compendia for which reimbursement is linked—much to the dismay of physicians who regard such interventions as high-handed,

intrusive, wasteful of precious clinic time, and counter to the best interests of their patients. Insurers legitimately oppose payment in most of those situations, though it is not uncommon for compassionate exceptions to be made in situations where other standard options have been exhausted. continued on page 114

EDITOR-IN-CHIEF SEARCH NEW CLINICAL CANCER INFORMATICS JOURNAL The American Society of Clinical Oncology (ASCO) is seeking candidates for the position of founding Editor-in-Chief for a new journal focusing on clinical cancer informatics (title to be determined), an online-only journal publishing high-quality studies representing actionable knowledge, clinical and care delivery research validations, and new research hypotheses based on the growing knowledge base represented by EHR, registry, and clinical trials data to omics databases. The new journal will also publish reviews, editorials, and commentaries on data studies relevant to cancer care. Lastly, the journal will seek to publish papers on the methodology and interpretation of clinical cancer informatics research. The Editor-in-Chief will be responsible for assembling a team of Associate Editors and an editorial board, setting the editorial scope and vision for the new journal, and overseeing the annual publication of six issues of approximately 48 editorial pages each. The target date for the first issue is the fourth quarter of 2016 or early 2017. The founding Editor-in-Chief’s three-year term will begin in early 2016. By October 31, 2015, interested candidates should submit a CV and brief letter of interest. Ideal candidates will be active in cancer informatics and have experience as a journal Associate/ Section Editor (or equivalent) or Editor-in-Chief. However, candidates without journal editorial leadership experience will be considered. Candidates should also be an active ASCO member. This role is eligible for an annual stipend and reimbursement for journal-related travel. Based on a written application and phone interview, an editor search committee will recommend a candidate for approval by the ASCO President and Board of Directors in January 2016. Submit letters of interest or nominations to: David Sampson Senior Director and Publisher, Journals American Society of Clinical Oncology 2318 Mill Road, Suite 800 Alexandria, VA 22314 Candidates may also request more information by sending an e-mail to david.sampson@asco.org

The ASCO Post | OCTOBER 10, 2015

PAGE 114

Perspective Charles L. Bennett, MD, PhD, and William S. Shimp, MD continued from page 113

Cost Issues

Until now, most clinical guidelines offered no guidance in terms of value. Equally effective drug choices may be listed side by side in guidelines, one very costly and the other less so, offering the physician no information about “choosing wisely” between the two options. In the United States, the FDA and the CMS do not weigh in on drug costs. A physician is left to figure it out alone— a difficult assignment amid a busy office day—sometimes resulting in the “dreaded” phone call from a utilization management physician who is making the case for equally effective care utilizing a less costly or less toxic regimen. As more novel prospective payment models appear online, oncologists will be more in need of a quick and efficient reference for factoring drug costs into regimen prescriptions. We are pleased that NCCN and ASCO have reported that help is on the way.

Evidence Limitations Although the vast majority of consensus-based NCCN recommendations are based on solid level 1 scientific evidence, there are examples where recommendations from a consensus of

an NCCN committee do not reflect evidence-based information. For instance, the combination of two costly long-acting antiemetics is supported by NCCN for use in chemotherapy regimens with moderate risk of nausea and vomiting, although no level 1 scientific evidence supports this regimen, and a combination of a short-acting and a long-acting agent is much more cost-effective. Formerly, the febrile neutropenia risk of carboplatin/paclitaxel regimens was listed as high by the NCCN Guidelines, until physicians advised NCCN that only patients of Asian ancestry were at that level of risk. NCCN subsequently amended its recommendations. For reasons that are unclear, FDA-approved doxorubicin fell off the NCCN list of active agents for treatment of ovarian cancer, in favor of liposomal doxorubicin; the former was reinstated in response to a petition to NCCN from clinical oncologists. Most recently, NCCN has supported the use of biologic agents in some cases of non–small cell lung cancer (NSCLC) that share molecular/genetic markers with other neoplasms such as breast cancer and melanoma, with no level 1 data to support that extrapolation. Two of these agents have subsequently been removed from the NCCN list of recommended drugs.

Moments in History

NCCN has always led the way as a trusted source of clinical information, it is now positioned to define the practice of value-based oncology medicine going forward into it’s third decade. —Charles L. Bennett, MD, PhD, MPP, (top) and William S. Shimp, MD

NCCN shoulders the obligation that all of its guidelines, which are relied on for quality and/or reimbursement considerations, must stay with the data, not venture prematurely into promising therapies that have not yet met full scientific scrutiny, and avoid supporting regimens that are commonly used but unsupported by solid scientific evidence. A particularly worrisome downstream effect of such variations is that participation in clinical trials can be discouraged unwittingly. In the case of NSCLC biologics, for example, an NCCN classification of 2A (even if premature) may become wedded to insurance coverage for some of those drugs. Knowing that, a physician and patient may decide to treat off-protocol with a covered drug rather than enroll in important datagenerating phase II or III clinical trials. With clinical trial participation at such an abysmal low point in the United States, the last thing needed is yet another incentive to avoid gathering important clinical data.

Outside Petitions: A Unique Aspect of NCCN Guidelines

President Franklin D. Roosevelt dedicated the new National Institutes of Health (NIH) campus in Bethesda on October 31, 1940. This event was held to celebrate NIH’s historic move from just one building in Washington, DC, to its new campus setting in Maryland on 45 acres of land donated by Luke and Helen Wilson. Source: http://www.nih.gov/about/almanac/historical/photo_gallery.htm

NCCN has always strived to maintain transparency in its work. For example, it has been open to considering and publishing on its website most (but not all) outside petitions sent to various Guidelines committees. Interestingly, only 7 of 194 petitions since 2010 have requested more rigid scientific scrutiny (and reconsideration) of NCCN recommendations, 3 of which resulted in palpable guidelines changes; the rest (96%) have come from pharmaceutical and diagnostic companies lobbying for inclusion of their products into NCCN Guidelines and occasionally from patient advocacy groups. This dis-

proportionate pressure from industry is notable but not surprising. By comparison, providers petition NCCN very infrequently, usually requesting additional scrutiny of the science behind NCCN recommendations. These petitions are not always published on the NCCN Web page. NCCN needs to maintain its commitment to rigid scientific evidence as the foundation of its guidelines and compendium, thereby retaining the confidence of clinicians and insurers. In addition, and of increasing importance, NCCN must continue its groundbreaking work of incorporating financial considerations into its guidelines, thus facilitating the practice of value-based oncology care. Its recent work on resource stratification of NCCN Cervical Cancer Guidelines is an important step in the right direction. Even more welcome is NCCN’s plan to issue financial and efficacy information on the drug regimens it recommends, starting with chronic myeloid leukemia and multiple myeloma. By moving value considerations further into the limelight of public awareness, as it plans to do in upcoming conferences, NCCN will be taking unprecedented action to address the “financial toxicity” determinants of the individual’s and society’s ability to afford the ever-increasing cost of care. As NCCN has always led the way as a trusted source of clinical information, it is now positioned to define the practice of value-based oncology medicine—an expanded and hugely important mission going forward into NCCN’s third decade. n Disclosure: Drs. Bennett and Shimp are consultants for Oncology Analytics, Inc, an oncology utilization management organization based in Plantation, Florida.

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