TAP Vol 5 Issue 11 by Harborside Press LLC

HER2-Positive Breast Cancer

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| B.J. Kennedy Lecture at ASCO

| Cost of Cancer Drugs

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VOLUME 5, ISSUE 11

JULY 10, 2014

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

ASCO Annual Meeting

The More Things Change, the More They Stay the Same

‘Impressive’ Outcomes Achieved With Pembrolizumab in Advanced Melanoma By Caroline Helwick

By Jimmie C. Holland, MD, and James F. Holland, MD

he latest bit of good news for the programmed death receptor-1 (PD-1)–targeting antibodies in advanced melanoma comes for pembrolizumab (MK-3475). While the results came from only a phase I study, they were among those chosen for presentation at an ASCO press briefing during the Annual Meeting. “We were excited to see that pembrolizumab was effective in previously untreated patients as well as in those who had multiple prior therapies, including ipilimumab (Yervoy). These are early data, but they tell us we are onto something really important,” said Antoni Ribas, MD, PhD, Professor of Medicine at the David Geffen School of Medicine at the University of California, Los Angeles. Steven O’Day, MD, Director, Clinical Research, Beverly Hills Cancer Center, Beverly Hills, California, who moderated the press briefing on progress in immunotherapy, commented, “The remarkable thing

is that almost 90% of the patients that respond are having durable responses with a toxicity profile that is almost unheard of in metastatic cancer. This is really extraordinary about this class of drugs.” Pembrolizumab is an Antoni Ribas, MD, PhD antibody designed to block the interaction of PD-1 on T cells and reactivate antitumor immunity. In April 2013, the U.S. Food and Drug Administration (FDA) had previously granted a Breakthrough Therapy designation to pembrolizumab (previously known as lambrolizumab) for advanced melanoma. In May 2014, the FDA granted pembrolizumab a Priority Review designation under its Accelerated Approval program. continued on page 15

Health-Care Policy

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

By Margot Fromer ancer patients’ out-of-pocket costs are rising dramatically, and insurance premiums, cost sharing, and ancillary expenses can be devastating. Many people go bankrupt as a result of the high costs of health care. Drugs are among the most serious economic culprits. They grow more expensive every year, and every year, more patients cannot pay. This was the subject of a recent Institute of Medicine (IOM) National Cancer Policy Forum workshop, held in Washington, DC.

continued on page 34

Dr. Jimmie C. Holland is Wayne E. Chapman Chair in Psychiatric Oncology, Memorial Sloan Kettering Cancer Center, New York. Dr. James F. Holland is Distinguished Professor of Neoplastic Diseases at Mount Sinai Medical Center, New York.

IOM Workshop Explores Growing Problems in Patient Access to Cancer Drugs

he ASCO Annual Meeting in June confirmed—and expanded—the excitement of the oncology community about molecular medicine and its future. The complex molecular pathways were pictured in living color on many slides in many large auditoriums. Newspapers across the country were equally enthusiastic as they attempted to describe the science behind the new targeted therapies. Needless to say, the public, always eager to hear good news, bought in, and the hype was on for this “new era of cancer cures.”

The Worst Problems

Shortages of some drugs, especially older ones that have gone off patent, have left many cancer patients out in the cold, mainly because the profit margin for some generics is too small to make continuing manufacture worthwhile. The end is similar, but the means are different for specialty pharmaceuticals—drugs and biologicals that are the hope of the future. A. Mark Fendrick, MD, Professor, Departments of Internal Medicine and Health Management and Policy, and Director, CenCost-containment efforts should ter for Value-Based Insurnot produce preventable reductions in ance Design, University of Michigan, Ann Arbor, said quality of care. that these drugs will com—A. Mark Fendrick, MD prise about half of all pharmaceutical reimbursement

MORE IN THIS ISSUE Oncology Meetings Coverage ASCO 50th Annual Meeting �� 1, 3, 4–6, 8, 13, 15, 72 Rev 2014 Forum on Navigating Cancer in the Era of Personalized Medicine ��23 American Society of Pediatric Hematology/Oncology �� 51 Amy Abernethy, MD, on Discontinuing Statins at End of Life �� 90 Lisa A. Carey, MD, on Ado-Trastuzumab Emtansine in HER2-Positive Breast Cancer �� 31 Panitumumab in Metastatic Colorectal Cancer ��42 Direct From ASCO �� 44–47

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The ASCO Post | JULY 10, 2014

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ASCO Annual Meeting Dermatologic Oncology

Ipilimumab Reduces Recurrences as Adjuvant Treatment of Melanoma By Caroline Helwick

pilimumab (Yervoy) has transformed the treatment of metastatic melanoma, producing long-term responses in about 20% of patients. A phase III study has now evaluated its impact in the adjuvant setting, and the results are a bit less striking.

Primary Endpoint The European Organisation for Research and Treatment of Cancer (EORTC) 18071/CA184-029 trial was presented at the 2014 ASCO Annual Meeting by Alexander M. Eggermont, MD, PhD, Director General of the Gustave Roussy Cancer Cen-

Alexander M. Eggermont, MD, PhD

ter in Villejuif, France.1 Adjuvant ipilimumab reduced the risk of recurrence by roughly 25%, compared to placebo, in the study of 951 surgically treated highrisk stage III melanoma patients. “The study met its primary endpoint of a significant improvement in recurrence-free survival with 10 mg/kg ipilimumab vs placebo,” Dr. Eggermont reported. “Results from prespecified subgroup and sensitivity analyses show a consistent pattern, with hazard ratios favoring ipilimumab relative to placebo.” Melanoma expert Steven J. O’Day, MD, Director, Clinical Research, Beverly Hills Cancer Center, Beverly Hills, California, who moderated a press briefing where the results were presented, remarked, “This is the first study to demonstrate the clinical benefit of ipilimumab in stage III melanoma. The magnitude of the clinical benefit, the side effects, and the dosing schedule warrant further follow-up and additional comparative studies with interferon, which are ongoing,” he said. “Ipilimumab was not shown to be superior,” Dr. O’Day emphasized. “We need to be cautious.”

Adjuvant Melanoma: An Unmet Need At a press briefing, Dr. Eggermont emphasized that high-risk patients with resected disease need better treatment

options. Also at the ASCO Annual Meeting, his research team presented a meta-analysis of 15 randomized trials involving more than 7,500 patients. The analysis showed that adjuvant interferonalfa reduces the risk of recurrence by just 14%, and the risk of death by only 9%.2 “Although there are approved adjuvant therapies, there is still an unmet need in this group of patients,” he said. “Ipilimumab was the first drug approved for metastatic melanoma, based on an overall survival improvement, so the EORTC trial is the first ever with a melanoma drug that has improved survival.”

Study Details The study population included 951 stage III patients, all with lymph node involvement, who had undergone complete resection. By the ipilimumab and placebo arms, respectively, stage III disease was present in 18% and 21%, stage IIIB in 45% and 43%, stage IIIC with one to three positive nodes in 15% and 17%, respectively, and stage IIIC with at least four positive nodes in 20% and 21%, respectively. Approximately half had microscopic nodal involvement and half macroscopic involvement (ie, palpable nodes). Patients were randomly assigned

Ipilimumab as Adjuvant Melanoma Treatment ■■ The EORTC 18071/CA184-029 trial evaluated ipilimumab as adjuvant treatment in high-risk resected melanoma patients, and found that it cut recurrence risk by 25%. ■■ The toxicity profile, however, was high, with five treatment-related deaths and significant increases in diarrhea, colitis, hepatic abnormalities, and endocrinopathies.

were higher in some subsets: those with ulceration of the primary lesions (HR = 0.67) and those with microscopic disease (HR = 0.68), he noted. Discontinuation due to disease progression was noted for 28% of the ipilimumab arm and 57.6% of the placebo arm.

Toxicity Observed The trade-off appears to be toxicity, Dr. Eggermont acknowledged. There were five treatment-related deaths (1.1%) in the ipilimumab arm: three due to colitis (two with gastrointestinal perforation), one due to myocarditis, and one related to Guillain-Barré syndrome. No deaths related to treatment occurred in the placebo arm. Nearly 50% of ipilimumab-treated patients discontinued the drug due to side effects, most of them within the

This is the first study to demonstrate the clinical benefit of ipilimumab in stage III melanoma. The magnitude of the clinical benefit, the side effects, and the dosing schedule warrant further follow-up and additional comparative studies with interferon. —Steven J. O’Day, MD

to placebo or ipilimumab at 10 mg/kg every 3 weeks for four doses, then continued at 3-month intervals for up to 3 years. At a median follow-up of 2.7 years, there were 294 recurrences in the placebo group compared to 234 in the ipilmumab group. Three-year recurrencefree survival rates were 34.8% and 46.5%, respectively (hazard ratio [HR] = 0.75; P = .0013), and median recurrence-free survival was 17.1 months vs 26.1 months with ipiliumumab, Dr. Eggermont reported. Overall, ipilimumab reduced recurrences by 25%, but the hazard ratios

first 3 months. Generally, however, “the safety profile is consistent with that observed in advanced melanoma, although the incidence of some immunerelated adverse events [eg, endocrinopathies] was higher in this study,” he said. “Most immune-related adverse events were manageable and resolved with established treatment algorithms.” Diarrhea of any grade was observed in 41.4% with ipilimumab and 16.7% with placebo; 9.6% and 0.4% of these cases, respectively, were grade 3. Colitis occurred in 15.9% and 1.3%, respectively, and was grade 3/4 in 7.6% and 0.2%. Endocrine disorders (hypophysitis,

hypothyroidism) were also a concern for 37.6% of the ipilimumab arm vs 6.5% of the placebo arm. Hepatic issues were observed in 25.1% and 4.4%, respectively. “We are not attempting to downplay the toxicity,” Dr. Eggermont said at the press briefing. “In the adjuvant setting, the discussion is about RISK, spelled in capital letters.” The majority of these grade 2–4 immune-related adverse events resolved within 6 weeks, including 89% of the skin toxicities, 94% of the gastrointestinal toxicities, and 95% of the hepatic abnormalities, but endocrine effects resolved in only 56% of patients and at a median of 31 weeks.

Better Than Interferon? In commenting on the EORTC 18071 findings at the press briefing, Dr. O’Day pointed out that, while no headto-head comparisons have yet generated data, the benefits seen with adjuvant ipilimumab are in line with what is achieved with the age-old interferon. “Ipilimumab shows activity in the adjuvant setting. There is a delay in recurrence. However, I would argue that this delay is about 10% at 3 years, which is comparable to interferon,” he said. Dr. Eggermont countered that in some subgroups, ipilimumab does seem better than interferon. His metaanalysis found that in patients with clinically palpable disease, hazard ratios with interferon or pegylated interferon ranged from 0.78 to 0.91, whereas in the EORTC study of ipilimumab, hazard ratios were 0.68 to 0.83. “There was a striking difference between the treatments in patients with palpable disease,” he observed. “And in the end, the hazard ratio was 0.75, which we don’t see with other treatments.” Dr. O’Day also highlighted the toxicity, “which seemed at a slightly higher level than we see in the metastatic setting, including five treatment-related continued on page 4

The ASCO Post | JULY 10, 2014

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ASCO Annual Meeting Dermatologic Oncology

Long-Term Follow-up of Phase I Nivolumab Trial By Caroline Helwick

n the longest follow-up to date of any programmed death (PD)-1 receptor inhibitor in previously treated advanced melanoma, one-third of patients are demonstrating durable responses to the investigational agent nivolumab, and in some cases, these persist following discontinuation of the drug, according to F. Stephen Hodi, Jr, MD, Director of the Melanoma Center and Director of the Center for Immuno-Oncology at Dana-Farber Cancer Institute, Boston.

CA209-003 Trial “Of 107 patients, 47 are still alive, with a median follow-up of 22 months and a range of 14 to 51 months,” Dr. Hodi reported at the 2014 ASCO Annual Meeting.1 Dr. Hodi presented the long-term follow-up of CA209-003 study of nivolumab monotherapy in 107 advanced melanoma patients. At a dose of 3 mg/kg every 2 weeks, the objective response rate was 41%, and median duration of response was 75 weeks. This is the dose selected for phase III studies, he said. Patients receiving this dose of nivolumab had a median progressionfree survival of 9.7 months and median overall survival of 20.3 months. Responses were ongoing in 19 of 34 (56%) responders at the time of analysis, and 11 of the 21 (52%) responding patients who discontinued the drug for reasons other than progression continued to respond for 24 weeks or longer. Of these

Ipilimumab in Melanoma continued from page 3

deaths,” he said. “We can salvage these patients in the metastatic setting, not just by improving overall survival but also by producing long-term survival/cure. The tolerance for toxicity and deaths in the adjuvant setting is a different bar.” He also stressed the need to evaluate the drug for overall survival. “In the metastatic setting, ipilimumab is underwhelming in terms of progression-free survival but has impressive effects on overall survival,” he said, “so we need to wait for the overall survival results and the direct comparison with interferon before we make firm conclusions about its role in the adjuvant setting.” While Dr. O’Day also pointed out that interferon compounds and doses

11, 7 (64%) remained in response for up to 56 weeks. Nearly half the responding patients showed a response at the first tumor assessment at 8 weeks, he added. The median overall survival was 17.3 months, and overall survival rates were 63% at 1 year, 48% at 2 years, and 41% at 3 years, Dr. Hodi reported. Ten patients demonstrated an immune-related type of response, which

Pidilizumab Phase II Trial Another investigational anti–PD-1 agent, pidilizumab, produced a more modest response rate, 5% to 6%, than has come to be expected from this emerging class of immune checkpoint inhibitors. The phase II open-label randomized trial of patients was reported by Michael B. Atkins, MD, Deputy Director of the GeorgetownLombardi Comprehensive Cancer Center

Patients who experience an immune-related–type response [on nivolumab] can have overall survival outcomes similar to those with RECIST responses. —F. Stephen Hodi, Jr, MD

was defined as ≥ 30% reduction in targeted lesions from baseline or after initial progression disease, or patients with progression disease for at least three tumor assessments, with a best change in tumor burden of ≤ 20% from baseline. “Patients who experience an immunerelated–type response can have overall survival outcomes similar to those with RECIST responses,” Dr. Hodi noted. At 42 weeks, almost 80% of both these subsets remained alive. Activity was seen across patient populations and prognostic factors. No new safety signals were observed.

in Washington, DC, and Professor of Oncology and Medicine at Georgetown University School of Medicine.2 “The study missed the primary endpoint of objective response rate but met the secondary endpoint of overall survival,” Dr. Atkins reported. At 12 months, 64.5% of patients remained alive. Dr. Atkins noted that “despite the low response rate, the 12-month survival in heavily pretreated patients appears to be better than anticipated and similar to that reported for other anti–PD-1 antibodies.” The 12-month survival rate was 64.5%, compared to 46% for ipilimumab

differ between the EORTC and U.S. cooperative group trials, Dr. Eggermont noted that his meta-analysis included high-dose, intermediate-dose, and low-dose interferons. “It was an independent patient data meta-analysis, which is the highest quality metaanalysis you can do,” he argued.

overall survival benefits, though some studies have shown a survival benefit.” Antonio Ribas, MD, a melanoma expert at the University of California, Los Angeles, had the last word on this at the press briefing: “Based on evidence, regulatory agencies have concluded that being on interferon treatment benefits patients.” The question of just which adjuvant approach is better may be answered by the ongoing phase III ECOG 1609 trial, which is comparing two doses of ipilimumab (3 mg/kg and 10 mg/kg) to high-dose interferon. n

Adjuvant Therapy Issues Finally, the issue of a placebo-controlled trial for adjuvant treatment was raised, with Dr. Eggermont indicating that in Europe, the use of adjuvant therapy is not a standard of care. Dr. O’Day noted that in the United States, adjuvant therapy is a standard but not the standard. “It’s controversial,” he acknowledged. “It’s consistently shown disease-free but not

Disclosure: Dr. Eggermont is a consultant/ advisor for Bristol-Myers Squibb. Dr. O’Day reported no potential conflicts of interest. Dr. Ribas reported a consultant or advisory role with Amgen, Compugen, GlaxoSmithKline,

Michael B. Atkins, MD

(Yervoy), 62% for nivolumab, and 81% for pembrolizumab, Dr. Atkins noted. The survival rate was approximately 80% for the 57% of patients who were treated after the study with ipilimumab, or who achieved stable disease or better with prior ipilimumab exposure, he added. n

Disclosure: Dr. Hodi is an unpaid consultant for and has received clinical trial support (via his institution) from Bristol-Myers Squibb, and has a licensing agreement with Bristol-Myers Squibb as per institutional policy. Dr. Atkins has provided expert testimony for CureTech and has served on advisory boards for Bristol-Myers Squibb, Merck, Genentech, GlaxoSmithKline, Pfizer, and Prometheus. For full disclosures of all the study authors, visit meetinglibrary.asco.org.

References 1. Hodi FS, Sznol M, Kluger HM, et al: Long-term survival of ipilimumab-naive patients with advanced melanoma treated with nivolumab in a phase 1 trial. ASCO Annual Meeting. Abstract 9002. Presented June 2, 2014. 2. Atkins MB, Kudchadkar RR, Sznol M, et al: Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma. ASCO Annual Meeting. Abstract 9001. Presented June 2, 2014.

Genentech, Merck, Novartis, and Pierre Fabre, stock ownership with Kite Pharma and Flexus Bio, and holds a position as an advisory board member and/or consultant for Merck.

References 1. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial. ASCO Annual Meeting. LBA 9008. Presented June 2, 2014. 2. Suciu S, Ives N, Eggermont AM, et al: Predictive importance of ulceration on the efficacy of adjuvant interferon-α: An individual patient data meta-analysis of 15 randomised trials in > 7500 melanoma patients. ASCO 2014 Annual Meeting. Abstract 9067. Presented May 31, 2014.

ASCOPost.com | JULY 10, 2014

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ASCO Annual Meeting Thoracic Oncology

Strong Showing for Anti–PD-1 Agents in Non–Small Cell Lung Cancer By Caroline Helwick

onoclonal antibodies targeting the programmed death receptor-1 (PD-1) pathway are expected to answer an unmet need in non–small cell lung cancer (NSCLC). With firstline platinum-doublets, 1-year overall survival is 30% to 50%, and while treatments targeting sensitizing mutations are more effective, they benefit only a few subsets of patients. Data presented at the 2014 ASCO Annual Meeting point to the anti–PD-1 agents as a means of filling this treatment gap.

Underlying Mechanism PD-1 is an inhibitory T-cell co-receptor expressed by activated T cells, whose pathway is hijacked by tumors to suppress immune control. PD-1 interacts with its ligands, PD-L1 and PD-L2, and this activation can lead to

suppression of antitumor immunity. Anti–PD-1 agents bind with the PD-1 receptor on T cells, selectively blocking its interaction with its ligands. This restores T-cell antitumor function. Very promising results were reported for nivolumab in the phase I CA209-012 multicohort study, which evaluated single-agent nivolumab, nivolumab combined with ipilimumab (Yervoy), and nivolumab combined with erlotinib (Tarceva) in the first-line setting, as well for the newest agent, pembrolizumab (formerly known as lambrolizumab).

Pembrolizumab in Previously Treated Patients In a phase I study of 217 previously treated NSCLC patients, pembrolizumab at 10 mg/kg every 2 weeks or 3 weeks demonstrated “robust anti-

tumor activity,” especially among patients whose tumors expressing PDL1, according to Edward B. Garon, MD, Assistant Professor of Medicine at the University of California, Los Angeles.1 The objective response rate was 20%, and was higher among the 159 patients with tumors expressing PDL1 (23%) than among those who did not (9%). Of the PD-L1–positive patients who responded, 82% remain on treatment. Compared with baseline, 58% of PD-L1–positive patients vs 30% of the negative group had some reduction in tumor size by RECIST criteria. Nearly two-thirds of patients had at least one drug-related adverse event of any grade, and 10% had grade 3/4 toxicity. Grade 3/4 pneumonitis was observed in four patients.

EXPERT POINT OF VIEW

artin Reck, MD, PhD, Head of Thoracic Oncology at the Hospital Grosshansdorf in Germany, discussed the anti–PD-1 abstracts at the ASCO Annual Meeting. “We have seen tremendous results for immunotherapies for the reactivation of the immune system in patients with advanced melanoma. The question is, is this also true for patients with lung cancer?” he asked.

the quality of the sample used for assessment, and so forth,” he noted.

Nivolumab Trials Regarding the nivolumab studies, he suggested that the combination of this drug with erlotinib “requires more validation and translational science,” especially with regard to its activity against T790M-mutant patients. “There is little knowledge about the

We have seen fascinating interim results, and we wait for their validation. —Martin Reck, MD, PhD

Commenting on pembrolizumab, he noted that the efficacy seems not dependent on histology of the tumors, though better response rates are seen in patients with PD-L1 expression. “We see a signal of better responses in these tumors; however, we have to be very cautious because there have been substantial differences with regard to the antibody used for assessment, the scoring system,

correlation of the T790M mutation and checkpoint inhibition,” he noted. “It’s of interest, as well, to see the effect of this combination in EGFR mutation–positive, T790M mutation–negative patients who are refractory to an EGFR tyrosine kinase inhibitor. The data have to be put into perspective of the third-generation tyrosine kinase inhibitors,” which are more efficacious in the T790M-mutant population.

For nivolumab plus ipilimumab, efficacy seems unrelated to differences in dosing and schedule, or to PD-L1 expression, but toxicity is fairly high, he said. “I think the 10-mg/kg dose may be too toxic for this combination, and especially we need to keep our eye on pulmonary toxicity,” he said. As monotherapy, nivolumab is better tolerated. “Severe adverse events were seen in 20%, and so far we have not seen any severe pulmonary toxicity,” he pointed out. A median progression-free survival of 9 months and 1-year overall survival rate of 75% is impressive, he commented. In PD-L1–positive patients, median progression-free survival was 46 weeks, with 80% of patients alive at 1 year. PDL1–negative patients did not respond. “Of interest, in PD-L1–negative patients, even without any responses, had a median progression-free survival of 36 weeks, and 1-year survival was 71%, but we have to remember we are talking about only seven patients,” he cautioned. Whether the anti-PD-1 agents are truly superior to the best chemotherapy and targeted agents in NSCLC will only be answered by randomized trials, he said, “but we have seen fascinating interim results, and we wait for their validation.” n Disclosure: Dr. Reck reported no potential conflicts of interest.

Scott N. Gettinger, MD

Single-Agent Nivolumab in First Line Scott N. Gettinger, MD, Associate Professor of Medicine at Yale Cancer Center, New Haven, presented interim data for nivolumab at 3 mg/kg every 2 weeks in chemotherapy-naive patients.2 The objective response rate was 30% and median duration of response had not been reached. Two patients had complete responses, with another unconfirmed, whereas 35% had stable disease, most lasting at least 24 weeks. Progression-free survival rate at 24 weeks was 60%, median progressionfree survival was 47.2 weeks in patients with nonsquamous histology and 15.1 in those with squamous tumors, and 1-year overall survival rate was 75%. Median overall survival was not reached at the time of analysis. All the responders were found to have PD-L1 staining in at least 5% of tumor cells (ie, were PD-L1–positive). In these patients, progressionfree survival rate at 24 weeks was 70%, compared to 57% in PD-L1–negative patients. Median progression-free survival was 45.6 weeks and 36.1 weeks, and 1-year overall survival rate was 80% and 71%, respectively. Treatment-related adverse events were observed in 85% of patients, mostly grade 1/2. Grade 3/4 toxicity was noted in only 20%. “First-line treatment for advanced NSCLC with nivolumab monotherapy demonstrated early and durable responses, and encouraging progressionfree and overall survival profiles,” Dr. Gettinger concluded. “These interim results support further studies of firstline nivolumab monotherapy and continued evaluation of PD-L1 expression as a potential biomarker for activity.”

Nivolumab Plus Ipilimumab There is great interest in dual immune checkpoint blockade, based on robust efficacy for the combination in advanced melanoma. Results from ancontinued on page 6

The ASCO Post | JULY 10, 2014

PAGE 6

ASCO Annual Meeting Anti–PD-1 Agents continued from page 5

other arm of the phase I CA209-012 study, presented by Scott J. Antonia, MD, PhD, Chair of Thoracic Oncology at H. Lee Moffitt Cancer Center, Tampa, Florida, were promising.3 A total of 49 chemotherapy-naive patients received nivolumab plus ipilimumab every 3 weeks for four cycles, followed by nivolumab monotherapy every 2 weeks until progression. Two schedules were evaluated: nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg or nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg. Depending on dose and histology, objective responses were observed in 11% to 33% of patients, the highest (33%) seen in squamous disease patients receiving nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg. Responses were ongoing in 75% of responders at the time of analysis. Overall, 60% of evaluable patients experienced a decrease in tumor burden. Median progression-free survival at 24 weeks ranged from 20% to 51% and median progression-free survival was 14.4 to 16.1 weeks. Median overall survival was reached only in patients of squamous histology receiving nivolumab at 1 mg/kg plus ipilimumab at 3 mg/ kg 16.1 weeks (44.3 weeks), and was

induction. Grade 3/4 adverse events were reported by 36% to 54% of patients across the combination doses during induction, and by 17% to 21% in the maintenance phase. Grade 3/4 toxicities were reported by 49% across the arms. Grade 3/4 pneumonitis occurred in 6% and was reversible. Serious diarrhea and colitis occurred in 8%, and increased liver enzymes in 6%. One-third of patients discontinued

Combining PD-1 blockade with therapies that target mutant EGFR signaling may be a novel approach to enhancing the treatment response, and may provide durable benefit. The response rate and duration of response are encouraging, relative to other available therapies for such patients. —Naiyer A. Rizvi, MD

due to adverse events, mostly those receiving nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg, and mostly during concurrent dosing. Three patients died due to drugrelated toxicities, one each from colitis, pulmonary hemorrhage, and toxic epi-

Anti–PD-1 in NSCLC ■■ In advanced non–small cell lung cancer, anti–PD-1 monoclonal antibodies show robust activity and produce durable responses. ■■ Nivolumab has been evaluated as monotherapy in the first line, and in combination with chemotherapy, erlotinib, and ipilimumab in previously treated patients, showing high response rates and durability. ■■ The investigational agent pembrolizumab showed robust antitumor activity in previously treated patients, especially those expressing PD-L1. ■■ Rates of grade 3/4 events can be high, with some doses and combinations more problematic than others.

not reached in the other arms. Exploratory PD-L1 analysis revealed that response rates and median progression-free survival were similar whether patients were PD-L1–positive or –negative, and median overall survival was not reached in either group. “The findings suggest this combination may be suitable for PD-L1−positive and −negative patients,” Dr. Antonia concluded. “There was no apparent correlation between response rate, progression-free survival, and overall survival and PD-L1 status, similar to previous observations with combined nivolumab plus ipilimumab in melanoma.” Toxicity occurred mainly during

Outcomes were impressive in the subgroup receiving pemetrexed/cisplatin plus nivolumab at 10 mg/kg. Their 24-week progression-free survival rate was 71% (vs 36% to 57% of the other arms); 1-year overall survival was 87%, and median overall survival was 83.4 weeks, Dr. Antonia reported. With paclitaxel/carboplatin plus nivolumab at 5 mg/kg, median overall survival was not reached, and median

dermal necrolysis (the patient had a history of ulcerative colitis).

Nivolumab Plus Chemotherapy Dr. Antonia also presented results on the 56 patients who received nivolumab at 10 mg/kg every 3 weeks plus a platinum-based doublet (gemcitabine/cisplatin, pemetrexed (Alimta)/cisplatin, or paclitaxel/carboplatin), followed by nivolumab at 5 mg/kg or 10 mg/kg until progression.4 Objective responses were observed in 33% to 47% of patients, and in both squamous and nonsquamous histology subsets. A decrease in tumor burden was noted in 84%.

progression-free survival was 31 weeks. Treatment-related grade 3/4 adverse events occurred in 45%, most commonly pneumonitis, fatigue, and acute renal failure. Most (73%) were seen with nivolumab at 10 mg/kg plus paclitaxel/ carboplatin. “Many of these were laboratory abnormalities reported in one patient each,” he explained. “The safety profile reflects the additive toxicity of nivolumab and chemotherapy,” he said. Discontinuations due to drug-related events were observed mainly during maintenance.

Nivolumab Plus Erlotinib Naiyer A. Rizvi, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, New York, presented the CA209-012 data on nivolumab combined with erlotinib in patients with epidermal growth factor receptor (EGFR) mutations.5 “Recent data suggest that constitutive oncogenic signaling through the EGFR pathway may promote tumor immune escape by inducing immune dysfunction in the tumor microenvironment,” he explained. Treatment of EGFR-mutant NSCLC cell lines with an EGFR tyrosine kinase inhibitor downregulates PD-L1 expression. The study included 21 patients with EGFR-mutated adenocarcinoma and prior erlotinib treatment; 33% had the deleterious T790M mutation. Of 21 patients, 4 (19%) responded, and responses were ongoing in 3 patients at

the time of analysis. The estimated duration of response was 60 weeks, and 15% of patients had stable disease. “Responses were seen in patients who had previously received multiple lines of EGFR inhibitor therapy, as well as patients with T790M mutations,” Dr. Rizvi reported. Progression-free survival at 24 weeks was 51%, median progression-free survival was 29.4 weeks, 1-year survival was 73%, and median overall survival was not yet reached. The toxicities were additive, but only 24% were grade 3/4. The data suggest that “combining PD-1 blockade with therapies that target mutant EGFR signaling may be a novel approach to enhancing the treatment response, and may provide durable benefit. The response rate and duration of response are encouraging, relative to other available therapies for such patients,” he concluded. n

Disclosure: Dr. Garon is an unpaid consultant/ advisor for and has received research funding from Merck. Dr. Gettinger is a consultant/advisor for, has stock ownership in, and has received honoraria from Bristol-Myers Squibb. Dr. Antonia is a consultant/advisor for, has stock ownership in, and has received honoraria from Bristol-Myers Squibb, and has received research funding from MedImmune. Dr. Rizvi is a consultant/advisor for Bristol-Myers Squibb, has received honoraria from Bristol-Myers Squibb, MedImmune, and Roche/Genentech, and has received research funding from Arisaph Pharmaceuticals, Millennium, and Pfizer.

References 1. Garon EB, Leighl NB, Rizvi NA, et al: Safety and clinical activity of MK3475 in previously treated patients with non-small cell lung cancer. ASCO Annual Meeting. Abstract 8020. Presented June 3, 2014. 2. Gettinger SN, Shepherd FA, Antonia SJ, et al: First-line nivolumab monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status. ASCO Annual Meeting. Abstract 8024. Presented June 3, 2014. 3. Antonia SJ, Gettinger SN, Chow LQ, et al: Nivolumab and ipilimumab in first-line NSCLC: Interim phase 1 results. ASCO Annual Meeting. Abstract 8023. Presented June 3, 2014. 4. Antonia SJ, Brahmer JR, Gettinger SN, et al: Nivolumab in combination with platinum-based doublet chemotherapy in advanced non-small cell lung cancer. ASCO Annual Meeting. Abstract 8113. Presented May 31, 2014. 5. Rizvi NA, Chow LQ, Borghael H, et al: Safety and response with nivolumab plus erlotinib in patient with epidermal growth factor receptor mutant advanced NSCLC. ASCO Annual Meeting. Abstract 8022. Presented June 3, 2014.

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The ASCO Post | JULY 10, 2014

PAGE 8

ASCO Annual Meeting Genitourinary Oncology

AR-V7 Predicts Resistance to Enzalutamide and Abiraterone in Men With Castration-Resistant Prostate Cancer By Alice Goodman

ndrogen receptor (AR) splice variant 7 (V7) appears to be a new biomarker for response and disease progression in patients treated with enzalutamide (Xtandi) or abiraterone (Zytiga). The presence of AR-

of the first public report on AR-V7 in metastatic castration-resistant prostate cancer treated with enzalutamide, which was presented at the 2014 Annual Meeting of the American Association for Cancer Research (see the May

If these results are supported by larger studies, detection of AR-V7 in circulating tumor cells may be used as a biomarker to predict resistance to enzalutamide, abiraterone, and ARtargeted agents, facilitate treatment selection, and fuel the development of AR N-terminal domain inhibitors. —Emmanuel S. Antonarakis, MD

V7 in circulating tumor cells predicted resistance to both drugs in men with metastatic castration-resistant prostate cancer in a study presented at the 2014 ASCO Annual Meeting in Chicago.1 The ASCO study comes on the heels

15 issue of The ASCO Post, page 14). Both enzalutamide and abiraterone target the androgen receptor. It is not yet clear whether AR-V7 would predict poor response to other therapies used for metastatic castration-resistant pros-

tate cancer that are not directed at AR, such as sipuleucel-T (Provenge) or radium-223 (Xofigo).

Potential Biomarker “If these results are supported by larger studies, detection of AR-V7 in circulating tumor cells may be used as a biomarker to predict resistance to enzalutamide, abiraterone, and ARtargeted agents, facilitate treatment selection, and fuel the development of AR N-terminal domain inhibitors,” stated lead author Emmanuel S. Antonarakis, MD, Asssistant Professor of Oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. Use of a simple blood test to detect AR-V7 has the potential to streamline therapeutic decision-making and steer patients who test positive for AR-V7 to other therapies that may be more effective. This test also has the potential to facilitate more prudent use of healthcare resources. Dr. Antonarakis and colleagues will continue to study AR-V7, but he said

the blood test is not yet ready for routine use. “Before we are ready to use ARV7 status to make treatment decisions, we would first like to obtain CLIA certification for our assay, as well as to validate our results using larger enzalutamide/abiraterone datasets with available clinical samples for analysis. Hopefully, our findings will be replicated very quickly by other multiple groups as well,” he said in an interview with The ASCO Post. “At this time,” he continued, “it would probably be unwise to withhold enzalutamide or abiraterone from patients who test positive for AR-V7. But if such patients are offered these drugs, they should be monitored very closely for signs of progression, and the treating clinician should have a low threshold for switching these patients to alternative treatments, such as chemotherapies or radiotherapies.” Although there are a number of AR splice variants, studies by Dr. Antonarakis and others suggest that AR-V7 is the most important one. The expression of continued on page 12

EXPERT POINT OF VIEW

“T

he magic of this research is that it requires a liquid biopsy [circulating tumor cells in the blood]—a simple blood collection,” said Eleni Efstathiou, MD, PhD, Associate Professor at The University of Texas MD Anderson Cancer Center, Houston, commenting on the study presented by Antonarakis and colleagues at the ASCO Annual Meeting. “Apart from predicting resistance to androgen receptor (AR)-directed therapies, this work paves the way for liquid biopsies to identify other predictors of resistance.”

tant prostate cancer associating primary resistance to enzalutamide with AR-V7 presence in tumor biopsies. The presence of AR-V7 in circulating tumor cells could help in making

chemotherapies, but this needs further study. “This research also paves the way for research on therapies directed to AR-V7 and other variants on the N terminus of the AR receptor,” she noted.

Apart from predicting resistance to androgen receptor–directed therapies, this work paves the way for liquid biopsies to identify other predictors of resistance. —Eleni Efstathiou, MD, PhD

Supportive Findings Dr. Efstathiou is involved in research on AR variants using tissuebased biopsies, which are invasive. She noted that the findings of Dr. Antonarakis and colleagues are in line with observations from experimental data and a recent report of a tissuebased study she conducted in men with bone metastatic castration-resis-

treatment decisions. “[If this work is validated], you would obviously not opt to treat that patient with enzalutamide or abiraterone,” she said. “We don’t want to waste time on treatments that don’t work.” Dr. Efstathiou noted that experimental data suggest that AR-V7 may also predict resistance to taxane-based

Another piece of evidence suggesting that the presence of AR-V7 predicts resistance in general, is that patients who converted from ARV7–negative to AR-V7–positive over the course of Dr. Antonarakis’ study had worse outcomes than those who remained AR-V7–negative throughout the study.

Other Uses “The fact that some patients convert also means that the blood test could be used at baseline and then throughout treatment to anticipate the emergence of resistance,” she added. Dr. Efstathiou said that the blood assay used in this study achieves a higher yield of circulating tumor cells than other currently available tests. “The blood test needs to be prospectively validated in a broader group of patients and in larger numbers to better understand its performance. CLIA certification will be required to assure cross-study uniformity,” she noted. If the assays perform well in heterogeneous patient populations, it will then find clinical utility and be used to select patients for treatment with enzalutamide or abiraterone and guide changes in therapy, she said. n Disclosure: Dr. Efstathiou reported no potential conflicts of interest.

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

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

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

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

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

Percentage surviving

80 60 40 20 0

7 8 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

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

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

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

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

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

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

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

75%

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

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

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | JULY 10, 2014

PAGE 12

ASCO Annual Meeting AR-V7 in Prostate Cancer continued from page 8

AR-V7 is increased 20-fold in metastatic castration-resistant prostate cancer, and it can be detected in clinical samples.

Study Details The study he reported at the Annual Meeting included men with castration-

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

ADRs

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

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

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

37 33 45 23 24 9 8 19 5 14

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

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

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

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

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

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

culating tumor cells) and the Adna Test Prostate Cancer Detect kit (AdnaGen, Langenhagen, Germany). Outcomes were prostate-specific antigen (PSA) response rate (> 50% PSA decline), PSA progression-free survival, clinical/radiographic progression-free survival, and overall survival (which is still premature). In the enzalutamide cohort, 38.7%

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

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

were AR-V7–positive and 61.3% were AR-V7–negative. Overall, about twothird of patients had received previous abiraterone and docetaxel and about one-third had visceral metastasis (the percentages of patients with these characteristics were much higher among AR-V7–positive patients). Best PSA response was 0% in the AR-V7–positive patients compared with 52.6% in the AR-V7–negative group. PSA progression-free survival and clinical/radiographic progressionfree survival were significantly better in the AR-V7–negative patients (P < .001 for both endpoints). In the abiraterone cohort, 19.4% were AR-V7–positive and 80.6% were

Role of AR-V7 in Prostate Cancer Therapy ■■ A blood test developed at Johns Hopkins can detect the presence of AR-V7 in circulating tumor cells of men with castrationresistant prostate cancer. ■■ AR-V7 appears to be a biomarker for resistance to androgen receptor–directed therapies such as enzalutamide and abiraterone. ■■ If these findings are replicated in larger prospective studies, the blood test for AR-V7 could be used to make treatment decisions, spare men treatments that do not work, and conserve resources.

Safety:10"

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

resistant prostate cancer who were about to begin treatment with enzalutamide (n = 31) or abiraterone (n = 31). Circulating tumor cell samples were collected at baseline, at the time of response to either drug, and at the time of resistance to either drug. The two-part test used to detect AR-V7 included the Adna Test Safety:7" Prostate Cancer Select kit (to isolate cir-

AR-V7–negative. Overall, only 12.9% had received prior enzalutamide, 16.1% had received prior docetaxel, and 25.8% had visceral metastases. Best PSA response was 0% in the AR-V7–positive patients compared with 68% in the AR-V7–negative group. As in the enzalutamide cohort, PSA progression-free survival and clinical/radiographic progression-free survival were significantly better in the AR-V7–negative group (P < .001 for both endpoints). Among 58 evaluable patients, those who were AR-V7–positive at baseline, remained so in subsequent samples; of 42 men who were AR-V7–negative at baseline, 6 (14%) converted to positive status and 36 remained negative. Clinical outcomes of the “converters” were intermediate, better than those who were ARV7–positive to begin with, but worse than those who remained AR-V7–negative. Dr. Antonarakis pointed out that these results suggest that detection of continued on page 13

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ASCO Annual Meeting Hematology

‘R-Squared’ Regimen Delivers a Punch to Diffuse Large B-Cell Lymphoma Subtype By Caroline Helwick

he combination of lenalidomide (Revlimid) and rituximab (Rituximab), dubbed the “R-squared” regimen, has gained attention lately, and ongoing trials are evaluating whether chemotherapy with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) can be improved by adding a nonchemotherapeutic agent like lenalidomide. At the 2014 ASCO Annual Meeting, researchers reported encouraging results of this

germinal center B-cell subtype, reported Grzegorz S. Nowakowski, MD, Assistant Professor of Medicine at the Mayo Clinic, Rochester, Minnesota. “The addition of lenalidomide may ameliorate the negative effect of [non– germinal center B-cell] phenotype on outcome,” Dr. Nowakowski said. The R2-CHOP treatment consisted of 25 mg lenalidomide daily on days 1 to 10 of a 21-day cycle in addition to standard R-CHOP given every three

The addition of lenalidomide may ameliorate the negative effect of [non–germinal center B-cell] phenotype on outcome.

EXPERT POINT OF VIEW

he ASCO Post asked for comment about the presentation by Nowakowski et al from Nathan Fowler, MD, who developed and led many of the early studies of R-Squared (lenalidomide [Revlimid], rituximab [Rituxan]), in lymphoma as well. Dr. Fowler is Associate Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, Houston. “We are very excited about the recent results of R2-CHOP in large cell

This study … emphasizes the concept that adding a biologic agent to a chemotherapy backbone in the correct setting can translate into significantly improved outcomes. —Nathan Fowler, MD

—Grzegorz S. Nowakowski, MD

approach in diffuse large B-cell lymphoma, especially with the non–germinal center B-cell (non-GCB) phenotype.1

Phase II Study In a phase II study of 64 patients with newly diagnosed diffuse large B-cell lymphoma, the addition of lenalidomide to R-CHOP (R2-CHOP), appeared to reduce the negative prognostic significance of the non–germinal center B-cell phenotype, producing progression-free and overall survival rates similar to those observed in the

cycles. The population had a median age of 65, with 20% older than 70 years. Sixty percent had stage IV disease, and about half the patients were considered high-risk.

Key Findings Among 55 evaluable patients, 33 were of the germinal center B-cell phenotype and 22 were non–germinal center B-cell patients. The R2-CHOP regimen was associated with similar outcomes in both subtypes, with 2-year progression-free survival of 60% and 50%, respectively,

R2-CHOP in Diffuse Large B-Cell Lymphoma ■■ For patients with diffuse large B-cell lymphoma of the non–germinal center B-cell phenotype, the addition of lenalidomide to R-CHOP led to outcomes similar to those in patients of the germinal center B-cell phenotype. ■■ At 2 years, progression-free survival for this subset was 50% and overall survival was 75% in this phase II study.

AR-V7 in Prostate Cancer continued from page 12

AR-V7 is associated with both primary and acquired resistance to enzalutamide and abiraterone.

Further Investigation When asked what other options patients might have who are resistant to these two drugs, he said, “It is possible

that the detection of AR-V7 might simply be a poor prognostic factor in the context of multiple therapies. In order to test this hypothesis, our group is currently investigating the role of AR-V7 in the context of docetaxel and cabazitaxel [ Jevtana] chemotherapy. It would also be interesting to evaluate the role of ARV7 in the context of immunotherapies such as sipuleucel-T or radiopharma-

lymphoma. Historically, the addition of cytotoxic agents to the CHOP combination has failed to show a consistent benefit over CHOP alone,” he said. “Nowakowski and colleagues have shown that R2-CHOP has significant activity in newly diagnosed patients and have suggested that R2-CHOP can ameliorate the inferior prognosis associated with non–germinal center subtype of [diffuse large B-cell lymphoma]. This study further confirms mounting preclinical evidence that lenalidomide has preferential antitumor activity in non–germinal center [diffuse large B-cell lymphoma] cells and emphasizes the concept that adding a biologic agent to a chemotherapy backbone in the correct setting can translate into significantly improved outcomes.” n

Disclosure: Dr Fowler has received research funding from and is on the scientific advisory boards of Celgene and Roche.

and 2-year survival rates of 83% and 75%, Dr. Nowakowski said. The response rate was 98%, and 80% of patients had complete responses. The R2-CHOP regimen was well tolerated, even in the older patients, he said. The most frequent grade 3/4 toxicity was neutropenia (87%), but febrile neutropenia was rare. Grade 3/4 thrombocytopenia (44%) and anemia (15%) were observed in some patients.

A case-matched historical analysis showed that outcomes with R-CHOP were substantially worse among patients with non–germinal center B-cell phenotype than for those with germinal center B-cell diffuse large B-cell lymphoma. At 2 years, 64% of germinal center B-cell patients were progression-free, compared to only 28% of the non–germinal center B-cell population

ceuticals such as radium-223.” He and his co-investigators plan to incorporate their blood-based AR-V7 assay into prospective clinical trials of enzalutamide and abiraterone, as well as into prospective trials of novel agents that may have activity against the AR-V7 splice variant. n

Astellas/Medivation. He has received research funding from both companies.

Disclosure: Dr. Antonarakis is a paid consultant and advisor to Janssen Biotech and

continued on page 14

Reference 1. Antonarakis ES, Lu C, Wang H, et al: Androgen receptor splice variant AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration resistant prostate cancer. 2014 ASCO Annual Meeting. Abstract 5001. Presented June 1, 2014.

The ASCO Post | JULY 10, 2014

PAGE 14

ASCO Annual Meeting ‘R-Squared’ Regimen continued from page 13

treated with R-CHOP (P = .00029). However, in the R2-CHOP treatment arms, these rates were 59% and 60%, respectively (P = .83). Similarly, 2-year overall survival was 74% and 46%, respectively, in the RCHOP treatment arms (P = .000036),

but were comparable in the R2-CHOP arms—75% and 83%, respectively (P = .61). These findings suggest that the addition of lenalidomide to R-CHOP may overcome the negative prognostic impact associated with the non–germinal center B-cell phenotype, he suggested. A randomized trial, Eastern Cooper-

ative Oncology Group (ECOG) 1412, is currently comparing R2-CHOP vs RCHOP for the initial treatment of diffuse large B-cell lymphoma. The study is also enrolling patients through the Alliance and SWOG. n Disclosure: Dr. Nowakowski and his coauthors reported no potential conflicts of interest.

Reference 1. Nowakowski GS, LaPlant B, Macon WR, et al: Effect of lenalidomide combined with R-CHOP (R2CHOP) on negative prognostic impact of nongerminal center phenotype in newly diagnosed diffuse large B-cell lymphoma: A phase 2 study. ASCO Annual Meeting. Abstract 8520. Presented June 1, 2014.

Nonadherence With Maintenance Medication an Issue in Children With Leukemia

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n estimated 25% of children in remission from acute lymphocytic leukemia (ALL) are missing too many doses of the oral agent mercaptopurine, a maintenance medication that minimizes their risk of relapse when taken every day for 2 years, according to a study recently published online in Blood.1 The study also reports that maintenance medication adherence was lower in African American and Asian children in remission from ALL than in non-Hispanic white children, with 46% of African Americans and 28% of Asians not taking enough to prevent relapse, compared with 14% of non-Hispanic whites. “While we don’t yet know why children of different races have significantly different survival rates for ALL, we know that their adherence to their maintenance medication is a critical factor in their survival,” said senior study author Smita Bhatia, MD, MPH, of City of Hope in Duarte, California.

Study Details Dr. Bhatia and a team of investigators began their research studying differences in mercaptopurine adherence among different racial groups of children in remission from ALL in 2012, reporting that Hispanic children did not follow their prescribed mercaptopurine maintenance regimen as consistently as non-Hispanic whites. To examine mercaptopurine adherence in African American, Asian, and non-Hispanic white children in remission from ALL, the research team enrolled 298 patients from 77 institutions in a study that tracked mercaptopurine drug levels in the bloodstream, responses from a questionnaire administered to their families, and, an electronic method for monitoring maincontinued on page 15

ASCOPost.com | JULY 10, 2014

PAGE 15

ASCO Annual Meeting Dermatologic Oncology

Pembrolizumab in Melanoma continued from page 1

In the KEYNOTE-001 trial involving 411 patients with advanced melanoma, pembrolizumab produced responses in 34% of patients, including 28% of patients whose disease had progressed on prior treatment with ipilimumab. At 1 year, 88% of responders were continuing to respond to treatment, Dr. Ribas reported at the Annual Meeting.

Durable Responses The study, which is the largest phase I clinical trial ever conducted in metastatic melanoma, included seven different expansion cohorts, some previously treated and some treatment-naive, who received three different dosing regimens of singleagent pembrolizumab. More than half the patients had M1c disease. Chemotherapy had been received by 22% of the ipilimumab-naive arm and 47% of the ipilimumab-pretreated arm; 23%

and 30%, respectively, had been treated with other immunotherapies. By independent review, 34% of patients responded, including 40% of the 190 patients not previously treated with ipilimumab and 28% of the 221 patients whose disease had progressed on prior ipilimumab. “The du-

The durability of response is exciting. This is a remarkably high response rate for an antibody that hits the immune system and not the tumor directly. —Antoni Ribas, MD, PhD

rability of response is exciting. This is a remarkably high response rate for an antibody that hits the immune system and not the tumor directly,” Dr. Ribas indicated. At the time of analysis (October 2013), 88% of reported responses were ongoing, and median duration of response had not been reached. The

EXPERT POINT OF VIEW

effrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center and Research Institute in Tampa, Florida, formally discussed the prembrolizumab study at the ASCO Annual Meeting. He called the response rate and the ongoing responses “impressive,” and the 1-year 69% overall survival rate “outstanding” and “promising,” though cautioned, “It’s still early days for pembrolizumab,” as many patients were just enrolled in the past year. He noted that two dosing regimens—2 mg/kg every 2 weeks and 10 mg/ kg every 2 weeks—look “equally effective,” and the higher dose was associated with slightly more toxicity. He noted that the 12% rate of grade 3/4 adverse events seemed high, and questioned whether this might be an error of how the toxicity was reported compared to other trials. Overall, he commented, pembrolizumab has “an excellent toxicity profile.” “Is pembrolizumab better than nivolumab? That is still an open question,” he maintained. “Overall, this study [demonstrated] slightly better outcomes; nonetheless, the record for overall survival and response rate were outstanding, and the drug looks very promising.” n Disclosure: Dr. Weber reported no potential conflicts of interest.

Maintenance Nonadherence continued from page 14

tenance. Each patient enrolled in the study, who was prescribed mercaptopurine, was provided with a pill bottle equipped with a microprocessor chip in the cap that recorded each date and time the bottle was opened for a period of 6 months. Of all three groups, the African American children took their mercaptopurine the least often, with 46% of them taking 90% or less of their medication, the threshold for nonadher-

longest response so far has been 76 weeks. The maximum percent change from baseline in tumor size was 72%. No one dosing regimen seemed superior to others, he said. At 6 months, 45% of patients had not progressed; median progressionfree survival was 5.5 months. The es-

ence at which risk of relapse became statistically significant. While the Asian children in the study group took their medication more consistently, 28% of them did not take at least 90% of their medication. Non-Hispanic white children were more adherent to their maintenance therapy regimen than any other group; however, 14% still did not take enough mercaptopurine to meet researchers’ criterion for drug adherence. Taken together, approximately 25% of the children enrolled in the study did not

timated overall survival rate at 1 year was 69% (74% in ipilimumab-naive and 65% in ipilimumab-exposed patients), and at 18 months was 62%. Median overall survival was not reached at the time of analysis, Dr. Ribas reported. Activity was observed across all dose levels and patient subgroups, irrespective of prior ipilimumab therapy, performance status, lactate dehydrogenase levels, BRAF mutation status, tumor stage, and number and type of prior therapies.

ited to 2% or fewer patients and only 12% overall had a grade 3/4 adverse event. Only 4% of patients discontinued treatment due to a drug-related side effect. Safety profiles were similar for ipilimumab-naive and previously treated patients. Immune-mediated adverse events are especially of interest with this class of agents, and again, the safety profile was very good, he said. The only such side effects that occurred in more than 1% of patients were hypothyroidism (8%) and pneumonitis (3%); these were grade 3/4 in only one or two patients receiving this drug. Ongoing randomized controlled studies are further evaluating pembrolizumab in advanced melanoma patients, both previously treated and not previously treated with ipilimumab. Studies in an adjuvant setting are planned. n

Relatively Benign Therapy

Disclosure: This research was supported by Merck. Dr. Ribas reported a consultant or advisory role with Amgen, Compugen, GlaxoSmithKline, Genentech, Merck, Novartis, and Pierre Fabre, stock ownership with Kite Pharma and Flexus Bio, and holds a position as an advisory board member and/or consultant for Merck. Drs. O’Day and Weber reported no potential conflicts of interest.

“This is one of the most benign therapies I’ve ever used in my clinic,” Dr. Ribas said at the press briefing. The most common adverse events of any grade were fatigue, pruritus, and rash, but grade 3/4 side effects (these and other toxicities) were lim-

Reference 1. Ribas A, Hodi FS, Kefford R et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients with melanoma. ASCO Annual Meeting. Abstract LBA9000. Presented June 2, 2014.

Pembrolizumab in Advanced Melanoma ■■ Pembrolizumab, an anti–PD-1 antibody, achieved a 40% response rate in patients not previously treated with ipilimumab, a 28% response rate in those resistant to ipilimumab, and a 1-year overall survival rate of 69%. ■■ Among responders, 88% had ongoing responses at 1 year; the median PFS of the entire group was 5.5 months. ■■ The tolerability of the drug was very good.

take their mercaptopurine at least 90% of the time, tripling their relapse risk, according to investigators.

Further Study Needed Dr. Bhatia noted in a news release that “our data demonstrate that one in four children in remission from ALL does not take the medicine needed to remain cancer free, and in an overwhelming majority, the primary reason why is that they forget to take their pills each day.” She added, “These results are the basis for further studies that will examine how

physicians can successfully intervene using technology, for example, to ensure that children do not experience an increased risk of relapse because they did not take their oral chemotherapy.” n

Disclosure: For full disclosures of the study authors, visit bloodjournal.hematologylibrary.org.

Reference 1. Bhatia S, Landier W, Hageman L, et al: Adherence to oral 6-mercaptopurine in African American and Asian children with acute lymphoblastic leukemia: A Children’s Oncology Group study. Blood. June 2, 2014 (early release online).

XOFIGO® IS INDICATED

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

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

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

600-10-0009-13c

05/14

Printed in USA

Prolong life. Treat bone metastases.

30%

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

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

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

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

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

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

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

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

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

radium Ra 223 dichloride INJECTION

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

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

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

Hematologic Laboratory Abnormalities

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

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

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

Manufactured for:

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

The ASCO Post | JULY 10, 2014

PAGE 20

ASCO Annual Meeting Dermatologic Oncology

Concurrent Immunotherapy Pays Off in Advanced Melanoma By Caroline Helwick

n advanced melanoma, two immune checkpoint inhibitors may be better than one, according to the promising outcomes of a study reported at the 2014 ASCO Annual Meeting. Concurrent treatment with the anti–CTLA-4 antibody ipilimumab (Yervoy) and nivolumab, an antibody targeting the programmed death (PD)

mg/kg) and ipilimumab (3 mg/kg [one cohort received 1 mg/kg] every 3 weeks for four doses, followed by nivolumab every 3 weeks for four doses, then maintenance with the combination every 12 weeks for eight doses. In the new cohort, the dose for induction was nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg; this was followed by

Concurrent therapy with nivolumab and ipilimumab results in what I believe to be an unprecedented 2-year survival [in patients with advanced melanoma]. —Mario Sznol, MD

receptor-1, resulted in a 2-year survival rate of 79% for patients with advanced melanoma, according to Mario Sznol, MD, lead study author and Professor of Medical Oncology at Yale School of Medicine, New Haven, Connecticut.1 “While this is a small trial, that is very impressive 2-year survival data,” Dr. Sznol said. “Concurrent therapy with nivolumab and ipilimumab results in what I believe to be an unprecedented 2-year survival.”

Sensible Combination PD-1 and CTLA-4 are nonredundant immune checkpoints in T-cell differentiation and function. Both are active in metastatic melanoma, and in murine models have shown antitumor synergy. “It makes sense to combine them,” he said. Dr. Sznol reported updated data for the initial 53 patients treated with concurrent combination treatment regimens in the phase I CA209-004 trial reported at last year’s ASCO Annual Meeting by Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Institute, New York,2 and subsequently published in the The New England Journal of Medicine.3 Dr. Sznol also reported preliminary response data in a new cohort of 41 patients treated with the regimen used in the subsequent phase II/III trials; this confirmatory cohort included patients from the University of Pittsburgh Medical Center and Georgetown University Medical Center. The induction schedule for the initial cohorts was nivolumab (0.3–3.0

nivolumab at 3 mg/kg every 2 weeks for up to 2 years. There was also a sequential treatment cohort; these outcomes will be presented at a later date. All 94 patients had stage III or IV melanoma and could have received up to three prior systemic therapies, although 55% had received no prior systemic treatments.

Combination Yields Promising Outcomes In the original cohort, the 1-year overall survival rate was 85%, and with 1 year of additional follow-up, the 2-year survival rate was 79%. The overall response rate was 42%, with confirmed complete responses increasing from 10% to 17%. To accommodate patients who had “unconventional” responses (ie, immune-related partial responses and prolonged stable disease), the researchers used an “aggregate clinical activity rate,” and this was 70%. Nearly 42% of patients had ≥ 80% reduction in overall tumor measurements, “and I can tell you from my own experience that many of those patients had near-complete responses,” he added. “This is larger than we would see with either agent alone.” In the new 41-patient cohort, the objective response rate was 43%, with 10% complete responses. (Of the four complete responses in this cohort, two were unconfirmed at the time of presentation.) The aggregate clinical activity rate was 53%, and 28% of patients experienced ≥ 80% reduction in tumor burden. These numbers are very

similar to those seen in the original cohort, “so we feel confident that the activity of this combination regimen is real,” Dr. Sznol stated. The responses were durable, and 18 of the 22 responses (82%) were ongoing at time of analysis, with median duration of response not yet reached. Clinical responses were seen regardless of tumor BRAF mutation status or PDL1 status. Responses were seen across all dose levels, though higher doses appeared to convey better overall survival, providing data supportive of synergy, he said. With nivolimab at 1 mg/kg plus ipilimumab at 3 mg/kg, the 1-year overall survival rate was 94% and 2-year survival was 88%, as compared to 57% and 50%, respectively, for the cohort receiving nivolumab at 0.3 mg/kg and ipilimumab at 3 mg/kg.

Increased Toxicity Combining ipilimumab with nivolumab did result in increased toxicity compared to therapy with either agent alone. Grade 3/4 side effects occurred in 58 of the 94 patients (62%). These events, however, “were generally manageable and reversible with algo-

EXPERT POINT OF VIEW

effrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center and Research Institute, Tampa, Florida,

for the original 53 patients, 2-year survival is 79%. In metastatic melanoma, it doesn’t get any better than that.” He continued, “This is not an atypical group of patients. I know

Responses were outstanding. Eight of nine patients in cohort 2 remain in response, as do 16 of 17 in the most recent cohort. And for the original 53 patients, 2-year survival is 79%. In metastatic melanoma, it doesn’t get any better than that. —Jeffrey S. Weber, MD, PhD

was very impressed by the response rate and survival outcomes. “Responses were outstanding. Eight of nine patients in cohort 2 remain in response, as do 16 of 17 in the most recent cohort,” he noted. “And

from seeing them myself, that many have a sizable disease burden. Looking at these data, I cannot help but be impressed.” Regarding the toxicities, Dr. Weber suggested that grade 3 elevations

in lipase and amylase are not particularly worrisome, if patients are otherwise feeling well. “If these go to grade 4, we let the levels come down and keep treating,” he said. “Much of the toxicity occurs early, and generally we can safely continue to treat patients with nivolumab alone.” Question to be answered pertain to the duration of treatment, need for maintenance, superiority of concurrent vs sequential treatment, and safety of continuing anti–PD-1 antibodies in the setting of grade 3/4 immune-related adverse events. Many of these questions will be answered in the current studies, he said. Enrollment has been completed for a phase III trial comparing nivolumab plus ipilimumab vs nivolumab or ipilimumab alone and a phase II trial comparing nivolumab plus ipilimumab to ipilimumab alone. n Disclosure: Dr. Weber reported no potential conflicts of interest.

ASCOPost.com | JULY 10, 2014

PAGE 21

ASCO Annual Meeting rithms that were established for ipilimumab,” Dr. Sznol said. The most common grade 3/4 toxicities were increased lipase and amylase—laboratory abnormalities that

Ipilimumab Plus Nivolumab in Melanoma

activity of the regimen would justify the increased rate in adverse events,” Dr. Sznol said. n Disclosure: The study was supported by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Sznol reported a consultant or advisory role with Symphogen, Anaeropharma, Bristol-Myers Squibb, Amgen, MedImmune, Nektar, and Genentech.

References 1. Sznol M, Kluger HM, Callahan MK, et al: Survival, response duration, and activity by BRAF mutation status of nivolumab and ipilimumab concurrent therapy in advanced melanoma. ASCO B:7.75” Annual Meeting. Abstract LBA9003. Presented June 2, 2014. T:7” S:6.5”HM, Callahan 2. Wolchok JD, Kluger

MK, et al: Safety and clinical activity of nivolumab in combination with ipilimumab in patients with advanced melanoma. ASCO Annual Meeting. Abstract 9012. Presented June 1, 2013. 3. Wolchok JD, Kluger H, Callahan MK, et al: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122133, 2013.

■■ Concurrent treatment with the ipilimumab and nivolumab led to a 2-year overall survival rate of 79% in advanced melanoma.

Now

■■ Among responders, 88% had ongoing responses at the time of analysis. ■■ Grade 3/4 toxicity was 62%, but the investigators felt that clinicians can manage this, with proper education.

were easily reversible, he said. Approximately 23% of patients discontinued the combination therapy due to treatment-related adverse events. Most of the toxicity occurred during induction, not maintenance, and in “the vast majority” of patients, all adverse events were reversible, he said. One drug-related death occurred in the latest cohort, a consequence of colitis. “We feel fairly confident that these are adverse events that can be managed with a little bit of education and training. It certainly appears as though the

Contact

The ASCO Post

BLADDER

Enrolling A Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (UBC) (NCT02108652, Study ID GO29293)

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

Patients with locally advanced or metastatic UBC who are treatment-naïve and ineligible for cisplatin-based chemotherapy or have failed platinum-containing therapy

Primary Endpoint:

N=330

MPDL3280A1 (an engineered anti-PDL1 antibody)

Secondary Endpoints:

• Objective response rate

• Duration of response • Progression-free survival • Overall survival • Safety: incidence of adverse events • Incidence of antitherapeutic antibodies

to MPDL3280A • Maximum serum concentration (Cmax)

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

of MPDL3280A

Key Inclusion Criteria 2: • Documented locally advanced or metastatic

Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654

•

Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

•

Advertising

Rates, reprints, or supplements

Key Exclusion Criteria 2:

• • • •

transitional cell carcinoma of the urothelium Representative tumor specimens ECOG performance status of 0-1 Life expectancy ≥12 weeks Measurable disease, as defined by RECIST v1.1 Adequate hematologic and end-organ function Refractory or ineligible for platinum-based chemotherapy

• History of autoimmune disease • Active hepatitis B or hepatitis C • HIV-positive • Administration of a live, attenuated vaccine

within 4 weeks before Cycle 1, Day 1 • Prior treatment with CD137 agonists, or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

The ASCO Post | JULY 10, 2014

PAGE 22

FDA Update

FDA Advisory Committee Votes Against Accelerated Approval for Olaparib in Ovarian Cancer

he U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 11 to 2 that current evidence from clinical studies does not support an accelerated approval for use of olaparib as a maintenance treatment for women with platinum-sensitive relapsed ovarian cancer who have the germline BRCA mutation, and who are in complete or partial response to platinumbased chemotherapy. The ODAC provides the FDA with independent, expert advice and recommendations, however, the final decision regarding approval is made by the FDA. The FDA granted priority review status for the New Drug Application (NDA) in April and set a Pre-

scription Drug User Fee Act (PDUFA) action date of October 3, 2014. The NDA filing was based on a subgroup analysis of phase II data recently published in The Lancet Oncology.1 The phase II study was a randomized, double-blind, placebo-controlled trial that

evaluated olaparib vs placebo as maintenance treatment in platinum-sensitive relapsed serous ovarian cancer patients who had received previous treatment with at least two platinum regimens and were in a maintained partial or

complete response following their last platinum regimen. The study met its primary endpoint of progression-free survival. A predefined subgroup analysis was conducted in patients who have germline BRCA mutations.

Phase III Study Underway A phase III trial (SOLO) has been initiated to evaluate the efficacy and safety of olaparib as a maintenance monotherapy in patients with BRCAmutated ovarian cancer patients who are in complete or partial response following platinum-based chemotherapy in the relapsed setting. There are few treatment options available for patients with germline BRCA-mutated serous ovarian cancer,

said Briggs Morrison, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, in a statement. “[W]e are continuing with our phase III clinical program to evaluate the benefit of olaparib for this patient population. We aim to have completed this study by the end of 2015.” n Reference 1. Ledermann J, Harter P, Gourley C,, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed srous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomized phase 2 trial. Lancet Oncol. May 30, 2014 (early release online).

News

Stronger Nicotine Dependency Associated With Higher Lung Cancer Risk

study by investigators at the National Cancer Institute (NCI) has indicated that people who are highly addicted to nicotine, ie, those who smoke their first cigarette within 5 minutes after awakening, are at higher risk of developing lung cancer than those who wait for 1 hour or more to smoke. The researchers found this measure of nicotine dependency improved lung cancer risk prediction beyond standard smoking measures, such as cigarettes per day, age, gender, history of chronic obstructive pulmonary disease and other lung

cancer risk factors. The results of this study were published online in the Journal of the National Cancer Institute.1 Neil E. Caporaso, MD, Senior Investigator, and Fangyi Gu, MMed, ScD, Postdoctoral Fellow, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, and their colleagues, analyzed data from about 1,800 lung cancer patients and 1,400 people without cancer from five cities in the Lombardy region in Italy. The researchers observed that people who had smoked their first

cigarette within 5 minutes of waking up had more than three times the risk of lung cancer compared with those who waited longer than an hour before smoking their first cigarette of the day, after taking into account other smoking characteristics, age and gender. The increased risks were observed for each category of cigarette per day, as well as each category of smoking history. Assessing time to a first cigarette may help clinicians quickly assess lung cancer risk. The findings underscore the need for even light smokers to quit,

because even light smokers who are, or who become dependent smokers, can be at substantial risk for developing lung cancer. The researchers plan to investigate the effect of nicotine addiction on risk for other health outcomes in future studies. n Reference 1. Gu F, Wacholder S, Kovalchik S, et al: Time to smoke first morning cigarette and lung cancer in a case-control study. J Natl Cancer Inst. June 19, 2014 (early release online).

Don’t Miss These Important Reports in This Issue of The ASCO Post Eleni Efstathiou, MD, PhD, on predictors of resistance in prostate cancer see page 8

Nathan Fowler, MD, on R2-CHOP in large cell lymphoma see page 13

Jeffrey S. Weber, MD, PhD, on nivolumab/ipilimumab in advanced melanoma see page 20

Lisa A. Carey, MD, on ado-trastuzumab emtansine in HER2-positive breast cancer see page 31

A. Kim Ritchey, MD, on pediatric hematology/oncology see page 51

Blase N. Polite, MD, MPP, on disparities in cancer care see page 69

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | JULY 10, 2014

PAGE 23

Issues in Oncology Quality of Care

Navigating Cancer in the Era of Personalized Medicine: Rev 2014 Explores Emerging Issues, Ideas for Action By Caroline McNeil

iagnosed with stage IV non– small cell lung cancer in 2011, Stephen Wright turned to patient support groups where he learned about the anaplastic lymphoma kinase (ALK) mutation and a new drug that targeted it, crizotinib (Xalkori). He asked—then insisted—that he be tested for the mutation. He found he was ALK-positive. He subsequently spent 4 hours on the phone convincing his insurance company to cover the drug, which had just been approved by the U.S. Food and Drug Administration.

Bradley Ozenberger, PhD

Two and a half years later, Stephen chased his children up and down the National Mall in Washington while waiting to attend Rev 2014, a forum focused on navigating cancer in the era of personalized medicine. For the oncologists, nurses, pathologists, patient advocates, and others gathered across from the Mall, his story encapsulated many of the issues they were there to talk about. Stephen is not the only one, said Bradley Ozenberger, PhD, of The Genome Institute at Washington University in an opening talk. Occasionally, other patients with advanced cancer have had the luck to find and benefit from a new targeted drug. “But how do we make the leap to have it work for everyone?” he asked. Answers to that question over the next 2 days ranged from greater patient engagement with their own diagnosis

son back in personalized medicine,” said Jimmie C. Holland, MD, who is Chair in Psychiatric Oncology at Memorial Sloan Kettering Cancer Center. In one talk, Frederica Williams, MBA, FCIS (UK), President and CEO of Whittier Street Health in the RoxDoug Ulman

and treatment, to a new understanding of quality of care that incorporates personalized medicine, to better access to data, including good and timely information for providers, pathologists, and patients about biomarkers, targeted drugs, and their companion diagnostics. Convened by the LIVESTRONG Foundation and Genentech, and with ASCO’s Conquer Cancer Foundation a featured participant, Rev 2014 (see sidebar below) was designed to generate new ideas and partnerships to address these issues. “The hope is that real, tangible actions will result,” said LIVESTRONG’s President and CEO, Doug Ulman.

Engaging and Empowering Patients Patient engagement, empowerment, and navigation were strong themes throughout the meeting. “We need communication about per-

Frederica Williams

sonalized medicine, … we need to pay attention to the psychosocial issues with targeted therapy, we need to put the per-

About Rev

We need communication about personalized medicine, … we need to pay attention to the psychosocial issues with targeted therapy, we need to put the person back in personalized medicine. —Jimmie C. Holland, MD

bury section of Boston, described a patient navigation program for the clinic’s mostly low-income, high-risk cancer patients. Although Dana-Farber Cancer Center is nearby, some of the Whittier Street patients were not comfortable going there, she said. After several years of planning, Whittier now has a community-based cancer center run by Dana-Farber in their building, staffed by medical oncologists and a nurse care coordinator. The nurse also serves as the patient navigator meets them at the door of the cancer center and guides them through their visit. Not only are the Whittier Street patients getting excellent cancer care, she said, but clinical trial participation has increased dramatically. About 8.9% of the Whittier Street patients are participating in clinical trials—nearly three times the national average of 2.9%. Patient navigation and engagement intertwines with the other key issues in personalized medicine. As Steven’s story showed, it is even important when it comes to tumor tissue testing, said Kimberly Allison, MD, a breast cancer pathologist at Stanford. Pathologists look for certain biomark-

■■ Rev is a collaborative forum of individuals in the cancer community, including clinicians, patients, patient advocates, business leaders, policy makers, and other leaders in oncology to discuss issues, build collaborations, and identify actions that are needed to improve the lives of people affected by cancer. The ultimate goal of Rev is to create actionoriented solutions to the most critical issues in cancer care. ■■ Rev was co-developed by the LIVESTRONG Foundation and Genentech. ■■ ASCO’s Conquer Cancer Foundation was a featured participant in Rev 2014.

ers routinely, such as estrogen receptor and HER2 status in breast cancer, she said, but it is not necessarily standard practice to test for the newer and less common markers, such as ALK in lung cancer. “Patients need to know when to ask

Kimberly Allison, MD

for additional testing,” she said. “Improving the quality of patient questions improves quality of care.” And the need for such questions is only going to grow.

Data Access “The discovery of new mutation subtypes that might be targeted is going on rapidly now—every week or

Clifford A. Hudis, MD, FACP

so there’s a new one,” said ASCO Immediate Past President Clifford A. Hudis, MD, FACP. “How can we make sure everyone has access to this information—that is our task.” Making better use of electronic health records is one of the answers, he said. ASCO’s CancerLinQ, now in development, will enable physicians to enter their own patients’ records (deidentified) into a shared database. That will create a trove of data for analysis, feedback, and insight, helping to “ensure that every cancer patient and physician, wherever they are, has the very latest knowledge at their fingertips,” in the words of CancerLinQ’s website (www.asco.org/quality-guidelines/ cancerlinq). A related theme in the era of personcontinued on page 24

The ASCO Post | JULY 10, 2014

PAGE 24

Issues in Oncology Rev 2014 Meeting continued from page 23

alized medicine is the prominence of technology, not only for accessing data but also for patient empowerment. “Technology gives us the ability to be our own advocate in conjunction with community,” said Alicia C. Staley, the CEO of Akari Health, a consulting group based in Boston. The company advises clients on how to use social media and social networks to build relationships with patient communities. “Information is key to personalized medicine,” said another speaker, Gena Cook, CEO of Navigating Cancer in Seattle. Her company provides cancer programs with a branded, online patient education and support services.

Tangible Actions After a day of presentations and roundtable discussions, participants

E. Blair Holladay, PhD

split up into small groups to talk about possible solutions in the areas of patient engagement, quality of care including tissue diagnostics, and data access and technology. In one of the tissue diagnostic groups, facilitator E. Blair Holladay, PhD, Executive Vice President of the American Society for Clinical Pathology, and others identified barriers to extensive biomarker testing, including the trend to smaller biopsies, which may not yield enough tissue for multiple tests and the need to bank tissue within an hour so the RNA remains intact.

Grant Announcement Funding up to $50,000 is available from Genentech for projects that address unmet needs related to patient empowerment, patientcentric use of data and technology, and psychosocial and emotional support. Applications are due July 31st. For more information, visit http://www.gene.com/good/ grants-giving.

They also discussed the need for more standardization and guidelines on what tests to perform for specific tumors. “The more [guidelines] the better,” said William Cance, MD, FACS, Surgeon-in-Chief at Roswell Park Cancer Institute. Another group, with Stanford’s Dr. Allison, talked about the need for pa-

tient engagement at the tissue diagnostics stage. Ideas included making sure patients know that the treatment plan is based on tissue diagnostics, having an online portal with patient translations of pathologist report terms, and letting patients know they can get a second opinion on their tissue. Ideas for action that emerged from

all the groups will be included in a white paper on the forum. “Today was just the start,” said LIVESTRONG’s Mr. Ulman. “The actions to follow are key…. Interaction to action is our main objective.” n Disclosure: Drs. Holland, Williams, Allison, and Hudis, and Mr. Holladay reported no potential conflicts of interest.

ASCOPost.com | JULY 10, 2014

PAGE 25

Announcements

National Institutes of Health Names New Council Members

he National Institutes of Health has announced the appointment of nine individuals to the NIH Council of Councils. The Council was established to advise the NIH Director on policies and activities of the Division of Program Coordination, Planning, and Strategic Initiatives

(DPCPSI), including making recommendations on research that represents important areas of emerging scientific opportunities, rising public health challenges, or knowledge gaps that deserve special emphasis or would otherwise benefit from strategic planning and coordination.

The council is composed of 27 members nominated by the NIH Institutes and Centers and from the Council of Public Representatives, an advisory committee to the NIH Office of the Director. Council members bring knowledge of institutes and centers and Office of the Director Of-

When you and your patient face the challenge of advanced medullary thyroid cancer (MTC),

Lead the way

with

FDA-approved in April 2011 as the ﬁrst medication for advanced MTC.1 CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

Important Safety Information, Including Boxed WARNING, for CAPRELSA WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH • CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA • Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration • Monitor electrolytes periodically • Avoid drugs known to prolong the QT interval • Only prescribers and pharmacies certiﬁed with the restricted distribution program are able to prescribe and dispense CAPRELSA To prescribe CAPRELSA, you must enroll in the CAPRELSA REMS Certiﬁcation Enrollment Program and complete the prescriber training program. Please see following pages for more information on the CAPRELSA REMS Program. Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

Lead Forward

fice missions and operations, not as official representatives, but to provide advice beyond the research agenda of any individual institute or center. “I am delighted to welcome this distinguished group of leaders to the Councontinued on page 26

The ASCO Post | JULY 10, 2014

PAGE 26

Announcements

continued from page 25

cil of Councils. Collectively the council will inform our approach to foster new ideas based on analysis of the science. We will benefit greatly from their diverse perspectives, insight, and experience.” said DPCPSI Director, James M. Anderson, MD, PhD.

The following members will serve terms on the council through Oct. 31, 2016: • Philip O. Alderson, MD, Saint Louis University • Marlene Belfort, PhD, University of Albany, State University of New York • Ana M. Cuervo, MD, PhD, Albert Einstein College of Medicine,

• • • •

Bronx, New York Judy E. Garber, MD, MPH, Dana Farber Cancer Institute and Harvard Medical School, Boston Lila Gierasch, PhD, University of Massachusetts, Amherst King K. Holmes, MD, PhD, University of Washington, Seattle Norma Sue Kenyon, PhD, University

of North Carolina Chapel Hill School of Medicine • Norbert J. Pelc, ScD, Richard M. Lucas Center for Imaging, Clark Center, Stanford, California A roster of the full Council of Councils with further information about the members is posted on the Council’s website, http://dpcpsi.nih.gov/council/index n

In the treatment of advanced medullary thyroid cancer (MTC),

CAPRELSA Signiﬁcantly Prolonged Progression-Free Survival (PFS)* vs Placebo in the ZETA Study2 65% Relative Reduction in Risk of Progression2 HR=0.35 (95% CI: 0.24, 0.53) P<.0001

1.0

Median PFS not reached Progression-free survival

NIH Council Members

(95% CI: 22.6 months, non-estimable)

0.75

Results from a phase 3, international, randomized, double-blind, placebocontrolled trial in adult patients (N=331) with unresectable locally advanced or metastatic MTC. At disease progression, patients had the option to receive open-label CAPRELSA.2,3

0.50 2

16.4 months median PFS (95% CI: 8.3, 19.7)

0.25

CAPRELSA 300 mg

Placebo

59/231

41/100

Events/Patients

0.0 0

Months Number at Risk CAPRELSA 300 mg

231

173

145

118

Placebo

100

Risk of Progression

Overall Survival (OS)

Subgroup analysis showed similar PFS results for2: • Symptomatic patients HR=0.31 (95% Cl: 0.19, 0.53) • Patients who had progressed within 6 months prior to ZETA study enrollment HR=0.41 (95% Cl: 0.25, 0.66)

• First OS analysis: at the time of the primary analysis of PFS, 15% of patients had died. There was no significant difference in OS between the 2 treatment groups2 • Further OS analysis will take place when ≥50% of patients have died3

Additional Important Safety Information for CAPRELSA (contd) • Do not use in patients with congenital long QT syndrome • CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA • Do not start CAPRELSA treatment in patients whose QTcF interval (corrected QT interval, Fridericia) is greater than 450 ms or who have a history of Torsades de pointes, bradyarrhythmias, or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction • Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose

• Because of the risk of QT prolongation, obtain an ECG and serum potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Following any dose reduction or interruptions greater than 2 weeks, conduct QT assessments as described above • Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions • Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation

ASCOPost.com | JULY 10, 2014

PAGE 27

Awards

American Association for the Advancement of Science Cancer Research Award

he American Association for the Advancement of Science (AAAS) has named Li Ma, PhD, of The University of Texas MD Anderson Cancer Center, and Jeffrey Tyner, PhD, of Oregon Health & Science University, co-winners of the dis-

tinguished Martin and Rose Wachtel Cancer Research Award. Dr. Ma is Assistant Professor of Experimental Radiation Oncology at MD Anderson. Dr. Tyner is a Professor at Oregon Health & Science University. The Wachtel Award is an annual

prize that honors early career investigators performing outstanding work in cancer research. Winners receive $25,000, deliver a public lecture on their research, and have their award entry essay published in the journal Science Translational Medicine. n

Additional Important Safety Information for CAPRELSA • Interstitial lung disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Interrupt CAPRELSA for acute or worsening pulmonary symptoms and discontinue CAPRELSA if ILD is confirmed • Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event • Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage • Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA • Diarrhea of Grade 3 or greater severity occurred in patients receiving CAPRELSA. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea and upon improvement resume CAPRELSA at a reduced dose • Increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA treated patients. Obtain TSH at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly • Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA

• Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS • Avoid administration of CAPRELSA with anti-arrhythmic drugs and other drugs that may prolong the QT interval • Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis • CAPRELSA is not recommended for patients with moderate and severe hepatic impairment, as safety and efficacy have not been established • CAPRELSA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid pregnancy and be advised that they must use effective contraception during CAPRELSA treatment and for at least 4 months following the last dose of CAPRELSA • The most commonly reported adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5% are diarrhea/ colitis (57%), rash (53%), acneiform dermatitis (35%), hypertension (33%), nausea (33%), headache (26%), upper respiratory tract infections (23%), decreased appetite (21%), and abdominal pain (21%) • CAPRELSA REMS Program: Because of the risks of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com

Affordable Access May Be Available With CAPRELSA Patient Access Services (CPAS) For more information, contact the CPAS Program at 1-800-367-4999 or visit www.CAPRELSACPAS.com Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages. * PFS is deﬁned as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment. 3 Centralized, independent blinded review of the imaging data was used in the assessment of PFS. 2 References: 1. FDA Web site. US Department of Health and Human Services, Food and Drug Administration. Notable FY 2011 approvals. http://www.fda.gov/AboutFDA/Reports ManualsForms/Reports/ucm276413.htm. Accessed March 27, 2014. 2. CAPRELSA [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013. 3. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.

2977331

4/14

www.LeadWithCAPRELSA.com

Li Ma, PhD

Jeffrey Tyner, PhD

The ASCO Post | JULY 10, 2014

PAGE 28

Announcements

Raja Flores, MD, Named Chair of New Thoracic Surgery Department at Mount Sinai

he Mount Sinai Health System has announced the creation of a new academic Department of Thoracic Surgery at the Icahn School of Medicine at Mount Sinai in New York. Raja M. Flores, MD, will be the Founding Chairman of the Department for the

Mount Sinai Health System. Dr. Flores, the Steven and Ann Ames Professor in Thoracic Surgery, will lead an established team of thoracic surgeons, as well as a broader coalition of newly recruited physicians and scientists, across the Health Sys-

tem. The Department will provide clinical care, conduct research, and offer educational activities

Raja M. Flores, MD

focused on acquired and congenital diseases of the thoracic cavity, including the lungs, esophagus, and chest wall. Dr. Flores is recognized for his pioneering efforts in the treatment of mesothelioma. n

Heart Heart Failure Failure HeartHeart failure, failure, including including fatalities, fatalities, occurred occurred in patients in patients treated treated with with CAPRELSA. CAPRELSA. Monitor Monitor for signs for signs and symptoms and symptoms of of heartheart failure. failure. Consider Consider discontinuation discontinuation of CAPRELSA of CAPRELSA in patients in patients with with heartheart failure. failure. HeartHeart failure failure may may not not be be reversible reversible uponupon stopping stopping CAPRELSA. CAPRELSA. Tablets Tablets forfor Oral Oral Use Use Diarrhea Diarrhea Diarrhea Diarrhea of Grade of Grade 3 or 3greater or greater severity severity occurred occurred in 11% in 11% of patients of patients receiving receiving CAPRELSA CAPRELSA in thein randomized the randomized MTCMTC BRIEF BRIEF SUMMARY. SUMMARY. Before Before prescribing, prescribing, please please see full see Prescribing full Prescribing Information. Information. study. study. If diarrhea If diarrhea occurs, occurs, carefully carefully monitor monitor serum serum electrolytes electrolytes and and ECGsECGs to reduce to reduce the risk the risk and and enable enable earlyearly detection detection of QTofprolongation QT prolongation resulting resulting fromfrom dehydration dehydration [see [see Warnings Warnings and Precautions]. and Precautions]. Interrupt Interrupt CAPRELSA CAPRELSA for for WARNING: QT PROLONGATION, TORSADES DE POINTES, ANDAND SUDDEN DEATH WARNING: QT PROLONGATION, TORSADES DE POINTES, SUDDEN DEATH severe severe diarrhea. diarrhea. UponUpon improvement, improvement, resume resume CAPRELSA CAPRELSA at a reduced at a reduced dosedose [see [see Dosage Dosage and Administration]. and Administration]. CAPRELSA can prolong the QT Torsades de pointes and and sudden deathdeath havehave occurred in patients CAPRELSA can prolong theinterval. QT interval. Torsades de pointes sudden occurred in patients Hypothyroidism Hypothyroidism receiving CAPRELSA. Do not CAPRELSA in patients withwith hypocalcemia, hypokalemia, hypomagnereceiving CAPRELSA. Do use not use CAPRELSA in patients hypocalcemia, hypokalemia, hypomagne- In theInrandomized the randomized MTCMTC studystudy in which in which 90%90% of theofpatients the patients enrolled enrolled had prior had prior thyroidectomy, thyroidectomy, increased increased dosing dosing of of semia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia priorprior to to semia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia thyroid thyroid replacement replacement therapy therapy was was required required in 49% in 49% of CAPRELSA-treated of CAPRELSA-treated patients patients compared compared to 17% to 17% of placeboof placeboCAPRELSA administration. Monitor electrolytes periodically. AvoidAvoid drugsdrugs known to prolong the the QT QT CAPRELSA administration. Monitor electrolytes periodically. known to prolong treated treated patients. patients. Obtain Obtain Thyroid-stimulating Thyroid-stimulating hormone hormone (TSH) (TSH) at baseline, at baseline, at 2 at- 42 weeks - 4 weeks and and 8 - 12 8 -weeks 12 weeks afterafter interval. OnlyOnly prescribers and and pharmacies certified withwith the restricted distribution program are able to to interval. prescribers pharmacies certified the restricted distribution program are able starting starting treatment treatment with with CAPRELSA, CAPRELSA, and every and every 3 months 3 months thereafter. thereafter. If signs If signs or symptoms or symptoms of hypothyroidism of hypothyroidism occur, occur, prescribe dispense CAPRELSA Warnings Precautions]. prescribe and and dispense CAPRELSA [see[see Warnings and and Precautions]. examine examine thyroid thyroid hormone hormone levelslevels and adjust and adjust thyroid thyroid replacement replacement therapy therapy accordingly. accordingly. Hypertension Hypertension INDICATIONS INDICATIONS AND AND USAGE USAGE Hypertension, Hypertension, including including hypertensive hypertensive crisis, crisis, has occurred has occurred in patients in patients treated treated with with CAPRELSA. CAPRELSA. Monitor Monitor all patients all patients CAPRELSA CAPRELSA is indicated is indicated for the fortreatment the treatment of symptomatic of symptomatic or progressive or progressive medullary medullary thyroid thyroid cancer cancer in patients in patients with with for hypertension. for hypertension. DoseDose reduction reduction or interruption or interruption for hypertension for hypertension may may be necessary. be necessary. If hypertension If hypertension cannot cannot be be unresectable unresectable locally locally advanced advanced or metastatic or metastatic disease. disease. Use Use CAPRELSA CAPRELSA in patients in patients with with indolent, indolent, asymptomatic asymptomatic or or controlled, controlled, do not do resume not resume CAPRELSA CAPRELSA [see [see Dosage Dosage and Administration]. and Administration]. slowly slowly progressing progressing disease disease only only afterafter careful careful consideration consideration of theoftreatment the treatment related related risksrisks of CAPRELSA. of CAPRELSA. Reversible Reversible Posterior Posterior Leukoencephalopathy Leukoencephalopathy Syndrome Syndrome DOSAGE DOSAGE AND AND ADMINISTRATION ADMINISTRATION Reversible Reversible posterior posterior leukoencephalopathy leukoencephalopathy syndrome syndrome (RPLS), (RPLS), a syndrome a syndrome of subcortical of subcortical vasogenic vasogenic edema edema The recommended The recommended dosedose of CAPRELSA of CAPRELSA is 300 is 300 mg taken mg taken orallyorally onceonce dailydaily untiluntil disease disease progression progression or unacceptable or unacceptable diagnosed diagnosed by anbyMRI an MRI of theofbrain, the brain, has occurred has occurred in patients in patients treated treated with with CAPRELSA. CAPRELSA. Consider Consider this syndrome this syndrome in any in any toxicity toxicity occurs. occurs. CAPRELSA CAPRELSA may may be taken be taken with with or without or without food.food. Do not Do take not take a missed a missed dosedose within within 12 hours 12 hours of theof the patient patient presenting presenting with with seizures, seizures, headache, headache, visualvisual disturbances, disturbances, confusion confusion or altered or altered mental mental function. function. In clinical In clinical next next dose.dose. Do not Do crush not crush CAPRELSA CAPRELSA tablets. tablets. The The tablets tablets can can be dispersed be dispersed in 2 inounces 2 ounces of water of water by stirring by stirring for for studies, studies, threethree of four of four patients patients who who developed developed RPLSRPLS whilewhile taking taking CAPRELSA CAPRELSA also also had had hypertension. hypertension. Discontinue Discontinue approximately approximately 10 minutes 10 minutes (will (will not completely not completely dissolve). dissolve). Do not Douse not other use other liquids liquids for dispersion. for dispersion. Swallow Swallow immediimmediCAPRELSA treatment treatment in patients in patients with with RPLS. RPLS. atelyately afterafter dispersion. dispersion. Mix any Mix remaining any remaining residue residue with with 4 additional 4 additional ounces ounces of water of water and swallow. and swallow. The dispersion The dispersion can canCAPRELSA Drug Drug Interactions Interactions also also be administered be administered through through nasogastric nasogastric or gastrostomy or gastrostomy tubes. tubes. AvoidAvoid administration administration of CAPRELSA of CAPRELSA with with anti-arrhythmic anti-arrhythmic drugsdrugs (including (including but but not not limited limited to amiodarone, to amiodarone, Dosage Dosage Adjustment Adjustment disopyramide, procainamide, procainamide, sotalol, sotalol, dofetilide) dofetilide) and and otherother drugsdrugs that that may may prolong prolong the QT theinterval QT interval (including (including but but For adverse For adverse reactions reactions The 300 The 300 mg daily mg daily dosedose can be canreduced be reduced to 200 to 200 mg (two mg (two 100 100 mg tablets) mg tablets) and then and then to 100 to 100 mg mgdisopyramide, not limited not limited to chloroquine, to chloroquine, clarithromycin, clarithromycin, dolasetron, dolasetron, granisetron, granisetron, haloperidol, haloperidol, methadone, methadone, moxifloxacin, moxifloxacin, and and for Common for Common Terminology Terminology Criteria Criteria for Adverse for Adverse Events Events (CTCAE) (CTCAE) Grade Grade 3 or 3greater or greater toxicities. toxicities. pimozide) pimozide) [see [see DrugDrug Interactions Interactions and Clinical and Clinical Pharmacology Pharmacology (12.2) (12.2) in fullinPrescribing full Prescribing Information]. Information]. Interrupt Interrupt CAPRELSA CAPRELSA for the forfollowing: the following: Renal Impairment Impairment • Corrected • Corrected QT interval, QT interval, Fridericia Fridericia (QTcF) (QTcF) greater greater thanthan 500 500 ms: ms: Resume Resume at a reduced at a reduced dosedose whenwhen the QTcF the QTcF returns returnsRenal Vandetanib Vandetanib exposure exposure is increased is increased in patients in patients with with impaired impaired renalrenal function. function. Reduce Reduce the starting the starting dosedose to 200 to 200 mg inmg in to less to less thanthan 450 450 ms. ms. patients with with moderate moderate to severe to severe renalrenal impairment impairment and and monitor monitor the QT the interval QT interval closely. closely. ThereThere is noisinformation no information • CTCAE • CTCAE GradeGrade 3 or greater 3 or greater toxicity: toxicity: Resume Resume at a reduced at a reduced dosedose whenwhen the toxicity the toxicity resolves resolves or improves or improves to CTCAE to CTCAE GradeGrade 1. 1.patients available for for patients patients with with end-stage end-stage renalrenal disease disease requiring requiring dialysis dialysis [see [see Boxed Boxed Warning, Warning, Dosage Dosage and and For recurrent For recurrent toxicities, toxicities, reduce reduce the dose the dose of CAPRELSA of CAPRELSA to 100 to 100 mg after mg after resolution resolution or improvement or improvement to CTCAE to CTCAE Grade Gradeavailable Administration, Use Use in Specific in Specific Populations Populations and Clinical and Clinical Pharmacology Pharmacology (12.3) (12.3) in fullinPrescribing full Prescribing Information Information ]. ]. 1 severity, 1 severity, if continued if continued treatment treatment is warranted. is warranted. Because Because of the of 19-day the 19-day half-life, half-life, adverse adverse reactions reactions including including a aAdministration, Hepatic Hepatic Impairment Impairment prolonged prolonged QT interval QT interval may may not resolve not resolve quickly. quickly. Monitor Monitor appropriately appropriately [see [see Warnings Warnings and Precautions]. and Precautions]. CAPRELSA is notis recommended not recommended for use for in usepatients in patients with with moderate moderate and and severe severe hepatic hepatic impairment, impairment, as safety as safety and and For patients For patients with with renalrenal impairment impairment Reduce Reduce the starting the starting dosedose to 200 to 200 mg in mgpatients in patients with with moderate moderate (creatinine (creatinineCAPRELSA efficacy efficacy have have not been not been established established [see [see Dosage Dosage and Administration]. and Administration]. clearance clearance ≥30≥to30<to50<mL/min) 50 mL/min) and and severe severe (creatinine (creatinine clearance clearance <30<mL/min) 30 mL/min) renalrenal impairment impairment [see [see Warnings Warnings and Precautions and Precautions and Use and Use in Specific in Specific Populations]. Populations]. Embryofetal Embryofetal Toxicity Toxicity For patients For patients with with hepatic hepatic impairment impairment CAPRELSA CAPRELSA is notisrecommended not recommended for use for in usepatients in patients with with moderate moderate and severe and severeBased Based on itsonmechanism its mechanism of action, of action, CAPRELSA CAPRELSA can cause can cause fetal fetal harmharm whenwhen administered administered to a to pregnant a pregnant woman. woman. In In hepatic hepatic impairment impairment [see [see Use Use in Specific in Specific Populations]. Populations]. nonclinical nonclinical studies studies in rats, in rats, vandetanib vandetanib was was embryotoxic, embryotoxic, fetotoxic, fetotoxic, and and teratogenic teratogenic at exposures at exposures equivalent equivalent to orto or lowerlower thanthan thosethose expected expected at theat recommended the recommended human human dosedose of 300 of 300 mg/day mg/day and and had had adverse adverse effects effects on female on female CONTRAINDICATIONS CONTRAINDICATIONS fertility, fertility, embryofetal embryofetal development, development, and postnatal and postnatal development development of pups. of pups. If thisIf drug this drug is used is used during during pregnancy, pregnancy, or if or if Do not Do use not in usepatients in patients with with congenital congenital longlong QT syndrome QT syndrome [see [see Boxed Boxed Warning]. Warning]. the patient the patient becomes becomes pregnant pregnant whilewhile taking taking this this drug,drug, the patient the patient should should be apprised be apprised of the of potential the potential hazard hazard to a to a WARNINGS WARNINGS AND AND PRECAUTIONS PRECAUTIONS fetus.fetus. Women Women of childbearing of childbearing potential potential should should avoidavoid pregnancy. pregnancy. Advise Advise women women of childbearing of childbearing potential potential that that they they QT QT Prolongation Prolongation andand Torsades Torsades de Pointes de Pointes use effective use effective contraception contraception during during CAPRELSA CAPRELSA treatment treatment and for andatforleast at least four four months months following following the last the dose last dose CAPRELSA CAPRELSA can prolong can prolong the QT theinterval QT interval in a concentration-dependent in a concentration-dependent manner manner [see [see Clinical Clinical Pharmacology Pharmacology (12.2) (12.2) in inmustmust of CAPRELSA [see [see Use Use in Specific in Specific Populations]. Populations]. full Prescribing full Prescribing Information]. Information]. Torsades Torsades de pointes, de pointes, ventricular ventricular tachycardia tachycardia and and sudden sudden deaths deaths havehave occurred occurred in inof CAPRELSA patients patients treated treated with with CAPRELSA. CAPRELSA. Do not Do start not start CAPRELSA CAPRELSA treatment treatment in patients in patients whose whose QTcFQTcF interval interval is greater is greater thanthanCAPRELSA CAPRELSA REMS REMS (Risk (Risk Evaluation Evaluation andand Mitigation Mitigation Strategy) Strategy) Program Program 450 450 ms. ms. Do not Do administer not administer CAPRELSA CAPRELSA to patients to patients who who havehave a history a history of Torsades of Torsades de pointes, de pointes, congenital congenital longlong QT QTBecause Because of the of risk the risk of QTof prolongation, QT prolongation, Torsades Torsades de pointes, de pointes, and and sudden sudden death, death, CAPRELSA CAPRELSA is available is available only only syndrome, syndrome, bradyarrhythmias bradyarrhythmias or uncompensated or uncompensated heartheart failure. failure. CAPRELSA CAPRELSA has has not been not been studied studied in patients in patients with withthrough through a restricted a restricted distribution distribution program program calledcalled the CAPRELSA the CAPRELSA REMS REMS Program. Program. OnlyOnly prescribers prescribers and pharmacies and pharmacies ventricular ventricular arrhythmias arrhythmias or recent or recent myocardial myocardial infarction. infarction. Vandetanib Vandetanib exposure exposure is increased is increased in patients in patients with with impaired impairedcertified certified with with the program the program are able are able to prescribe to prescribe and dispense and dispense CAPRELSA. CAPRELSA. To learn To learn aboutabout the specific the specific REMS REMS requirerequirerenalrenal function. function. Reduce Reduce the starting the starting dosedose to 200 to 200 mg in mgpatients in patients with with moderate moderate to severe to severe renalrenal impairment impairment and andments ments and to andenroll to enroll in theinCAPRELSA the CAPRELSA REMS REMS Program, Program, call 1-800-236-9933 call 1-800-236-9933 or visit or visit www.caprelsarems.com. www.caprelsarems.com. monitor monitor QT interval QT interval frequently. frequently. Obtain Obtain an ECG an ECG and and serum serum potassium, potassium, calcium, calcium, magnesium magnesium and and TSH TSH at baseline, at baseline,ADVERSE ADVERSE REACTIONS REACTIONS 2-4 2-4 weeks weeks and and 8-128-12 weeks weeks afterafter starting starting treatment treatment with with CAPRELSA, CAPRELSA, and and everyevery 3 months 3 months thereafter. thereafter. Monitor MonitorThe following The following serious serious adverse adverse reactions reactions are discussed are discussed elsewhere elsewhere in theinlabel: the label: electrolytes electrolytes and and ECGsECGs moremore frequently frequently in patients in patients who who experience experience diarrhea. diarrhea. Following Following any dose any dose reduction reduction for QT for QT• QT• Prolongation QT Prolongation and Torsades and Torsades de Pointes de Pointes [see [see Boxed Boxed Warning, Warning, Warnings Warnings and Precautions] and Precautions] prolongation prolongation or any or dose any dose interruption interruption greater greater thanthan 2 weeks, 2 weeks, conduct conduct QT assessments QT assessments as described as described above. above. Maintain Maintain• Skin • Skin Reactions Reactions and Stevens-Johnson and Stevens-Johnson Syndrome Syndrome [see [see Warnings Warnings and Precautions] and Precautions] serum serum potassium potassium levelslevels of 4 of mEq/L 4 mEq/L or higher or higher (within (within normal normal range) range) and maintain and maintain serum serum magnesium magnesium and calcium and calcium• Interstitial • Interstitial LungLung Disease Disease [see [see Warnings Warnings and Precautions] and Precautions] levelslevels within within normal normal ranges ranges to reduce to reduce the risk the risk of QTofprolongation. QT prolongation. AvoidAvoid usingusing CAPRELSA CAPRELSA with with drugsdrugs known known to to • Ischemic • Ischemic Cerebrovascular Cerebrovascular Events Events [see [see Warnings Warnings and Precautions] and Precautions] prolong prolong the QT theinterval QT interval [see [see Warnings Warnings and Precautions and Precautions and Drug and Drug Interactions]. Interactions]. If such If such drugsdrugs are given are given to patients to patients • Hemorrhage • Hemorrhage [see [see Warnings Warnings and Precautions] and Precautions] already already receiving receiving CAPRELSA CAPRELSA and and no alternative no alternative therapy therapy exists, exists, perform perform ECG ECG monitoring monitoring of the of QT theinterval QT interval moremore • Heart • Heart Failure Failure [see [see Warnings Warnings and Precautions] and Precautions] frequently. frequently. StopStop CAPRELSA CAPRELSA in patients in patients who who develop develop a QTcF a QTcF greater greater thanthan 500 500 ms until ms until the QTcF the QTcF returns returns to less to less thanthan • Diarrhea • Diarrhea [see [see Warnings Warnings and Precautions] and Precautions] 450 450 ms. ms. Dosing Dosing of CAPRELSA of CAPRELSA can then can then be resumed be resumed at a reduced at a reduced dosedose [see [see Dosage Dosage and Administration]. and Administration]. • Hypothyroidism • Hypothyroidism [see [see Warnings Warnings and Precautions] and Precautions] SkinSkin Reactions Reactions andand Stevens-Johnson Stevens-Johnson Syndrome Syndrome • Hypertension • Hypertension [see [see Warnings Warnings and Precautions] and Precautions] Severe Severe skin skin reactions reactions (including (including Stevens-Johnson Stevens-Johnson syndrome), syndrome), somesome leading leading to death, to death, havehave occurred occurred in patients in patients • Reversible • Reversible Posterior Posterior Leukoencephalopathy Leukoencephalopathy Syndrome Syndrome [see [see Warnings Warnings and Precautions] and Precautions] treated treated with with CAPRELSA. CAPRELSA. Consider Consider permanent permanent discontinuation discontinuation of CAPRELSA of CAPRELSA for severe for severe skin skin reactions reactions [see [see Dosage Dosage • Embryofetal • Embryofetal Toxicity Toxicity [see [see Warnings Warnings and Precautions] and Precautions] and and Administration]. Administration]. Photosensitivity Photosensitivity reactions reactions can occur can occur during during CAPRELSA CAPRELSA treatment treatment and and up toup4 to months 4 months afterafter Clinical Clinical Studies Studies Experience Experience treatment treatment discontinuation. discontinuation. Because Because clinical clinical trialstrials are conducted are conducted underunder widely widely varying varying conditions, conditions, adverse adverse reaction reaction ratesrates observed observed in the in the Interstitial Interstitial Lung Lung Disease Disease clinical trialstrials of a drug of a drug cannot cannot be directly be directly compared compared to rates to rates in theinclinical the clinical trialstrials of another of another drugdrug and may and may not reflect not reflect Interstitial Interstitial LungLung Disease Disease (ILD)(ILD) or pneumonitis, or pneumonitis, including including fatalities, fatalities, has has occurred occurred in patients in patients treated treated with withclinical the rates observed observed in practice. in practice. Patients Patients with with unresectable unresectable locally locally advanced advanced or metastatic or metastatic medullary medullary thyroid thyroid cancer cancer CAPRELSA. CAPRELSA. Consider Consider a diagnosis a diagnosis of ILD of in ILDpatients in patients presenting presenting with with non-specific non-specific respiratory respiratory signssigns and symptoms. and symptoms.the rates treated treated with with CAPRELSA CAPRELSA 300 300 mg (n=231) mg (n=231) or Placebo or Placebo (n=99). (n=99). The population The population exposed exposed to CAPRELSA to CAPRELSA was was 58%58% Interrupt Interrupt CAPRELSA CAPRELSA for acute for acute or worsening or worsening pulmonary pulmonary symptoms. symptoms. Discontinue Discontinue CAPRELSA CAPRELSA if ILDif is ILDconfirmed. is confirmed. werewere male,male, 94%94% white, white, and and had had a median a median age age of 50ofyears. 50 years. The The data data described described below below reflect reflect a median a median exposure exposure to to Ischemic Ischemic Cerebrovascular Cerebrovascular Events Events CAPRELSA for 607 for 607 days.days. The The mostmost commonly commonly reported reported adverse adverse drugdrug reactions reactions which which occurred occurred in >in20% >20% of of Ischemic Ischemic cerebrovascular cerebrovascular events, events, including including fatalities, fatalities, occurred occurred in patients in patients treated treated with with CAPRELSA. CAPRELSA. In the In theCAPRELSA CAPRELSA-treated patients patients and with and with a between-arm a between-arm difference difference of ≥of 5%≥included, 5% included, in order in order of decreasing of decreasing frequency: frequency: randomized randomized medullary medullary thyroid thyroid cancer cancer (MTC) (MTC) study, study, ischemic ischemic cerebrovascular cerebrovascular events events occurred occurred moremore frequently frequentlyCAPRELSA-treated diarrhea/colitis, rash,rash, acneiform acneiform dermatitis, dermatitis, hypertension, hypertension, nausea, nausea, headache, headache, upperupper respiratory respiratory tracttract infection, infection, with with CAPRELSA CAPRELSA compared compared to placebo to placebo (1.3% (1.3% compared compared to 0%). to 0%). The The safety safety of resumption of resumption of CAPRELSA of CAPRELSA therapy therapydiarrhea/colitis, decreased appetite, appetite, and and abdominal abdominal pain.pain. Among Among CAPRELSA-treated CAPRELSA-treated patients, patients, dosedose interruption interruption occurred occurred in 109 in 109 afterafter resolution resolution of anofischemic an ischemic cerebrovascular cerebrovascular eventevent has not hasbeen not been studied. studied. Discontinue Discontinue CAPRELSA CAPRELSA in patients in patients who whodecreased (47%) (47%) and dose and dose reduction reduction occurred occurred in 83in(36%). 83 (36%). Adverse Adverse reactions reactions led toledstudy to study treatment treatment discontinuation discontinuation in 28inof28 of experience experience a severe a severe ischemic ischemic cerebrovascular cerebrovascular event. event. 231 231 patients patients (12%) (12%) receiving receiving CAPRELSA CAPRELSA and and in 3 inof 399of patients 99 patients (3.0%) (3.0%) receiving receiving placebo. placebo. Adverse Adverse reactions reactions Hemorrhage Hemorrhage leading to permanent to permanent discontinuation discontinuation in 2 inor2more or more (≥0.9%) (≥0.9%) patients patients treated treated with with CAPRELSA CAPRELSA were:were: asthenia asthenia Serious Serious hemorrhagic hemorrhagic events, events, including including fatalities, fatalities, occurred occurred in patients in patients treated treated with with CAPRELSA. CAPRELSA. Do not Do administer not administerleading (1.7%), rashrash (1.7%), (1.7%), diarrhea diarrhea (0.9%), (0.9%), fatigue fatigue (0.9%), (0.9%), pyrexia pyrexia (0.9%), (0.9%), elevated elevated creatinine creatinine (0.9%), (0.9%), QT prolongation QT prolongation CAPRELSA CAPRELSA to patients to patients with with a recent a recent history history of hemoptysis of hemoptysis of ≥of 1/2≥teaspoon 1/2 teaspoon of redofblood. red blood. Discontinue Discontinue CAPRELSA CAPRELSA(1.7%), in patients in patients with with severe severe hemorrhage. hemorrhage. (0.9%), (0.9%), and hypertension and hypertension (0.9%). (0.9%).

® ® CAPRELSA CAPRELSA

(vandetanib) (vandetanib)

ASCOPost.com | JULY 10, 2014

PAGE 29

Announcements

James R. Downing, MD, Named CEO of St. Jude Children’s Research Hospital

t. Jude Children’s Research Hospital has announced the appointment of James R. Downing, MD, as its new Chief Executive Officer, effective July 15, 2014. Dr. Downing most recently has served as the Deputy Director, Executive Vice President and Scientific Director

of the hospital. Dr. Downing’s primary focus immediately upon assuming the office of CEO will be to oversee a new era of clinical, research, and infrastructure expansion throughout the St. Jude global network. He succeeds William E. E vans, MD, who is retiring from the

position after 10 years and returning full time to his long-standing pharmacogenomics research program at St. Jude.

Visionary Approach “Dr. Downing is an exceptional scientist whose visionary approach to the

® (vandetanib) ® (vandetanib) CAPRELSA Tablets Tablets CAPRELSA

TableTable 1 – 1Per-Patient – Per-Patient Incidence Incidence of Selected of Selected Adverse Adverse Reactions Reactions Occurring Occurring at a at Higher a Higher Incidence Incidence in in 5%≥5% CAPRELSA-Treated CAPRELSA-Treated Patients Patients During During Randomized Randomized Treatment Treatment [Between-Arm [Between-Arm Difference Difference of ≥of 1] 1] (All Grades) (All Grades) System System OrganOrgan ClassClass Preferred Preferred TermTerm

CAPRELSA CAPRELSA 300 mg 300 mg N=231 N=231

Placebo Placebo N=99N=99

All Grades All Grades (%) (%)

GradeGrade 3-4 3-4 (%) (%)

All Grades All Grades (%) (%)

GradeGrade 3-4 3-4 (%) (%)

Diarrhea/Colitis Diarrhea/Colitis

57 57

11 11

27 27

Nausea Nausea

33 33

16 16

Abdominal Abdominal Pain2Pain2

21 21

11 11

Vomiting Vomiting

15 15

Dyspepsia Dyspepsia

11 11

Dry Mouth Dry Mouth

Gastrointestinal Disorders Gastrointestinal Disorders

TableTable 2 – 2Per-Patient – Per-Patient Incidence Incidence of Selected of Selected Laboratory Laboratory Abnormalities Abnormalities in Patients in Patients withwith MTCMTC Occurring Occurring at a at a 1] 1] Higher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference of ≥of 5%≥(All 5% Grades) (All Grades) Higher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference Laboratory Laboratory Abnormalities Abnormalities CAPRELSA CAPRELSA 300 mg 300 mg Placebo Placebo N = 231 N = 99 N = 231 N = 99 All Grades 3-4 3-4 All Grades 3-4 3-4 All Grades GradeGrade All Grades GradeGrade (%) (%) (%) (%) (%) (%) (%) (%) Chemistries Chemistries Hypocalcemia Hypocalcemia 57 57 6 6 25 25 3 3 ALT Increased ALT Increased 51 51 2 2 19 19 0 0 Hypoglycemia Hypoglycemia 24 24 0 0 7 7 1 1 Creatinine Increased Creatinine Increased 16 16 0 0 1 1 0 0 Hypomagnesemia Hypomagnesemia 7 7 <1 <1 2 2 0 0 Hematologic Hematologic Neutropenia Neutropenia 10 10 <1 <1 5 5 2 2 Thrombocytopenia Thrombocytopenia 9 9 0 0 3 3 0 0 1.

1. CTCAE CTCAE version version 3 was3 used was used to grade to grade laboratory laboratory abnormalities. abnormalities.

No patient No patient with with a Grade a Grade 3-4 ALT 3-4 ALT elevation elevation had ahad concomitant a concomitant increase increase in bilirubin in bilirubin in theinMTC the MTC study. study. DRUG DRUG INTERACTIONS INTERACTIONS 3 3 Effect Effect of CYP3A4 of CYP3A4 Inducers Inducers on CAPRELSA on CAPRELSA RashRash 53 53 5 5 12 12 0 0 Rifampicin, Rifampicin, a strong a strong CYP3A4 CYP3A4 inducer, inducer, decreased decreased vandetanib vandetanib plasma plasma concentrations. concentrations. AvoidAvoid concomitant concomitant use use of of Dermatitis Acneiform/Acne Dermatitis Acneiform/Acne 35 35 1 1 7 7 0 0 known known strong strong CYP3A4 CYP3A4 inducers inducers during during CAPRELSA CAPRELSA therapy. therapy. AvoidAvoid concomitant concomitant use of useSt.ofJohn’s St. John’s WortWort because because it canit can Dry Skin 15 15 0 0 5 5 0 0 Dry Skin decrease decrease vandetanib vandetanib exposure exposure unpredictably unpredictably [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in fullinPrescribing full Prescribing Information]. Information]. Effect Effect of CAPRELSA of CAPRELSA on OCT2 on OCT2 Transporter Transporter Photosensitivity Reaction 13 13 2 2 0 0 0 0 Photosensitivity Reaction CAPRELSA CAPRELSA increased increased plasma plasma concentrations concentrations of metformin of metformin that that is transported is transported by the by organic the organic cation cation transporter transporter Pruritus 11 11 1 1 4 4 0 0 Pruritus type type 2 (OCT2). 2 (OCT2). Use Use caution caution and and closely closely monitor monitor for toxicities for toxicities whenwhen administering administering CAPRELSA CAPRELSA with with drugsdrugs that that are are transported transported by OCT2 by OCT2 [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in full in Prescribing full Prescribing Information]. Information]. 4 4 Nail abnormalities 9 9 0 0 0 0 0 0 Nail abnormalities Effect Effect of CAPRELSA of CAPRELSA on Digoxin on Digoxin Alopecia Alopecia 8 8 N/A N/A 0 0 N/A N/A CAPRELSA CAPRELSA increased increased plasma plasma concentrations concentrations of digoxin. of digoxin. Use Use caution caution and and closely closely monitor monitor for toxicities for toxicities whenwhen administering administering CAPRELSA CAPRELSA with with digoxin digoxin [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in fullinPrescribing full Prescribing Information]. Information]. Vascular Disorders Vascular Disorders Drugs Drugs thatthat Prolong Prolong the the QT QT Interval Interval Hypertension/Hypertensive Hypertension/Hypertensive AvoidAvoid concomitant concomitant use of useCAPRELSA of CAPRELSA with with agents agents that may that may prolong prolong the QT theinterval QT interval [see [see Warnings Warnings and Precautions]. and Precautions]. USEUSE IN SPECIFIC IN SPECIFIC POPULATIONS POPULATIONS Crisis/Accelerated Hypertension Crisis/Accelerated Hypertension 33 33 9 9 5 5 1 1 Pregnancy Pregnancy Pregnancy Pregnancy Category Category D [see D [see Warnings Warnings and Precautions]. and Precautions]. Nervous System Disorders Nervous System Disorders RiskRisk Summary Summary Based Based on itsonmechanism its mechanism of action, of action, CAPRELSA CAPRELSA can cause can cause fetal fetal harmharm whenwhen administered administered to a pregnant to a pregnant woman. woman. Vandetanib Vandetanib is embryotoxic, is embryotoxic, fetotoxic, fetotoxic, and and teratogenic teratogenic in rats, in rats, at exposures at exposures less less thanthan or equal or equal to those to those Headache Headache 26 26 1 1 9 9 0 0 expected expected at theatrecommended the recommended human human dosedose of 300 of 300 mg/day. mg/day. If CAPRELSA If CAPRELSA is used is used during during pregnancy, pregnancy, or if or theifpatient the patient Dysgeusia Dysgeusia 8 8 0 0 3 3 0 0 becomes becomes pregnant pregnant whilewhile taking taking this drug, this drug, the patient the patient should should be apprised be apprised of theofpotential the potential hazard hazard to a fetus. to a fetus. General Disorders General Disorders Animal Animal data data WhenWhen vandetanib vandetanib was was administered administered to female to female rats prior rats prior to mating to mating and through and through the first the week first week of pregnancy of pregnancy at a dose at a dose of 25ofmg/kg/day 25 mg/kg/day (approximately (approximately equalequal to thetohuman the human exposure exposure at theatrecommended the recommended dosedose basedbased on Con maxC),max), 5 5 Fatigue Fatigue 24 24 6 6 23 23 1 1 therethere werewere increases increases in pre-implantation in pre-implantation loss loss and post-implantation and post-implantation loss loss resulting resulting in a reduction in a reduction in theinnumber the number of liveof live Infections Infections embryos. embryos. During During organogenesis, organogenesis, a vandetanib a vandetanib dosedose of 25ofmg/kg 25 mg/kg administered administered to rats to rats caused caused an increase an increase in postin postimplantation implantation loss,loss, including including occasional occasional totaltotal litterlitter loss.loss. At doses At doses greater greater thanthan 10 mg/kg 10 mg/kg (approximately (approximately 0.4 times 0.4 times the the 6 6 Respiratory Infections UpperUpper Respiratory TractTract Infections 23 23 0 0 16 16 0 0 human human exposure exposure at theatrecommended the recommended dosedose by Cby C ) treatment ) treatment with with vandetanib vandetanib resulted resulted in increases in increases in late in embrylate embrymax max Metabolic and Nutritional Disorders Metabolic and Nutritional Disorders ofetalofetal deathdeath and decreases and decreases in fetal in fetal birthbirth weight. weight. A noAeffect no effect levellevel for malformations for malformations was was not identified not identified in this in study. this study. Administration Administration of vandetanib of vandetanib at doses at doses greater greater thanthan or equal or equal to 1 to mg/kg/day 1 mg/kg/day (approximately (approximately 0.030.03 times, times, the Cthe maxCin max in Decreased Appetite 21 21 4 4 12 12 0 0 Decreased Appetite patients patients with with cancer cancer at theatrecommended the recommended dose)dose) resulted resulted in dose in dose dependent dependent increases increases in both in both malformations malformations of theof the Hypocalcemia 11 11 2 2 3 3 0 0 Hypocalcemia heartheart vessels vessels and and skeletal skeletal variations variations including including delayed delayed ossification ossification of theof skull, the skull, vertebrae, vertebrae, and and sternum, sternum, indicating indicating delayed delayed fetal fetal development. development. In a rat In aprerat preand post-natal and post-natal development development study, study, at doses at doses producing producing mildmild maternal maternal toxicity toxicity Investigations Investigations (1 and (1 10 andmg/kg/day) 10 mg/kg/day) during during gestation gestation and/or and/or lactation, lactation, vandetanib vandetanib decreased decreased pup survival pup survival and/or and/or reduced reduced post-natal post-natal 7 7 ECG ECG QT Prolonged 14 14 8 8 1 1 1 1 QT Prolonged pup growth. pup growth. Reduced Reduced post-natal post-natal pup growth pup growth was was associated associated with with a delay a delay in physical in physical development. development. Nursing Nursing Mothers Mothers Eye Disorders Eye Disorders In nonclinical In nonclinical studies, studies, vandetanib vandetanib was was excreted excreted in ratinmilk rat milk and found and found in plasma in plasma of pups of pups following following dosing dosing to lactating to lactating 8 8 Corneal Abnormalities 13 13 0 0 1 1 0 0 Corneal Abnormalities rats.rats. Vandetanib Vandetanib transfer transfer in breast in breast milk milk resulted resulted in relatively in relatively constant constant exposure exposure in pups in pups due to duethetolong the long half-life half-life of theof the drug.drug. It is not It isknown not known whether whether this drug this drug is excreted is excreted in human in human milk.milk. Because Because manymany drugsdrugs are excreted are excreted in human in human milk milk and and Blurred Blurred VisionVision 9 9 0 0 1 1 0 0 because because of theofpotential the potential for serious for serious adverse adverse reactions reactions in nursing in nursing infants infants fromfrom CAPRELSA, CAPRELSA, a decision a decision should should be made be made Disorders RenalRenal Disorders whether whether to discontinue to discontinue nursing nursing or toor discontinue to discontinue the drug, the drug, taking taking into account into account the importance the importance of theofdrug the drug to thetomother. the mother. Pediatric Pediatric UseUse Proteinuria 10 10 0 0 2 2 0 0 Proteinuria Safety Safety and efficacy and efficacy of CAPRELSA of CAPRELSA in pediatric in pediatric patients patients havehave not been not been established. established. Psychiatric Disorders Psychiatric Disorders Geriatric Geriatric UseUse Depression 10 10 2 2 3 3 0 0 Depression The MTC The MTC studystudy of CAPRELSA of CAPRELSA did not did include not include sufficient sufficient numbers numbers of patients of patients agedaged 65 years 65 years and over and over to determine to determine whether whether they they respond respond differently differently compared compared to younger to younger patients. patients. Endocrine Disorders Endocrine Disorders Renal Renal Impairment Impairment Hypothyroidism 6 6 0 0 0 0 0 0 Hypothyroidism Vandetanib Vandetanib exposure exposure is increased is increased in patients in patients with with impaired impaired renalrenal function. function. Reduce Reduce the starting the starting dosedose to 200 to 200 mg inmg in patients patients with with moderate moderate (creatinine (creatinine clearance clearance ≥30≥to30<to50<mL/min) 50 mL/min) and severe and severe (creatinine (creatinine clearance clearance <30<mL/min) 30 mL/min) Musculoskeletal Disorders Musculoskeletal Disorders renalrenal impairment impairment [see [see Dosage Dosage and Administration, and Administration, Warnings Warnings and Precautions, and Precautions, and Clinical and Clinical Pharmacology Pharmacology (12.3) (12.3) in in Muscle Spasms 6 6 0 0 1 1 0 0 Muscle Spasms full Prescribing full Prescribing Information]. Information]. Hepatic Hepatic Impairment Impairment 1. CTCAE 1. CTCAE version version 3 was3 used was used to grade to grade adverse adverse events. events. The The pharmacokinetics pharmacokinetics of CAPRELSA of CAPRELSA werewere evaluated evaluated afterafter a single a single dosedose of 800 of 800 mg inmgsubjects in subjects with with mildmild (n = (n 8),= 8), 2. Includes 2. Includes abdominal abdominal pain, pain, abdominal abdominal pain upper, pain upper, lowerlower abdominal abdominal pain and painabdominal and abdominal discomfort. discomfort. moderate moderate (n = (n 7),=and 7), and severe severe (n = (n 6) =hepatic 6) hepatic impairment impairment and and normal normal hepatic hepatic function function (n = (n 5).=Subjects 5). Subjects with with mildmild 3. Includes 3. Includes rash,rash, rash rash (erythematous, (erythematous, generalized, generalized, macular, macular, maculo-papular, maculo-papular, papular, papular, pruritic, pruritic, and exfoliative), and exfoliative), dermatitis, dermatitis, (Child-Pugh (Child-Pugh class class A), moderate A), moderate (Child-Pugh (Child-Pugh class class B), and B), and severe severe (Child-Pugh (Child-Pugh class class C) hepatic C) hepatic impairment impairment had had dermatitis dermatitis bullous, bullous, generalized generalized erythema, erythema, and eczema. and eczema. comparable comparable meanmean AUCAUC and and clearance clearance values values to those to those with with normal normal hepatic hepatic function. function. ThereThere are limited are limited data data in in 4. Includes 4. 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Includes laryngitis, laryngitis, nasopharyngitis, nasopharyngitis, pharyngitis, pharyngitis, sinusitis, sinusitis, upperupper respiratory respiratory tract tract infection, infection, acuteacute sinusitis, sinusitis, rhinitis, rhinitis, and andrecommended been been established. established. [see [see Dosage Dosage and Administration and Administration and Warnings and Warnings and Precautions]. and Precautions]. tracheitis. tracheitis. Females Females andand Males Males of Reproductive of Reproductive Potential Potential 7. 69% 7. 69% had QT hadprolongation QT prolongation >450ms >450ms and 7% andhad 7%QT hadprolongation QT prolongation >500ms >500ms by ECG by using ECG using Fridericia Fridericia correction. correction. Contraception Females Females of reproductive of reproductive potential potential should should avoidavoid pregnancy. pregnancy. Use Use effective effective contraception contraception during during 8. Includes 8. Includes corneal corneal edema, edema, corneal corneal opacity, opacity, corneal corneal dystrophy, dystrophy, corneal corneal pigmentation, pigmentation, keratopathy, keratopathy, arcusarcus lipoides, lipoides, corneal corneal deposits, deposits,Contraception treatment treatment and up andtoup4 to months 4 months afterafter the last the dose last dose of CAPRELSA. of CAPRELSA. acquired acquired corneal corneal dystrophy. dystrophy. Infertility Infertility ThereThere are no aredata no data on the oneffect the effect of CAPRELSA of CAPRELSA on human on human fertility. fertility. Results Results fromfrom animal animal studies studies indicate indicate that that Clinically Clinically important important uncommon uncommon adverse adverse drugdrug reactions reactions in patients in patients who who received received CAPRELSA CAPRELSA versus versus patients patients who whovandetanib vandetanib can impair can impair malemale and female and female fertility fertility [see [see Nonclinical Nonclinical Toxicology Toxicology (13.1) (13.1) in fullinPrescribing full Prescribing Information]. Information]. received received placebo placebo included included pancreatitis pancreatitis (0.4% (0.4% vs. 0%) vs. 0%) and and heartheart failure failure (0.9% (0.9% vs. 0%). vs. 0%). Blurred Blurred vision vision was was moremoreOVERDOSAGE OVERDOSAGE common common in patients in patients who who received received CAPRELSA CAPRELSA versus versus patients patients who who received received placebo placebo for medullary for medullary thyroid thyroid cancer cancerIn theInevent the event of anofoverdose, an overdose, monitor monitor patients patients closely closely for QTc for prolongation. QTc prolongation. Because Because of theof19-day the 19-day half-life, half-life, adverse adverse (9% (9% vs. 1%, vs. 1%, respectively). respectively). Scheduled Scheduled slit lamp slit lamp examinations examinations revealed revealed corneal corneal opacities opacities (vortex (vortex keratopathies) keratopathies) in inreactions reactions may may not resolve not resolve quickly. quickly. treated treated patients, patients, which which can can lead lead to halos to halos and and decreased decreased visualvisual acuity. acuity. Perform Perform ophthalmologic ophthalmologic examination, examination,Distributed Distributed by:AstraZeneca by:AstraZeneca Pharmaceuticals Pharmaceuticals LP, Wilmington, LP, Wilmington, DE 19850 DE 19850 including including slit lamp slit lamp examination, examination, in patients in patients who who report report visualvisual changes. changes. CAPRELSA CAPRELSA is a registered is a registered trademark trademark of theofAstraZeneca the AstraZeneca group group of companies of companies ClassClass effects effects CAPRELSA CAPRELSA is anisinhibitor an inhibitor of vascular of vascular endothelial endothelial growth growth factorfactor receptor receptor (VEGFR) (VEGFR) signaling. signaling. Inhibition Inhibition© AstraZeneca © AstraZeneca 2014.2014. All Rights All Rights Reserved. Reserved.3/143/14 2975903 29759035/145/14 of VEGFR of VEGFR signaling signaling can can resultresult in intestinal in intestinal perforation. perforation. Intestinal Intestinal perforation perforation occurred occurred in 0.4% in 0.4% of CAPRELSA of CAPRELSA treated treated patients patients versus versus 0% of 0%placebo of placebo treated treated patients. patients. The The incidence incidence of Grade of Grade 1-2 bleeding 1-2 bleeding events events was was 14%14% in in patients patients receiving receiving CAPRELSA CAPRELSA compared compared with with 7% on 7%placebo on placebo in thein randomized the randomized portion portion of theof medullary the medullary thyroid thyroid cancer cancer (MTC) (MTC) study. study. Skin Skin and Cutaneous Disorders and Cutaneous Disorders

next era of growth and discovery at St. Jude will mirror the legacy established by Danny Thomas more than 50 years ago,” said Terry Burman, Chairman of the St. Jude Board of Governors. “Dr. Downing’s seminal contributions to understanding genetic origins of disease, as both the catalyst and leader of the St. Jude Pediatric Cancer Genome Project initiatives, have laid a foundation for a new period of research and treatment of childhood cancer and other life-threatening diseases.” “Today’s intersection of science and technology is paving the way for un-

James R. Downing, MD

precedented discovery and innovative treatment. I am honored to lead an institution that values collaboration and daring, forward-thinking investigation; an institution where the translational goal of our research makes it impossible to separate research from patient care; an organization that provides unsurpassed care for today as we work to identify the next advances and improve cure rates for tomorrow,” Dr. Downing said.

Plans for Expansion Dr. Downing outlined his vision for St. Jude’s next generation of clinical and research expansion, which included the following goals: • Continuing growth in the number of cancer patients treated on the St. Jude campus • Expansion of the institution’s treatment and research program on pediatric solid tumors • Significant expansion of St. Jude’s International Outreach Program • Incorporation of an unprecedented level of comprehensive genomic analyses into the clinical workup of every child treated • Growth in the number of patients enrolled on the St. Jude LIFE longterm follow-up survivor study • Establishment of a formalized patient advocacy consortium. n Watch future issues of The ASCO Post for an in-depth interview with Dr. Downing regarding his vision for St. Jude and his pioneering work in genomics.

The ASCO Post | JULY 10, 2014

PAGE 30

Journal Spotlight Breast Cancer

Ado-Trastuzumab Emtansine Improves Progression-Free Survival vs Physician’s Choice in Advanced HER2-Positive Breast Cancer By Matthew Stenger

here are few treatment options for breast cancer patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic disease. In the open-label phase III TH3RESA trial reported in The Lancet Oncology by Ian E. Krop, MD, PhD, of the Dana-Farber Cancer

performance status 0 to 2 were randomly assigned 2:1 between September 2011 and November 2012 to receive ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 21 days (n = 404) or physician’s choice of treatment (n = 198). Patients were stratified according

Ado-trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib. —Ian E. Krop, MD, PhD

Institute, Boston, and colleagues, adotrastuzumab emtansine (Kadcyla) significantly prolonged progression-free survival compared with physician’s choice of therapy in patients with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab (Herceptin) and lapatinib (Tykerb), and previous taxane therapy in any setting.1 Interim analysis showed an overall survival benefit of ado-trastuzumab emtansine that did not meet the stopping boundary. Ado-trastuzumab emtansine is an antibody-drug conjugate consisting of the cytotoxic agent DM1 linked to trastuzumab. It was recently approved for single-agent use in patients with HER2-positive metastatic breast cancer who had previous treatment with trastuzumab and a concurrent or sequential taxane in any setting on the basis of findings in the phase III EMILIA trial.2 In this trial, ado-trastuzumab emtansine was associated with significant improvements in progression-free and overall survival and less severe toxicity compared with lapatinib plus capecitabine.

Study Details In the TH3RESA trial, 602 adult patients from 22 countries in Europe, North America, South America, and Asia-Pacific with left-ventricular ejection fraction ≥ 50% and Eastern Cooperative Oncology Group (ECOG)

to region (United States vs western Europe vs other), number of previous regimens (2–3 vs > 3), (excluding single-agent hormonal therapy) for the treatment of advanced disease and presence of visceral disease (any vs none). The coprimary endpoints were investigator-assessed progression-free and overall survival in the intentionto-treat population. The current report provides the final progression-free survival analysis and the first interim overall survival analysis. The ado-trastuzumab emtansine and physician’s choice groups were generally balanced for age (median, 53 and 54 years), region (eg, Western Europe for 42% and 43%, United States for 25% and 24%), race (80% and 81% white, 14% and 12% Asian),

94%), measurable disease (85% and 82%), median number of previous regimens for advanced disease (4 in both, including ≤ 3 in 33% and 39%, 4–5 in 37% and 33%, > 5 in 30% and 28%), median duration of exposure to trastuzumab (24 months in both) and lapatinib (8 months in both), and previously treated asymptomatic brain metastases (10% and 14%) In the physician’s choice group, treatment consisted of combinations with a HER2-directed agent in 83%, including trastuzumab plus chemotherapy in 68% and trastuzumab plus lapatinib in 10%, and single-agent chemotherapy in 17%; chemotherapy use with or without HER2-directed therapy included vinorelbine in 32%, gemcitabine in 16%, eribulin (Halaven) in 9%, and paclitaxel in 9%.

Improved Progression-Free Survival At the time of data cutoff (February 11, 2013), 44 patients assigned to physician’s choice had crossed over to ado-trastuzumab emtansine. After a median follow-up of 7.2 months in the ado-trastuzumab emtansine group and 6.5 months in the physician’s choice group, median progression-free survival was 6.2 months vs 3.3 months (stratified hazard ratio [HR] = 0.528, P < .0001). Median progression-free survival was also significantly improved with ado-trastuzumab emtansine compared with the subgroups of physician’s choice patients who received trastuzumab (6.2 vs 3.2 months, stratified HR = 0.558, P < .0001) or did not re-

New Data for Ado-Trastuzumab Emtansine ■■ Ado-trastuzumab emtansine reduced risk of cancer progression or death by 47% compared with physician’s choice of treatment. ■■ An interim analysis of overall survival suggests benefit of ado-trastuzumab emtansine. ■■ Ado-trastuzumab emtansine patients had a lower frequency of grade 3 or worse adverse events.

ECOG performance status (0 in 45% and 41%, 1 in 50% and 51%, 2 in 5% and 8%), hormone receptor status (estrogen receptor– or progesterone receptor–positive in 51% and 52%, estrogen receptor– and progesterone receptor–negative in 46% and 43%), disease extent (metastatic in 97% and

ceive trastuzumab (6.2 vs 3.4 months, stratified HR = 0.428, P < .0001) as part of their regimen. The progression-free survival benefit with ado-trastuzumab emtansine was consistent across subgroups, including significant hazard ratios according to age (0.55 for < 65, 0.42

for 65–74, and 0.14 for ≥ 75 years), hormone receptor status (0.56 for estrogen receptor– or progesterone receptor–positive, 0.51 for estrogen receptor– and progesterone receptor– negative), disease involvement (0.56 for visceral and 0.41 for nonvisceral involvement), number of previous regimens for advanced disease (0.48 for ≤ 3, 0.55 for >3), and previously treated asymptomatic brain metastases (0.47 for yes, 0.53 for no). The progression-free survival benefit was significant in the western Europe and other region subgroups but not in the U.S. subgroup (HR = 0.71, 95% confidence interval = 0.44-1.14). At the time of the first interim overall survival analysis, death had occurred in 15% of the ado-trastuzumab emtansine group and in 22% of the physician’s choice group. Ado-trastuzumab emtansine was associated with reduced risk of death (stratified HR = 0.552, P = .0034); however, the result was not statistically significant, because it did not cross the prespecified O’Brien-Fleming stopping boundary of HR = 0.370 (which would have required a P value < .0000016).

Adverse Events The most common adverse events of any grade in the ado-trastuzumab emtansine group were fatigue (27% vs 25% in the physician’s choice group), asthenia (16% vs 16%), and thrombocytopenia (15% vs 3%). Adverse events of grade 3 or higher occurred in 32% of the ado-trastuzumab emtansine group vs 43% in the physician’s choice group; neutropenia (2% vs 16%), diarrhea (< 1% vs 4%), and febrile neutropenia (< 1% vs 4%) were more common in the physician’s choice group and thrombocytopenia (5% vs 2%) was more common in the ado-trastuzumab emtansine group. Serious adverse events occurred in 18% vs 21% of patients. No patients had a decrease in left-ventricular ejection fraction to < 40% in either group, and 1% of each group had a ≥ 15% absolute decrease in left-ventricular ejection fraction to < 50%. Grade 3 or higher hemorrhage of any type occurred in 9 (2%) ado-trastuzumab emtansine patients and in 1 (< 1%) physician’s choice patient. Adverse events led to dose reduction in 9% vs

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Perspective

Ado-Trastuzumab Emtansine as a Late Treatment for HER2-Positive Metastatic Breast Cancer—Better and Less Toxic Than Physician’s Choice By Lisa A. Carey, MD

H3RESA is a randomized phase III open-label study, reported in The Lancet Oncology and summarized in this issue of The ASCO Post, which examined the activity of adotrastuzumab emtansine (Kadcyla) in heavily pretreated HER2-positive metastatic breast cancer.1 Formerly known as T-DM1, ado-trastuzumab emtansine is an antibody-drug conjugate that includes a cytotoxic agent, the maytansine analog DM1, linked to the anti-HER2 monoclonal antibody trastuzumab (Herceptin). In this way the drug is a Trojan horse—the trastuzumab, which is itself an effective drug, also acts as a vehicle to deliver a potent chemotherapy drug to the intracellular component of HER2positive breast cancer cells. Ado-trastuzumab emtansine was approved for use in the setting of pretreated disease after the EMILIA study, which compared the agent to the commonly used second-line combination of capecitabine plus lapatinib (Tykerb) in patients previously treated with taxane and trastuzumab. This trial proved ado-trastuzumab emtansine to be both more effective, with progression-free survival of 9 months vs 6 months and overall survival of 31 months vs 25 months, and less toxic than the control regimen.2

Dr. Carey is The Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, Division Chief of Hematology and Oncology, Physician-inChief at North Carolina Cancer Hospital, Medical Director of the UNC Breast Center, and Associate Director for Clinical Research, UNC Lineberger Comprehensivce Cancer Center, Chapel Hill, North Carolina.

20% of patients and to discontinuation of treatment in 7% vs 11%. Death occurred in 5 (1%) patients in the ado-trastuzumab emtansine group and in 3 (2%) in the physician’s choice group. Three deaths in the ado-trastuzumab emtansine group (due to hepatic encephalopathy, subarachnoid hemorrhage, and pneumonitis) and one in the physician’s choice group (due to noncardiogenic pulmonary edema) were considered related to study treatment. The investigators noted:

TH3RESA studied ado-trastuzumab emtansine in the more heavily pretreated setting and compared it to treatment of the physician’s choice. TH3RESA was a “win/win”; adotrastuzumab emtansine once again outperformed treatment of the physician’s choice in both progression-free

mone receptor–positive. Enrolled patients were randomly assigned in a 2:1 fashion to ado-trastuzumab emtansine or treatment of the physician’s choice, which could include chemotherapy, endocrine therapy, and/or HER2-targeting, but could not include palliative care alone. Most

TH3RESA confirms that, in addition to benefit in earlier-line treatment shown in the EMILIA trial, ado-trastuzumab emtansine is more effective and less toxic than other options in heavily pretreated patients who have had disease progression on multiple prior HER2targeting regimens. —Lisa A. Carey, MD

survival and toxicity, and there was a trend toward improved overall survival, although this last endpoint is immature.1

TH3RESA Findings The trial design was simple. To be eligible, women needed to have centrally confirmed HER2-positive metastatic breast cancer that had progressed on both trastuzumab and lapatinib and to have previously received a taxane. Participants were heavily pretreated, with a median of four prior lines of therapy. Reflecting the nature of HER2-positive disease, approximately three-quarters of patients had visceral involvement and 50% were both HER2- and horTogether with EMILIA, findings from TH3RESA substantiate the potential of antibody–drug conjugates to achieve a more favourable benefit-to-risk profile than that seen with traditional combinations of chemotherapy and targeted agents in epithelial cancers. Data from these two large phase 3 studies suggest that trastuzumab emtansine is effective across the natural history of HER2-positive advanced breast cancer, spanning from disease with previous exposure only to adjuvant treatment, to

(80%) of the control arm received a trastuzumab-based regimen. The coprimary endpoints of the study were progression-free and overall survival. Progression-free survival in the ado-trastuzumab emtansine arm was 6.2 months vs 3.3 months in the control arm (hazard ratio = 0.53), while interim overall survival analysis revealed a trend toward a survival advantage that did not cross stopping boundaries. In addition to a 3-month improvement in remaining progression-free, patients treated on the ado-trastuzumab emtansine arm had significantly fewer adverse events—only 32% had grade 3 or greater toxicity compared with 43% in the control arm. progressive heavily pretreated disease after regimens incorporating trastuzumab and lapatinib.

They concluded, “Trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib.” n Disclosure: The study was funded by Genentech. For complete disclosures of the study authors, visit www.thelancet.com.

Toxicity of ado-trastuzumab emtansine, which has been lower than the comparator arm in all trials reported to date, was similar to previous reports; 5% had grade 3 or greater thrombocytopenia, and there was no evidence of either clinical or radiologic cardiac toxicity. Forest plot analysis suggested that all patient subsets benefited from adotrastuzumab emtansine. Interestingly, patients with central nervous system involvement by tumor, a particular problem for HER2-positive metastatic breast cancer, appeared to be similarly advantaged by the use of ado-trastuzumab emtansine, with a progression-free survival hazard ratio of 0.47.

HER2 and Oncogene Addiction For many HER2-positive metastatic breast cancers, continued targeting of this oncogene remains effective across multiple lines of therapy. This is why HER2-positive breast cancer is considered an example of “oncogene addiction,” in which the cell becomes solely dependent upon signaling from an individual pathway for growth and proliferation. Clinical evidence in support of this precept continues to mount, including the results of TH3RESA. We now have four approved drugs for metastatic HER2-positive breast cancer—trastuzumab, the anti-HER2 heterodimerization domain monoclonal antibody pertuzumab (Perjeta), the HER1/HER2 small-molecule inhibitor lapatinib, and ado-trastuzumab emtansine. Appropriate use of continued on page 34

References 1. Krop IE, Kim SB, González-Martín A, et al: Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): A randomised, open-label, phase 3 trial. Lancet Oncol. May 1, 2014 (early release online). 2. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.

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References: 1. Nagorsen D, Baeuerle PA. Exp Cell Res. 2011;317:1255-1260. 2. Baeuerle PA, Kufer P, Bargou R. Curr Opin Mol Ther. 2009;11:22-30. 3. Rabinovich GA, Gabrilovich D, Sotomayer EM. Annu Rev Immunol. 2007;25:267-296. 4. Baeuerle PA, Reinhardt C. Cancer Res. 2009;69:4941-4944. 5. Leone P, Shin EC, Perosa F, Vacca A, Dammacco F, Racanelli V. J Natl Cancer Inst. 2013;105:1172-1187. 6. Warrington R, Watson W, Kim HL, Antonetti FR. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S1.

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The ASCO Post | JULY 10, 2014

PAGE 34

Perspective

Lisa A. Carey, MD continued from page 31

these drugs at this point in time, taking TH3RESA into account, includes trastuzumab plus pertuzumab and a taxane in the first-line setting, adotrastuzumab emtansine in the secondline setting, then capecitabine and lapatinib, although many other regimens including HER2-targeted drugs are reasonable. However, it should be noted that since neither EMILIA nor TH3RESA allowed crossover, these recommended lines of treatment serially maximize progression-free survival; it is not at all certain that the order of use matters for overall survival. Studies not yet reported include MARIANNE, a three-arm study in the first-line setting comparing the control arm of taxane plus trastuzumab with

The More Things Change… continued from page 1

The First New Era Have we been here before? When chemotherapies were first developed and tested in the 1950s and 1960s, oncologists were excited—both by the new level of science and by the fact that patients were being cured who in the past would have died. The newspapers told us the War on Cancer was almost over. Suddenly there was a new level of hope about cancer and its treatment. At that time, the targeted therapy was aimed at the organ, not the molecule, but with no less enthusiasm by oncologists. We began to talk about cancer and used the word with patients. Much of the fatalism and fears began to be dissipated. The War on Cancer moved a few more yards down the field. Chemotherapy had many side effects, but most patients were willing to take the risk and try it. In fact, when we asked patients in the 1980s why they accepted chemotherapy treatment, the answer was simple: “ I hoped it would help; I feared doing nothing would be bad; and I trusted the doctor.”1

ado-trastuzumab emtansine or adotrastuzumab emtansine plus pertuzumab. In the adjuvant setting, only trastuzumab added to various chemotherapy regimens is approved (although pertuzumab added to trastuzumab plus chemotherapy gained accelerated approval in the neoadjuvant setting in 2012). Large adjuvant studies incorporating pertuzumab or lapatinib are due to be reported within the next few years, and adjuvant ado-trastuzumab emtansine trials are not far behind. The multiplicity of options available for controlling HER2-positive metastatic disease may within a few years be recapitulated in a menu of (neo)adjuvant options.

Conclusions Ado-trastuzumab emtansine is an excellent addition to the HER2-

targeting armamentarium, although like all HER2-targeted drugs it is extremely expensive at nearly $10,000 per month. The optimal timing of including this treatment is not clear, and establishing optimal timing would be beneficial, since patients with metastatic HER2-positive breast cancer often receive multiple lines of HER2-directed therapy over time. TH3RESA confirms that, in addition to benefit in earlier-line treatment shown in the EMILIA trial, ado-trastuzumab emtansine is more effective and less toxic than other options in heavily pretreated patients who have had disease progression on multiple prior HER2targeting regimens. A role in the first-line and adjuvant settings re-

With all this new hype and high hope for cancer cures, patients who are diagnosed today have higher expectations. As a result, doctor-patient communication has become an even more important part of treatment that cannot be replaced by a computer screen. —Jimmie C. Holland, MD, and James F. Holland, MD

citing. Enthusiastic responses of oncologists to the science and new treatment avenues is understandable, and newspapers still want to sell papers. Patients, too, have new high hopes for cancer cures that will be important for oncology to live up to in the coming years. In fact, human emotions have not

changed at all; they remain predictable across the centuries, with the Ancient Greek virtue of courage still alive and well to help people cope with adversities like cancer. And the basic emotions are the same as we found in the 1980s: hope (“I want to live if I can”) and, most important, trust (“I have trust in my doctor”).

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

Crucial Communication Communication between oncologist and patient becomes all the more crucial in this new era. Patients need to understand the science behind the treatment, or at least have it outlined to them at their level—some will want to know all the facts, and others will say, “I don’t want to hear the details.” Being sure that the decision about treatment is understood and shared is the bottom line. As the complexity of the treatment increases and is less understood by the patient, the responsibility of the doctor increases to be sure that the level of trust is justified when the patient says—and believes, “I know you will do the right thing for me, doc.” With all this new hype and high hope for cancer cures, patients who are diagnosed today have higher expectations. As a result, doctor-patient communication has become an even more important part of treatment that cannot be replaced by a computer screen. n Disclosure: Drs. Holland and Holland reported no potential conflicts of interest.

Oncology Today Fast forward to 2014, and what is different? The science is at a wonderful new and complex level. Genomic medicine is surely different and ex-

mains to be demonstrated, but this is a drug that is clearly good at the two goals of therapy for metastatic breast cancer—disease control and tolerability. n

James F. Holland, MD, and Jimmie C. Holland, MD © ASCO Post

Reference 1. Penman D, Holland JC, Bahna G, et al: Informed consent for investigational chemotherapy: Patients’ and physicians’ perceptions. J Clin Oncol 2:849-855, 1984.

ASCOPost.com | JULY 10, 2014

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Journal Spotlight Breast Cancer

ASCO Clinical Practice Guideline: Disease Management in Advanced HER2-Positive Breast Cancer With Brain Metastases By Matthew Stenger

s many as half of all patients with metastatic HER2-positive breast cancer develop brain metastases over time. The American Society of Clinical Oncology recently released a clinical practice guideline on disease management for patients with advanced HER2positive breast cancer and brain metastases, published in the Journal of Clinical Oncology.1 A companion ASCO clinical practice guideline on systemic therapy for patients with advanced HER2-posi-

based on the best available evidence and clinical experience. The ASCO expert panel was cochaired by Sharon H. Giordano, MD, of The University of Texas MD Anderson Cancer Center, Houston, and Eric P. Winer, MD, of Dana-Farber Cancer Institute, Boston.

Guideline Questions

The overarching question addressed by the clinical practice guideline is: “What is the appropriate course of treatment for patients with HER2-positive advanced breast cancer and brain metastases?” The guideline recommendations are summarized below, according to four associated questions. A recommendation strength of weak was assigned to recommendaSharon H. Giordano, MD Eric P. Winer, MD tions unless otherwise inditive breast cancer has also been published cated; this rating indicates that there is in the Journal of Clinical Oncology (see some confidence that the recommendapage The ASCO Post, June 25, page 63).2 tion offers the best current guidance for The guideline recommendations practice. were developed using evidence from observational studies and clinical expe- Recommendations Does the approach to local therapy of rience. A literature search for evidence on brain metastases was conducted, but brain metastases differ in patients with no publications met the inclusion crite- HER2-positive breast cancer? ria. On review of the available evidence, the ASCO expert panel concluded that Single Brain Metastasis, the majority of the evidence was insuf- Favorable Prognosis ficient to inform evidence-based rec- • Patients with favorable prognosis and a single brain metastasis should ommendations for a traditional ASCO be evaluated by an experienced neuclinical practice guideline. rosurgeon for the option of surgical Thus, the recommendations were resection, particularly if the metastadeveloped by a multidisciplinary sis is > 3 to 4 cm or if there is evigroup of experts and reviewed by a dence of symptomatic mass effect. consensus ratings panel including ra(Evidence quality = intermediate, diation oncologists, neurosurgeons, recommendation strength = strong.) members of the ASCO Breast Cancer Guidelines Advisory Group, and oth- • Patients with favorable prognosis and a single brain metastasis < 3 to ers using a formal consensus process

ASCO Guideline on HER2-Positive Breast Cancer With Brain Metastases ■■ Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated, with local therapies including surgery, wholebrain radiotherapy, and stereotactic radiosurgery. ■■ Treatment depends on factors such as prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. ■■ Clinicians should not perform routine MRI to screen for brain metastases, but should have a low threshold for MRI due to the high incidence of brain metastases in this setting.

4 cm without symptomatic mass effect may be offered either stereotactic radiosurgery or surgical resection, depending on the location and surgical accessibility of the tumor, need for tissue diagnosis, and other considerations, such as medical risk factors for surgery and patient preference. (Evidence quality = intermediate). If such patients choose to undergo stereotactic radiosurgery, clinicians may discuss the options of adding whole-brain radiotherapy to stereotactic radiosurgery. (Evidence quality = intermediate.) • For most patients who undergo surgical resection, clinicians should recommend postoperative radiotherapy to the resection bed to reduce the risk of local recurrence. (Evidence quality = intermediate.) • For patients with favorable prognosis and a single brain metastasis > 3 to 4 cm that is deemed unresectable and unsuitable for stereotactic radiosurgery, clinicians may discuss the options of whole-brain radiotherapy or fractionated stereotactic radiotherapy. (Evidence quality = low.) • After treatment, serial imaging every 2 to 4 months may be used to monitor for local and distant brain failure. (Evidence quality = low.) Limited Metastases, Favorable Prognosis • In patients with favorable prognosis and multiple but limited metastases (2–4), treatment options depend on the size, resectability, and mass effect of the lesions. • For patients with limited metastases suitable for stereotactic radiosurgery, clinicians may discuss stereotactic radiosurgery with or without wholebrain radiotherapy. (Evidence quality = intermediate.) • For patients with a large (> 3 to 4 cm) lesion associated with symptomatic mass effect, clinicians may discuss surgical resection of the larger lesion. Remaining lesions may be treated with stereotactic radiosurgery with or without whole-brain radiotherapy. (Evidence quality = intermediate.) • For patients with lesions that are unresectable and unsuitable for stereotactic radiosurgery, clinicians may recommend whole-brain radiother-

apy and may discuss stereotactic radiosurgery after whole-brain radiotherapy. (Evidence quality = low.) Diffuse Disease/ Extensive Metastases • For patients with symptomatic leptomeningeal brain metastases, clinicians may recommend whole-brain radiotherapy. (Evidence quality = low, recommendation strength = moderate.) • For patients with more favorable prognosis and many diffuse brain metastases (≥ 5), clinicians may recommend whole-brain radiotherapy. (Evidence quality = low.) Poor Prognosis • For patients with poor prognosis, clinicians should discuss the options of best supportive care and/or palliative care, which may or may not include radiation therapy. (Evidence quality = low.) • Patients with symptomatic brain metastases and poor prognosis may be offered whole-brain radiotherapy if there is a reasonable expectation of symptomatic improvement that outweighs acute and subacute treatment-related toxicities. (Evidence quality = low.) Progressive Intracranial Metastases Despite Initial Therapy • For patients with progressive intracranial metastases, treatment options depend on prior therapies, burden of disease, performance status, and overall prognosis. Brain Recurrence and Irradiation, Limited Recurrence • For patients with favorable prognosis and limited recurrence after treatment with whole-brain radiotherapy, clinicians may discuss stereotactic radiosurgery, a trial of systemic therapy, or enrollment onto a clinical trial. For those with favorable prognosis and limited recurrence after treatment with stereotactic radiosurgery, clinicians may discuss repeat stereotactic radiosurgery, surgery, whole-brain radiotherapy, a trial of systemic therapy, or enrollment onto a clinical trial. (Evidence quality = low, recommendation strength = moderate.) continued on page 39

NOW

IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

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

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

Important Safety Information

• In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Rare cases of StevensJohnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Lifethreatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. 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. • Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package

insert for instructions on the identification of patients eligible for treatment with Vectibix®. • Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% 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®.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who

were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS mCRC

• Keratitis and ulcerative keratitis, known risk factors for corneal • Because many drugs are excreted into human milk and because of

perforation, have been reported with Vectibix® use. Monitor for evidence the potential for serious adverse reactions in nursing infants from of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for Vectibix®, a decision should be made whether to discontinue nursing acute or worsening keratitis. or to discontinue the drug, taking into account the importance of • In an interim analysis of an open-label, multicenter, randomized the drug to the mother. If nursing is interrupted, it should not be clinical trial in the first-line setting in patients with mCRC, the resumed earlier than 2 months following the last dose of Vectibix®. addition of Vectibix® to the combination of bevacizumab and ® chemotherapy resulted in decreased OS and increased incidence • Women who become pregnant during Vectibix treatment are of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC encouraged to enroll in Amgen’s Pregnancy Surveillance Program. grade 3-4 adverse reactions occurring at a higher rate in Vectibix®- Women who are nursing during Vectibix® treatment are encouraged treated patients included rash/acneiform dermatitis (26% vs 1%), to enroll in Amgen’s Lactation Surveillance Program. Patients or diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring their physicians should call 1-800-77-AMGEN (1-800-772-6436) in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/ to enroll. mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). ® • NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix in Vectibix®-treated patients (7% vs 3%) and included fatal events were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in three (< 1%) Vectibix®-treated patients. • As a result of the toxicities experienced, patients randomized to in the Vectibix® arm were general physical health deterioration and Vectibix®, bevacizumab, and chemotherapy received a lower mean intestinal obstruction. relative dose intensity of each chemotherapeutic agent (oxaliplatin, • In Study 3, the most commonly reported adverse reactions (≥ 20%) irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first in patients with wild-type KRAS mCRC receiving Vectibix® 24 weeks on study, compared with those randomized to bevacizumab (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were and chemotherapy. • Advise patients of the need for adequate contraception in both males diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, and females while receiving Vectibix® and for 6 months after the last anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, dose of Vectibix® therapy. Vectibix® may be transmitted from the pruritus, and dry skin. Serious adverse reactions (≥ 2% difference mother to the developing fetus, and has the potential to cause fetal between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. harm when administered to pregnant women. References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aflibercept) prescribing information, sanofi-aventis. Avastin is a registered trademark of Genentech, Inc. Erbitux is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap is a registered trademark of Regeneron Pharmaceuticals, Inc. Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 05/14 80389-R1-V1

Visit www.vectibix.com

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)]. 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 in Full Prescribing Information]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information]. limitation of use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information]. DoSage anD aDminiStration Patient Selection Prior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and administration Do not administer Vectibix® as an intravenous push or bolus. contrainDicationS None. WarningS anD PrecautionS Dermatologic and Soft tissue toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. 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 KRAS-mutant mcrc Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14) in Full Prescribing Information]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®. electrolyte Depletion/monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. infusion reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1), 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. acute renal failure in combination with chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary fibrosis/interstitial lung Disease (ilD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. ocular toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. increased mortality and toxicity with Vectibix® in combination with Bevacizumab and chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. aDVerSe reactionS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]

• Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] clinical trials experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from two clinical trials in which patients received Vectibix®: Study 1, an open-label, 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 frequently reported (> 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)

SyStem organ claSS Preferred Term eye DiSorDerS Growth of eyelashes gaStrointeStinal DiSorDerS Nausea Diarrhea Vomiting Stomatitis general DiSorDerS anD aDminiStration Site conDitionS Fatigue Mucosal inflammation infectionS anD infeStationS Paronychia reSPiratory, tHoracic, anD meDiaStinal DiSorDerS Dyspnea Cough SKin anD SuBcutaneouS tiSSue DiSorDerS Erythema Pruritus Acneiform dermatitis Rash Skin fissures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

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

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

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

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

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

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

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

2 (< 1)

2 (< 1) 1 (< 1)

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

SyStem organ claSS Preferred Term eye DiSorDerS Conjunctivitis gaStrointeStinal DiSorDerS Diarrhea Stomatitis general DiSorDerS anD aDminiStration Site conDitionS Mucosal inflammation Asthenia infectionS anD infeStationS Paronychia inVeStigationS Weight decreased metaBoliSm anD nutrition DiSorDerS Anorexia Hypomagnesemia Hypokalemia Dehydration reSPiratory, tHoracic, anD meDiaStinal DiSorDerS Epistaxis

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

folfoX alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

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

46 (14)

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

SyStem organ claSS Preferred Term SKin anD SuBcutaneouS tiSSue DiSorDerS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

Vectibix® Plus folfoX (n = 322) Any Grade Grade 3-4 n (%) 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) 10 (3) 4 (1)

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

30 (9)

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

24 (7)

30 (9)

4 (1)

9 (3)

1 (< 1)

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: Stevens-Johnson syndrome, toxic epidermal necrolysis, skin necrosis, angioedema [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] Drug interactionS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. uSe in SPecific PoPulationS Pregnancy Pregnancy category c. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. nursing mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-7726436) to enroll. Pediatric use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. geriatric use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. oVerDoSage Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient counseling information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

22 (7)

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

folfoX alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved. v20 05/14

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Perspective

ASCO Guideline for Management of Brain Metastases From HER2-Positive Breast Cancer: An Important Framework By Priscilla K. Brastianos, MD, and Daniel P. Cahill, MD, PhD

rain metastases are a devastating complication of cancer, and occur in up to 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer. Management of brain metastases requires individualized coordination between the traditional treatment modalities for intracranial sites of disease, which include surgery, radiosurgery, and/or whole-brain radiation therapy, and the need for ongoing systemic therapy in a patient with metastatic disease. With the increase in screening brain magnetic resonance imaging scans and the prolongation of survival from improved treatment of systemic disease, there is an increasing prevalence of brain metastases in HER2-positive breast cancer patients. Often, these lesions are small and Dr. Brastianos is Director of MGH Brain Metastasis Clinic, Instructor in Medicine, Harvard Medical School, Massachusetts General Hospital, and Dr. Cahill is Assistant Professor in Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston.

Clinical Practice Guideline

Control of brain metastases can become a rate-limiting step in both quality of life and overall survival, and represents a leading edge in the ongoing efforts to improve outcomes for these patients. —Priscilla K. Brastianos, MD, and Daniel P. Cahill, MD, PhD

asymptomatic. Importantly, due to the potential for neurologic morbidity associated with unrestrained growth of a metastatic focus in the brain, control of brain metastases can become a rate-limiting step in both quality of life and overall survival, and represents a leading edge in the ongoing efforts to improve outcomes for these patients.

Diffuse Recurrence • For patients with diffuse recurrence after whole-brain radiotherapy, clinicians may discuss palliative options such as repeat reduced-dose wholebrain radiotherapy, a trial of systemic therapy, enrollment onto a clinical trial, or best supportive care. (Evidence quality = low.) • For patients with diffuse recurrence after stereotactic radiosurgery, clinicians may discuss palliative options such as whole-brain radiotherapy, a trial of systemic therapy, enrollment onto a clinical trial, or best supportive care. (Evidence quality = low, recommendation strength = moderate.)

curs in both the brain and elsewhere)? • Systemic therapy should not be switched in patients who received a standard surgical- or radiotherapybased approach, are receiving antiHER2-based therapy, and do not have progressive systemic disease at the time of diagnosis. (Evidence quality = low, recommendation strength = moderate.) • For patients receiving a standard surgical- and/or radiotherapy-based approach whose systemic disease is progressive at the time of brain metastasis diagnosis, clinicians should offer HER2-targeted therapy according to the algorithms for treatment of HER2-positive metastatic breast cancer. (Evidence quality = intermediate, recommendation strength = moderate.)

How should systemic therapy be managed in patients with HER2-positive brain metastases (including management of systemic therapy when the brain is the only site of progression vs when progression oc-

Is there a role for systemic therapy specifically to treat brain metastases in HER2-positive breast cancer? • For patients with asymptomatic, low-volume brain metastases who

continued from page 35

To establish the current best practices, the American Society of Clinical Oncology recently provided clinical guidelines for the management of brain metastases from HER2positive breast cancer, as reported by R amakrishna and colleagues in the Journal of Clinical Oncology1 and reviewed in this issue of The ASCO have not received radiation therapy, clinicians may discuss upfront therapy with lapatinib (Tykerb) and capecitabine as an option. Patients should be informed that radiation therapy is still the primary option in this setting. (Evidence quality = low.) • For patients developing intracranial disease progression after whole-brain radiotherapy or stereotactic radiosurgery (including those who are not candidates for reirradiation), clinicians may discuss systemic therapy as an alternative, using a regimen with some evidence of activity in CNS disease. (Evidence quality = low.) Should patients with HER2-positive breast cancer be screened for development of brain metastases? • Patients with no known history or symptoms of brain metastases should not undergo routine surveillance with brain magnetic resonance imaging (MRI). (Evidence quality = low.) • Clinicians should have a low thresh-

Post. Although general guidelines for the management of brain metastases exist,2 including guidelines from the National Comprehensive Cancer Network, there is a paucity of diseasespecific guidelines. Nevertheless, it is becoming increasingly clear that the management of brain metastases must account for the histology of the primary malignancy, since clinical decision-making takes place against the baseline expectation of overall survival and anticipates the administration of differing treatments for systemic metastatic disease. The ASCO recommendations, formulated by expert consensus, provide us with a general framework for managing brain metastases from HER2-positive breast cancer.

Prolonging Survival In the Breast Cancer Graded Prognostic Assessment, a prognostic scoring metric derived from a multi-institutional database of 400 breast cancer patients, the median overall survival was 17 months (95% confidence incontinued on page 40

old for performing diagnostic brain MRI in patients with any neurologic symptoms suggestive of brain involvement, such as new-onset headaches, unexplained nausea/vomiting, or change in motor/sensory function. (Evidence quality = low, recommendation strength = strong.) n Disclosure: For complete disclosures of the guideline authors, visit jco.ascopubs.org.

References 1. Ramakrishna N, Temin S, Chandarlapaty S, et al: Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2–positive breast cancer and brain metastases: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. May 5, 2014 (early release online). 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. May 5, 2014 (early release online).

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Perspective

Priscilla K. Brastianos, MD, and Daniel P. Cahill, MD continued from page 39

terval [CI] = 13–23) in HER2-positive patients with brain metastases3; significant prognostic factors were Karnofsky performance status, age, HER2 status, and the interaction between estrogen receptor and progesterone receptor status and HER2. Other large retrospective series have reported median survival as high as 23 months in these patients.4 Given the potential for prolonged survival in many patients, it is critical to individualize treatment in this population. For example, controversy exists around the optimal timing for whole-brain radiation therapy, which is highly effective for securing local and distal/regional control of often-radiosensitive breast cancer brain metastases, but interrupts systemic treatment cycles and can be associated with transient neurocognitive effects. The new recommendations frame the key considerations for appropriately guiding management decisions in this patient population, including assessing performance status, the number of symptomatic lesions, the status of systemic disease, and the potential short- and longterm toxicities of therapies.

Evolving Recommendations These recommendations also highlight the areas of need for randomized trials of systemic agents in both newly diagnosed and recurrent brain metastases. Indeed, interpreting results from clinical trials and their applicability to patients has been a challenge, given the heterogeneous patient populations and variable endpoints across trials. Traditional cytotoxic agents have some activity in the brain,5 but

have often required coordination with radiation and/or surgical interventions to obtain durable control. As systemic therapies improve and begin to include combinations of agents with penetration across the bloodbrain barrier, the guidelines will also likely evolve to include more frequent use of chemotherapeutic regimens as a primary treatment modality for HER2-positive breast cancer brain metastases. As the prototypic example, the small-molecule tyrosine kinase inhibitor lapatinib (Tykerb) as a single agent has modest activity in recurrent brain metastases, with more recent data indicating that the combination of lapatinib and capecitabine shows promise both upfront6 and in the progressive setting.7 A recent study presented at the ASCO Annual Meeting investigated the use of carboplatin and bevacizumab (Avastin) in progressive brain metastases (including HER2-positive and HER2negative patients), demonstrating a very promising response rate of 63% in the central nervous system.8

Heterogeneity in Trial Designs As mentioned above, one of the key challenges in assessing data from clinical trials in brain metastases is the significant variability in response criteria across trials. To improve this situation, the Response Assessment in Neuro-Oncology (RANO) Working Group recently published guidelines for assessing response to therapy in high-grade gliomas,9 and this group is now working on compiling similar criteria for brain metastases,10,11 with the goal of standardizing endpoint and response criteria. Such guidelines are urgently need-

ed, given the heterogeneity in trial designs. More comprehensive guidelines for the management of leptomeningeal metastases are also needed. One limitation to developing such guidelines is the lack of high-quality studies in this often very disabled patient population.

Conclusions In summary, the ASCO clinical practice guideline for brain metastases in HER2-positive breast cancer presents an important working framework for the practicing oncologist in the management of this common complication of breast cancer, using currently available evidence. In addition, it highlights the key areas where additional well-conducted clinical trials in well-defined patient populations (with standardized response criteria) are needed for further improvement in the care of these patients. n

Disclosure: Drs. Brastianos and Cahill reported no potential conflicts of interest.

References 1. Ramakrishna N, Temin S, Chandarlapaty S, et al: Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. May 5, 2014 (early release online). 2. Brastianos PK, Curry WT, Oh KS: Clinical discussion and review of the management of brain metastases. J Natl Compr Canc Netw 11:1153-1164, 2013. 3. Sperduto PW, Kased N, Roberge D, et al: Effect of tumor subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases. Int J Radiat Oncol Biol Phys 82:2111-2117, 2012.

4. Gori S, Rimondini S, De Angelis V, et al: Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: Incidence, survival, and risk factors. Oncologist 12:766-773, 2007. 5. Cocconi G, Lottici R, Bisagni G, et al: Combination therapy with platinum and etoposide of brain metastases from breast carcinoma. Cancer Invest 8:327334, 1990. 6. Lin NU, Dieras V, Paul D, et al: Multicenter phase II study of lapatinib in patients with brain metastases from HER2positive breast cancer. Clin Cancer Res 15:1452-1459, 2009. 7. Bachelot T, Romieu G, Campone M, et al: Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): A single-group phase 2 study. Lancet Oncol 14:64-71, 2013. 8. Lin NU, Gelman RS, Younger J, et al: Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM). J Clin Oncol 31(suppl):Abstract 513, 2013. 9. Wen PY, Macdonald DR, Reardon DA, et al: Updated response assessment criteria for high-grade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 28:1963-1972, 2010. 10. Lin NU, Lee EQ, Aoyama H, et al: Challenges relating to solid tumour brain metastases in clinical trials, part 1: Patient population, response, and progression. A report from the RANO group. Lancet Oncol 14:e396-e406, 2013. 11. Lin NU, Wefel JS, Lee EQ, et al: Challenges relating to solid tumour brain metastases in clinical trials, part 2: Neurocognitive, neurological, and quality-oflife outcomes. A report from the RANO group. Lancet Oncol 14:e407-e416, 2013.

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The ASCO Post | JULY 10, 2014

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In the Clinic Gastrointestinal Oncology

Panitumumab Plus FOLFOX for KRAS Wild-Type Metastatic Colorectal Cancer By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

anitumumab (Vectibix) was recently approved by the U.S. Food and Drug Administration (FDA) for use in combination with FOLFOX (fluorouracil, leucovorin, oxaliplatin) in firstline treatment of patients with wild-type KRAS (exon 2) metastatic colorectal cancer as determined by an FDA-approved test.1 The therascreen KRAS test (Qiagen) was simultaneously approved as a companion diagnostic test. Panitumumab should not be used in patients with KRAS-mutant metastatic colorectal cancer or in those with unknown KRAS mutation status. Panitumumab was first approved by the FDA in 2006, for use in epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer that has progressed on or following fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy regimens.

Supporting Trial The new indication was supported by the open-label phase III PRIME trial, in which 656 patients with wild-type KRAS (of 1,183 enrolled patients) were randomly assigned to panitumumab at 6 mg/kg given over 60 minutes plus FOLFOX (n = 325) vs FOLFOX alone (n = 331) every 14 days.1,2 The trial excluded patients with known central nervous system metastases, clinically significant cardiac disease, interstitial lung disease, or active inflammatory bowel disease. The prespecified primary endpoint in the wild-type KRAS population was progression-free survival. Overall, patients had a median age of 61.5 years, 64% were male, 92% were white, 66% had colon cancer, 34% had rectal cancer, and Eastern Coop-

erative Oncology Group performance status was 0 in 56% and 1 in 38%. Median progression-free survival was 9.6 months in the panitumumab/FOLFOX group vs 8.0 months in the FOLFOX group (hazard ratio [HR] = 0.80, P = .02). The objective response rate was 54% vs 47%. In an exploratory analysis, median overall survival was 23.8 vs 19.4 months (HR = 0.83, 95% confidence interval = 0.70–0.98).

How It Works Panitumumab is an EGFR antagonist. The interaction of EGFR with its normal ligands results in phosphorylation and activation of intracellular proteins that regulate transcription of genes involved in cell growth and survival, motility, and proliferation. Signal transduction through EGFR results in activation of wild-type KRAS protein, whereas KRAS-mutant protein is continuously

OF NOTE Panitumumab binds to EGFR and competitively inhibits the binding of EGFR ligands, thereby inhibiting the growth and survival of selected tumor cell lines expressing EGFR.

active and appears independent of EGFR regulation in cells with activating KRAS somatic mutations. Panitumumab binds specifically to EGFR on both normal and tumor cells and competitively inhibits the binding of EGFR ligands. Preclinical studies show that binding of panitumumab prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases and thus results in inhibition of cell growth, induction of apoptosis, decreased production of proinflammatory cytokines and vascular growth factor, and internalization of EGFR. Studies in vitro and in vivo in animals have shown that panitumumab inhibits the growth and survival of selected tumor cell lines expressing EGFR.

New Indication for Panitumumab ■■ Panitumumab (Vectibix) was recently approved for combined use with FOLFOX in first-line treatment of patients with wild-type KRAS metastatic colorectal cancer as determined by the companion diagnostic, therascreen KRAS test (Qiagen). ■■ Panitumumab is given at 6 mg/kg via intravenous infusion over 60 minutes (≤ 1,000 mg) or 90 minutes (> 1,000 mg) every 14 days.

How It Is Given Panitumumab is given at 6 mg/kg via intravenous infusion over 60 minutes (≤ 1,000 mg) or 90 minutes (> 1,000 mg) every 14 days. The infusion rate should be reduced by 50% for mild infusion-related reactions and infusion should be terminated for severe reactions. The drug should be withheld or discontinued for severe or intolerable dermatologic toxicity. For grade 3 dermatologic toxicity, one or two doses should be withheld with reinitiation at the original dose if toxicity resolves to less than grade 3 after the first occurrence, at 80% of the original dose if toxicity resolution occurs after the second occurrence, and at 60% of the original dose if resolution occurs after the third occurrence. The drug should be permanently discontinued if there is a fourth occurrence of grade 3 toxicity.

Safety Profile In the phase III trial, the most common adverse events of any grade in patients receiving panitumumab/FOLFOX were diarrhea (62% vs 52% in the FOLFOX group), rash (56% vs 7%), anorexia (36% vs 26%), acneiform dermatitis (32% vs 0%), and hypomagnesemia (30% vs 8%). The most common grade 3 or 4 adverse events were diarrhea (18% vs 9%), rash (17% vs < 1%), acneiform dermatitis (10% vs 0%), and hypokalemia (10% vs 5%). Deep-vein thrombosis occurred in 5.3% vs 3.1% of patients. Serious adverse reactions that occurred with ≥ 2% greater frequency in the panitumumab/FOLFOX group were diarrhea and dehydration. Adverse events leading to discontinuation of treatment in ≥1% of panitumumab/FOFLOX patients were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One case of grade 5 hypokalemia was observed. In clinical trials of panitumumab monotherapy in 725 patients, 3% had infusion reactions, with a grade 3 or 4 reaction occurring in three patients (< 1%). The incidence of neutralizing antipanitumumab antibodies (excluding preexisting and transiently positive patients) was 0.8% in 1,123 patients receiving monotherapy and (excluding preexisting positive patients) 0.2% in 1,297 receiving panitumumab in combination with chemotherapy. No evidence of an altered safety profile was found in patients who developed antibodies. Panitumumab carries a boxed warn-

OF NOTE Panitumumab carries a boxed warning for dermatologic toxicity and infusion reactions.

ing for dermatologic toxicity and infusion reactions. It also carries warnings/ precautions for dermatologic and softtissue toxicity; increased tumor progression, increased mortality, or lack of benefit in patients with KRAS-mutant disease; electrolyte depletion; infusion reactions; pulmonary fibrosis/interstitial lung disease; and ocular toxicities. Panitumumab recipients should be monitored for dermatologic and soft-tissue toxicities and should limit sun exposure. They should have electrolytes monitored regularly and should be monitored for keratitis or ulcerative keratitis. Panitumumab should be interrupted or discontinued in patients with acute or worsening keratitis and discontinued in patients developing interstitial lung disease. Animal data suggest that panitumumab can cause fetal harm. Physicians are encouraged to enroll pregnant patients in Amgen’s pregnancy surveillance program. Nursing mothers should discontinue nursing or discontinue panitumumab. n References 1. VECTIBIX® (panitumumab) injection for intravenous infusion, Amgen Inc, May 2014. Available at http://pi.amgen.com/ united_states/vectibix/vectibix_pi.pdf. 2. Douillard JY, Siena S, Cassidy J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol 28:4697-4705, 2010.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

A more aggressive GBM may be hiding in plain sight EGFRvIII has been shown to be a marker for more aggressive tumor growth and reduced survival1-3 • The epidermal growth factor variant three (EGFRvIII) mutation is associated with increased growth and more rapid recurrence in GBM1-3 • EGFRvIII may also be a negative predictor of survival3 – In a study of 196 GBM patients, those who survived beyond the first year and expressed EGFRvIII (n=32) had significantly shorter median overall survival times (1.12 years, P<0.0001) compared to those who either expressed EGFR wild type (n=19, 2.02 years) or lacked EGFR (n=38, 2.03 years). This effect remained significant in multivariate analysis after adjustment for other cofactors3 But could EGFRvIII also prove to be an important therapeutic target? Celldex Therapeutics is conducting research on EGFRvIII. Take a closer look at celldex.com. References: 1. Lal A et al. Cancer Res. 2002;62:3335-3339. 2. Nishikawa R et al. Proc Natl Acad Sci U S A. 1994;91:7727-7731. 3. Heimberger AB et al. Clin Cancer Res. 2005;11:1462-1466.

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Direct From ASCO

2014 Breast Cancer Symposium to Focus on Collaborative Learning

SCO’s educational symposia have historically provided attendees with a forum for learning and discussion, demonstrating ASCO’s commitment to promoting a network of global oncology expertise. The 2014 Breast Cancer Symposium, to be held in San Francisco from Thursday,

care for breast cancer, the whole cancer community has to work together,” explained Banu Arun, MD, Associate Professor of Breast Medical Oncology and Clinical Cancer Prevention, and Co-Director of Clinical Cancer Genetics at The University of Texas MD Anderson Cancer Center, and Co-Chair

To achieve evidence-based clinical care for breast cancer, the whole cancer community has to work together. Only with collaboration will we be able to advance the field of multidisciplinary breast care. —Banu Arun, MD

September 4, to Saturday, September 6, will be no exception, as it brings together attendees from all disciplines of oncology practice and research to exchange ideas and learn from each other, with the ultimate goal of improving patient care. The theme for this year’s Symposium—Enhancing Clinical Care Through Collaboration—highlights the importance of cross-disciplinary interaction and cooperation in making progress against breast cancer. “To achieve evidence-based clinical

of this year’s Program Committee. “Only with collaboration will we be able to advance the field of multidisciplinary breast care.”

Truly Multidisciplinary The Breast Cancer Symposium is open to all members of the oncology community interested in the prevention, screening, evaluation, and management of breast cancer, resulting in a diverse group of attendees and a vibrant setting for discussion. Medical oncologists, radiation oncologists,

surgeons, and other members of the cancer care team will find ample opportunities to make connections with other breast cancer specialists and expand their professional networks. With an educational program designed to be as multifaceted as its attendees, the Symposium will provide a comprehensive view of current best practices and explore the clinical impact of major scientific advancements. Sessions on topics ranging from risk assessment to survivorship care will feature presentations from a wide range of perspectives, and multidisciplinary panels of experts will discuss important advances and unresolved questions from their respective fields. This synthesis of viewpoints will ensure that each attendee is able to expand his or her breast cancer knowledge in every session.

Interactive Elements Expanded In the past, Symposium attendees have been able to participate in select sessions through an audience response system and electronic Q&A. These sys-

tems have been expanded for 2014 to allow more attendees to participate in more sessions. Participants will be able to answer questions posed by speakers in real time from their mobile device and can similarly ask questions via text, tweet, or web submission. A new feature of the 2014 program is the addition of framing case studies to each day’s program. These cases will synthesize content from the day’s presentations, placing key findings into clinical context and generating discussion of how the latest research will impact practice. “These case studies and discussions will bring together the topics covered that day and will make the meeting even more interactive,” said Dr. Arun. “It will be a two-way meeting, rather than just one-way.” Another collaborative element will be included in this year’s Tumor Board

Yanyan Lou, MD, PhD, Receives Inaugural 2014 Young Investigator Award Supported by the Women Who Conquer Cancer Campaign

anyan Lou, MD, PhD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, is the recipient of the very first 2014 Conquer Cancer Foundation of ASCO Young Investigator Award (YIA), generously supported by the Women Who Conquer Cancer. After receiving her medical degree from Henan Medical University in China, Dr. Lou completed her doctor-

ate degree in oncology at West China University of Medical Sciences and an internal medicine residency at UT Southwestern in Austin. “My personal experience with my grandfather who died from lung cancer first stimulated my desire to pursue a career in cancer medicine. Driven by a passion for developing new cancer therapies, I entered medical school and then graduate school where I re-

This study will help us to understand the mediators of EMT-associated immunosuppression and whether this immunosuppression contributes to the drug resistance and metastases known to be associated with EMT. —Yanyan Lou, MD, PhD

ceived structured training in translational research with a specific focus on cancer immunotherapy,” said Dr. Lou.

YIA Research Project Dr. Lou received a 2014 YIA for her project “Investigating tumor microenvironment immune phenotypes in epithelial-mesenchymal transition and EGFR tyrosine kinase inhibitor-resistant NSCLC: Implication for immunotherapy.” She is comentored by John Heymach, MD, PhD (2003 YIA, 2004 CDA) and Patrick Hwu, MD. Epithelial-mesenchymal transition (EMT) is a key process that drives cancer metastases. Data have demonstrated that EMT in non–small cell lung carcinoma (NSCLC) is associated with epidermal growth factor re-

ceptor (EGFR) tyrosine kinase inhibitor resistance independent of EGFR mutation status. Furthermore, preliminary data demonstrate that both EMT and EGFR tyrosine kinase inhibitor resistance are highly associated with upregulated programmed cell death 1 ligand (PD-L1), a key immune checkpoint molecule inducing immunosuppression. PD-1 and its ligand PD-L1 have emerged as a critical inhibitory pathway that regulates T cell response continued on page 46

ASCOPost.com | JULY 10, 2014

PAGE 45

Direct From ASCO sessions, which will be built around cases submitted by attendees. Attendees can help shape the discussion at the Symposium by submitting their cases for the Early Disease Tumor Board and the Metastatic Disease Tumor Board online before August 7, 2014.

Gianni Bonadonna Breast Cancer Award

Switzerland. An international leader in the field of breast cancer, Dr. Goldhirsch has dedicated his career to research focused on new adjuvant treatments, definition of biologic features that predict responsiveness or resistance to anticancer treatments, and quality-of-life–oriented approaches. His commitment to international co-

operation and clinical trials led him to chair the Update committee of the Early Breast Cancer Trialists’ Collaborative Group, which conducts largescale meta-analyses of breast cancer treatments. He is also Vice-Chair of the Breast International Group, a consortium of cooperative groups around the world for conducting clinical trials

for breast cancer therapies. The 2014 Breast Cancer Symposium hotel reservation and early registration deadline is July 30, 2014. For more information and to register, please visit breastcasym.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Gianni Bonadonna Breast Cancer Award and Lecture will also be presented at the Symposium. First given in 2007, it recognizes an active clinical and/or translational researcher with a distinguished record of accomplishments in advancing the field of breast cancer. The award provides $50,000 to a fellow in the institution of the award recipient. This year’s recipient is Aron Goldhirsch, MD, Director of the Multidisciplinary Program of Senology and Deputy Scientific Director at

NOW ENROLLING: Aron Goldhirsch, MD

the European Institute of Oncology in Milan, Italy, and Professor of Medical Oncology at the University of Bern,

Newly Updated: Cancer Survivorship

New trials for patients with mutant EGFR non-small cell lung cancer

Phase 2 expansion

2nd line and 3rd line+, T790M+ mutant EGFR NSCLC (NCT01526928)

1 prior EGFR TKI

CO-1686

≥2 prior EGFR TKI or chemo

CO-1686

Primary endpoint: ORR

his latest ASCO Answers guide helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Copies can be purchased through the ASCO University Bookstore at www .cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. It is also available for download at www.cancer.net/survivorship. n

Phase 2

2nd line T790M+ mutant EGFR NSCLC (NCT02147990)

1 prior EGFR TKI

CO-1686

Primary endpoint: ORR

For more information, visit ClinicalTrials.gov, TIGERtrials.com, or contact clinicaltrials@clovisoncology.com CO-1686 is an investigational product and is not approved in any country. Copyright © 2014 Clovis Oncology.

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The ASCO Post | JULY 10, 2014

PAGE 46

Direct From ASCO

2001 Young Investigator Award Recipient Pasi Jänne, MD, PhD, Presents Research on Promising New Therapy for Treatment-Resistant NSCLC

t the 2014 ASCO Annual Meeting, Pasi Jänne, MD, PhD, Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School, presented findings from a phase I study of AZD9291, a new mutant-selective EGFR tyrosine kinase inhibitor that offers a promising new treatment option for patients with advanced, EGFR-mutant, non–small cell lung cancer that is resistant to stan-

vanced lung cancer and have an EGFR mutation, initial therapy with an EGFR inhibitor is better than conventional chemotherapy. Unfortunately, all patients ultimately develop resistance to current generation EGFR inhibitors, such as erlotinib (Tarceva) and afatinib (Gilotrif ), and additional therapies are needed. Importantly, AZD9291 (a drug manufactured by AstraZeneca) se-

Although it is still a bit early, our study suggests that AZD9291 may offer an effective new therapy option for [patients with treatment-resistant NSCLC], without the skin side effects we typically see with existing EGFR inhibitors. —Pasi Jänne, MD, PhD

dard EGFR inhibitors. Roughly 50% of patients experienced tumor shrinkage, and the drug worked particularly well in patients with the T790M mutation (detected in 60% of patients), which causes the most common form of EGFR therapy resistance.

EGFR mutations were discovered in a subset of lung cancer patients in 2004, and since then several clinical trials have shown that for patients who are newly diagnosed with ad-

lectively targets mutant EGFR in tumors and appears to cause fewer skin toxicities than approved EGFR tyrosine kinase inhibitors. While existing drugs block both the mutant EGFR in the tumor and the normal EGFR in the skin and other organs, often leading to debilitating skin rash or acne, AZD9291 acts mostly on the mutant EGFR in a patient’s tumor. “There is currently no standard treatment for patients with lung cancer who experience disease progression after initial therapy with an EGFR kinase inhibitor,” said Dr. Jänne. “Al-

Yanyan Lou, MD, PhD

Potential Impact for Patients

continued from page 44

Lung cancer is the leading cause of cancer death in the United States. Although identification of mutations and development of EGFR tyrosine kinase inhibitor have led to an evolution of treatment in NSCLC, all such treated patients will eventually acquire resistance despite an initial response. According to Dr. Lou, “This study will help us to understand the mediators of EMT-associated immunosup-

Targeting EGFR-Mutant Lung Cancer

and maintains immunosuppression in tumor microenvironment. Based on these findings, Dr. Lou hypothesizes that EMT and EGFR tyrosine kinase inhibitor resistance are associated with an immunosuppressive phenotype in tumor microenvironment and targeting this immune suppression will potentially inhibit metastases and reduce tumor growth in EGFR tyrosine kinase inhibitor–resistant NSCLC.

though it is still a bit early, our study suggests that AZD9291 may offer an effective new therapy option for these patients, specifically in those with the T790M resistance mechanism, without the skin side effects we typically see with existing EGFR inhibitors.”

Conquer Cancer Foundation Grants Dr. Jänne received a 2001 Young Investigator Award (YIA) from the Conquer Cancer Foundation early in his career to examine whether selective and nonselective cyclooxygenase-2 (COX2) inhibitors can prevent or delay the development of lung adenocarcinomas in a genetic murine model. “The YIA got me interested in studying lung cancer to begin with,” said Dr. Jänne. “During my fellowship, I knew I was going to do lung cancer research, but receiving the YIA gave me extra encouragement and motivation that this was the right track moving forward.” Part of the team that originally discovered the EGFR mutation in 2004, Dr. Jänne has spent the past 10 years studying EGFR-mutant lung cancer, trying to understand drug resistance and develop therapies, both preclinically and now clinically. In addition to his own research, Dr. Jänne is also a mentor to several promising physician scientists who have successfully received Conquer Cancer Foundation grants themselves, including Geoffrey

Oxnard, MD (2010 YIA, 2012 CDA) and Curtis Chong, MD (2013 YIA). He recently chaired the 2013–2014 Conquer Cancer Foundation Grants Selection Committee, which reviews YIA and CDA applications, and has also served on the Journal of Clinical Oncology Editorial Board, ASCO Cancer Education Committee, and ASCO Scientific Program Committee. The Conquer Cancer Foundation believes that it is important to invest in early-career researchers, like Dr. Jänne, because that is how the treatments of tomorrow are born. As Dr. Jänne explains, “Donating to the Conquer Cancer Foun-

dation helps support very important early career grants. It is incredibly important to support people early in their research career because that is ultimately how we make advances in cancer.” Help the Conquer Cancer Foundation accelerate breakthroughs, launch careers, and improve cancer care by donating today at www.conquercancerfoundation.org/ donate. n © 2014. American Society of Clinical Oncology. All rights reserved.

pression and whether this immunosuppression contributes to the drug resistance and metastases known to be associated with EMT. Importantly, it will potentially identify the biomarkers for selecting which patients benefit from PD-1/PD-L1 blockade and establish a rationale mechanistic basis for combining PD-L1 blockade with targeted agents.”

Women Who Conquer Cancer campaign brings together women from across the country to fund promising careers and outstanding research through the Young Investigator Award (YIA). Interested in learning more about Women Who Conquer Cancer? Visit www.conquercancerfoundation.org/ wwcc. n

Women Who Conquer Cancer

The Conquer Cancer Foundation’s

ASCOPost.com | JULY 10, 2014

PAGE 47

Direct From ASCO

Be Counted in 2014 ASCO National Oncology Census— No Login Information Required

lease be counted in this year’s ASCO National Oncology Census—the only annual survey of the entire oncology community that aims to capture and describe changes in cancer care over time. Through the 2013 census, more than 8,000 oncologists in community practices, hospitals, and academic medical centers shared with ASCO the challenges they are facing every day. The data and insights obtained from the 2013 census are chronicled in ASCO’s The State of Cancer Care in America: 2014 (available online at www.asco.org/ practice-research/cancer-care-america) and are driving ASCO’s policy and advocacy efforts. The 2014 survey tool does not require user IDs or passwords, so you can take the survey today and be counted

immediately: www.asco.org/census The 2014 ASCO National Oncology Census results will be used to identify continuing and emerging oncology clinical care trends across the entire oncology community. Your participation in the 2014 ASCO National Oncology Census is crucial to its success. From the information you provide, ASCO can educate the cancer community on the changes, issues, challenges and opportunities oncologists face in delivering care. Whether you are a new or returning participant, 2014 is a new opportunity to be counted! To participate in the 2014 ASCO National Oncology Census, please go to: www.asco.org/census. n

ASCO to Hold Community Research Forum Annual Meeting in September

oin fellow community-based researchers at the ASCO Community Research Forum Annual Meeting, September 28 to 29, 2014, at ASCO headquarters in Alexandria, Virginia. As part of ASCO’s efforts to support community-based researchers, this meeting provides a unique opportunity to discuss barriers and develop solutions to common challenges faced in the community research setting. This meeting provides a forum to: • Collaborate and network with colleagues

Volume 7, Issue 3

May 2011

Journal of oncology Practice

• Discuss barriers to conducting research • Work to develop strategies to effectively conduct community-based research • Influence the direction of ASCO initiatives • Provide input on policy issues impacting clinical research Space is limited, so register early. For more information, visit asco.org/ communityresearchforum. n © 2014. American Society of Clinical Oncology. All rights reserved.

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

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

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Quality Measures for Palliative Care in Patients With Cancer: A Systematic Review by Arif H. Kamal, et al

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Colorectal Cancer Survivors’ Needs and Preferences for Survivorship Information by Talya Salz, et al

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ASCOPost.com | JULY 10, 2014

PAGE 51

American Society of Pediatric Hematology/Oncology Annual Meeting

Following ‘Fruitful’ Year of Collaboration, Advocacy, and Growth, Pediatric Hematology/Oncology Moves to Next Level Reflections from ASPHO Immediate Past President A. Kim Ritchey, MD By Charlotte Bath

inishing up a 2-year term as President of the American Society of Pediatric Hematology/Oncology (ASPHO), A. Kim Ritchey, MD, summarized ASPHO’s achievements in advocacy, education, and professional development in his State of the Society address at the ASPHO 27th Annual Meeting in Chicago. He also challenged members to “take it to the next level,” by supporting the goals of ASPHO’s new “Enriching the Future” campaign. Following the Presidential Symposium, Dr. Ritchey, Vice Chair of Clinical Affairs, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, expanded on these themes during an interview with The ASCO Post.

pharmaceutical companies and nonNCI sources,” he explained, so the sequestration “preferentially hit pediatric oncology research more than adult oncology research.” He expects the collaboration to continue to be fruitful. Small groups of members from both ASHPO and AAP have been created to serve as “subject matter experts for policy review,” he said. “With ideas solicited from the membership, new policies to enhance patient care in pediatric hematology/

Two years ago, we launched our most important collaboration, with the American Academy of Pediatrics. The goal of this collaboration was to ensure that one voice represented pediatric hematology/oncology and also to join forces with the Academy in advocating for our patients and their families. The collaboration has been very fruitful.

‘Most Important Collaboration’ “Two years ago, we launched our most important collaboration, with the American Academy of Pediatrics [AAP],” Dr. Ritchey stated at the ASPHO Presidential Symposium. “The goal of this collaboration was to ensure that one voice represented pediatric hematology/oncology and also to join forces with the Academy in advocating for our patients and their families. The collaboration has been very fruitful.” That collaboration resulted in a united and “more powerful voice in advocating for our patients,” Dr. Ritchey explained in the interview. ASPHO and AAP have led advocacy efforts to resolve the shortage of chemotherapy drugs and to consider the needs of pediatric patients in drug development. “Frequently an agent goes through drug development and it is only approved for adults, without an indication for children.” Dr. Ritchey said that those developing and approving drugs need to be reminded that children might benefit, too. Working together, ASPHO and the AAP had a strong presence in Washington during hearings about the sequestration of funds and how it impacted pediatric oncology research, Dr. Ritchey said. “Pediatric oncology research is funded almost exclusively by the National Cancer Institute [NCI], whereas adult oncology research is funded predominantly by

composed of two early career members from each committee. The purpose of this council is to reflect on the issues that confront ASPHO and our specialty from the early career perspective, and to advise the board, who are fairly far from their early career, regarding their perceptions and reflections of their group.” Younger physicians starting out in their careers are well represented within ASPHO. “We give free membership to all fellows, and we have reduced

—A. Kim Ritchey, MD

oncology practice will be adopted.” ASPHO has also joined together with ASCO and other professional societies, as well as parent-led organizations such as the Alliance for Childhood Cancer. “We work closely with the Children’s Oncology Group [COG],” he said, to advance pediatric clinical trials and other research. Dr. Ritchey previously served as principal investigator for the COG at the University of Pittsburgh and continues to participate in enrolling patients in COG clinical trials.

Encouraging Early Career Members “One of my goals as ASPHO President was to encourage early career members—with early career defined as during fellowship or 5 years afterward—to become active within A SPHO,” Dr. Ritchey noted at the Presidential Symposium. “I asked that there be at least two early career members on each committee, and we’ve now formed an early career council

the membership fee for the first year after they graduate from their fellowship program to encourage continued membership,” Dr. Ritchey explained.

Mentorship and Fellowship Training “Regarding career development support, there have been three major initiatives. The first is a mentorship program that has had a great start,” Dr. Ritchey said. The second issue concerns fellowship training. “The American Board of Pediatrics has indicated that it is now the responsibility of the subspecialty societies like ours to evaluate ‘entrustable professional activities’ that will be used to assess the readiness of trainees for practice.” Examples of these entrustable professional activities would be that “every pediatric hematologist/oncologist has to know how to perform a bone marrow aspiration” or “every pediatric fellow has to know how to give bad news,” Dr. Ritchey said. “We have developed a set of these activities and are

well ahead of other specialty societies in this regard,” Dr. Ritchey noted. “It will require considerable ongoing effort,” he added, “to determine if these evaluations are adequately assessing the readiness of fellows to graduate.” The third initiative concerns the pediatric workforce. Dr. Ritchey said. “Are we training too many fellows or not enough?” To get the answers, ASPHO conducted a nationwide survey. The results are now being analyzed and are expected to be published soon. “We want to make sure that our fellows have jobs, but the workforce is changing in pediatric hematology/oncology. There are more midlevel providers—nurse practitioners and physician assistants. There is an increased number of hospitalists throughout medicine, and that is affecting us as well. So we want to make sure that we are in touch with the facts about the workforce in pediatric oncology.”

‘Enriching the Future’ Membership in ASPHO continues to grow, as does attendance at the ASPHO Annual Meeting. The recent meeting had more than 1,000 registrants representing 36 counties and 48 of the 50 United States. “We are now on much firmer financial ground,” Dr. Ritchey said. “We are not rich by any means, but at least we are solvent.” More funds are needed, however, “to develop new programs designed to enhance our members’ careers and move our Society to the next level,” Dr. Ritchey stated. To raise that money, ASPHO has launched its “Enriching the Future” campaign. “Our goal is to raise $150,000 by the end of 2015, and I am pleased to say that all of the past presidents and board members are 100% behind this campaign.” The campaign committee, led by former ASPHO President William G. Woods, MD, Professor of Pediatrics at Emory University School of Medicine, Atlanta, “has selected three areas for support by the campaign funds: clinician educator awards, visiting professorships, and travel awards,” Dr. Ritchey reported. “Clinician educator awards are designed to support scholarship in medicontinued on page 52

The ASCO Post | JULY 10, 2014

PAGE 52

American Society of Pediatric Hematology/Oncology Annual Meeting A. Kim Ritchey, MD continued from page 51

cal education, including research, advanced training, and development of new educational resources. The goal of this award is to strengthen medi-

are designed to allow leaders in our field to share their experience and wisdom with other ASPHO members who might not get a chance to have such interaction, especially at smaller institutions,” he continued. “ASPHO travel awards will expand our current travel award program, and we hope that early career members and inter-

national members who currently are unable to participate in ASPHO educational activities will benefit. Our goal is to expand essential learning opportunities provided by attendance at the Annual Meeting and to provide an S:6.75” opportunity for those unable to participate because of financial constraints.” These three initiatives could be

complemented by others in the future. In encouraging ASPHO members to contribute to the campaign, Dr. Ritchey said, “Your participation reflects your confidence in the future of ASPHO, and I think we have an optimistic future.” n

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

William G. Woods, MD

cal scholarship in pediatric oncology/ hematology, providing needed support for this emerging career pathway,” he said. “ASPHO Visiting Professorships

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Rights & Permissions e-mail: Permissions@harborsidepress.com

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Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

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

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

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

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

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

05/14 [COM-0086]

B:17

T:1

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Announcements

Andrew S. Kraft, MD, Named Director of University of Arizona Cancer Center

ndrew S. Kraft, MD, prostate cancer physician-scientist and cancer center administrator, has been named the Sydney E. Salmon Endowed Chair and Director of the University of Arizona Cancer Center and Associate Vice President for Oncology Programs for the

University of Arizona Health Sciences Center. In addition to his cancer center leadership role, Dr. Kraft joins the University as a tenured Professor of MediS:6.75” cine in the Department of Medicine’s Division of Hematology/Oncology and Senior Associate Dean for Translational

Research in the College of Medicine. Dr. Kraft is scheduled to begin his new leadership role in September. He replaces Anne E. Cress, MD, who has served as Interim Director of the University of Arizona Cancer Center since July 2013.

Led Former Institution to NCI-Designated Status Recruited to the Medical University of South Carolina in 2004, Dr. Kraft led the Hollings Cancer Center’s efforts to become a National Cancer Institute– continued on page 54

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

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

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

PFS

1.0

COMETRIQ® (n=219) Placebo (n=111)

0.9 0.8 0.6

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

0.7 0.5 0.4

median

4.0 4.0

0.3

11.2 11.2 months months

months months

0.2

Probability of patients who are progression free

AE/AS

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

31 3

12 2

2 0

1 0

Months 219 111

121 35

78 11

55 6

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%). Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. Please see accompanying brief summary of Prescribing Information, including Boxed Warnings. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

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The ASCO Post | JULY 10, 2014

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Announcements Andrew S. Kraft, MD continued from page 53

designated cancer center. Under his leadership, Hollings attained NCI cancer center status in 2009. An accomplished prostate cancer researcher and developer of novel cancer drugs, Dr. Kraft is the principal investigator for numerous clinical trials. His research

Andrew S. Kraft, MD

has received funding from the NCI since 1985. He has also received support from the U.S. Department of Defense and the Prostate Cancer Research Foundation. In his new role, Dr. Kraft will have overall responsibility for the Cancer Center’s $35 millionS:6.75” research portfolio and oversight of oncology clinical operations in Tucson, in partnership with

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None. 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

the UA Health Network. In addition, he will oversee the development and implementation of clinical and research operations at the new University of Arizona Cancer Center facility in Phoenix in collaboration with Dignity Health/ St. Joseph’s Hospital and Medical Center. The new facility is slated for completion in summer 2015. n

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

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

B:17.

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Awards

First Tang Prize for Biopharmaceutical Science Awarded to James P. Allison, PhD, and Tasuku Honjo, MD, PhD

PROD ED AE/AS CW CD

Dr. Allison developed an antibody to block CTLA-4, an off-switch on T cells, to unleash immune attack on tumors. Ipilimumab (Yervoy), a drug based on his antibody, has extinguished untreatable late-stage melanoma in 22% of patients in clinical trials for 3 years or longer, unprecedented results. FDA approved ipilimumab for metastatic melanoma in 2011. Dr. Honjo discovered the second immune checkpoint on T cells, called PD1. A variety of experimental drugs to block PD1 and its activating ligand, PD-L1, are showing great promise in clinical trials. Dr. Allison and Dr. Honjo were selected from hundreds of international nominees for the award, which recognizes original research that has led to significant advances in preventing, diagnosing, and treating major human diseases. Academia Sinica, Taiwan’s preeminent academic organization, similar to the National Academy of Sciences in the United States, administered award selection. n

DATE

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The first Tang Prize for Biopharmaceutical Science has been awarded to James P. Allison, PhD, (left) Chair of Immunology at The University of Texas MD Anderson Cancer Center and Tasuku Honjo, MD, PhD, (right) of Japan’s Kyoto University for their research leading to cancer immunotherapy.

Disk

B:11.25”

Dr. Allison launched an entirely new way to treat cancer by blocking molecules on immune system T cells that turn off immune response. The treatment, called immune checkpoint blockade, grew out of his basic science research to understand the biology of T cells—the immune system’s customized attackers. “Receiving the Tang Prize is a great honor for me, as well as recognition of the growing importance of cancer immunotherapy,” Dr. Allison said.

S:9.75”

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

Placebo N=1073 (%) 15

Immune Checkpoint Blockade Discoveries

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. 17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash. • COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking. • COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss. • To contact their healthcare provider before any planned surgeries, including dental procedures. • COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking. • Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water. • Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment. Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

established the biennial Tang Prize in December 2012. The 2014 prizes provide a cash award [in New Taiwan dollars] of NT$40 million ($1.3 million) and research grant of NT$10 million (approximately $333,000).

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

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose.

cine,” said Lee Yuan-tseh, PhD, Taiwan’s winner of the 1986 Nobel Prize in chemistry, at the award announcement in Taipei, Taiwan in June. Taiwanese entrepreneur Samuel Yin

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

asuku Honjo, MD, PhD, of Japan’s T Kyoto University for their research leading to cancer immunotherapy. S:6.75” “Both scholars’ discoveries have opened a new therapeutic era in medi-

he first Tang Prize for Biopharmaceutical Science has been awarded to James P. Allison, PhD, Chair of Immunology at The University of Texas MD Anderson Cancer Center and

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2014-2015 Oncology Meetings July Breast Cancer: New Horizons, Current Controversies July 10-12 • Boston, Massachusetts For more information: www.hms-cme.net/341279/ The 12th Annual Scientific Meeting of Japanese Society of Medical Oncology July 17-19 • Fukuoka, Japan For more information: www.congre.co.jp/jsmo2014/en/ The 13th Annual International Congress on the Future of Breast Cancer® July 17-19 • Huntington Beach, California For more information: www.gotoper.com/conferences/ibc 2014 Pan Pacific Lymphoma Conference July 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/ panpacificlymphoma.htm

AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

ISEH Society for Hematology and Stem Cells 43rd Annual Scientific Meeting August 21-24 • Montreal, Canada For more information: www.iseh.org

August

Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org 6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org ASH Meeting on Lymphoma Biology August 10-13 • Colorado Springs, Colorado For more information: www.hematology.org/LymphomaBiology/ Hematology and Medical Oncology Best Practices August 14-21 • Arlington, Virginia For more information: smhs.gwu.edu/ cehp/activities/courses/hemonc Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org

5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php

2014-2015

16th Annual Scientific Meeting: AGITG Trials in Action August 20-22 • Brisbane, Australia For more information: www.agitg.asnevents.com.au 6th Latin American Conference on Lung Cancer August 21-23 • Lima, Peru For more information: www.lalca2014.org

September Association of Pediatric Hematology/Oncology Nurses 38th Annual Conference September 4-6 • Portland, Oregon For more information: www.aphon.org Breast Cancer Symposium September 4-6 • San Francisco, California For more information: breastcasym.org 2014 APAO Annual Conference September 10-14, 2014 • Austin, Texas Sheraton Austin at the Capitol For more information: www.apao.cc/node/9 American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: www.aonnonline.org

NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/ meetings/hematological/ Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/ meetings--workshops/specialconferences/advances-in-melanomafrom-biology-to-therapy.aspx European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29-October 2 • Cambridge, Massachusetts For more information: steelelab.mgh.harvard.edu

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org International Cancer Imaging Society Meeting and 14th Annual Teaching Course October 9-11 • Heidelberg, Germany For more information: www.icimagingsociety.org.uk/index. cfm?task=meetings&meetingid=37 continued on page 58

For Your NPs and PAs A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2nd Loews Royal Pacific Hotel at Universal Orlando, FL apsho.org/jadprolive

The ASCO Post | JULY 10, 2014

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2014-2015 Oncology Meetings

2014-2015

continued from page 56

11th Meeting of the European Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php 2nd Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/ breastcancer/pages/index.aspx 18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home.aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org 16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com 14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org

CNS Anticancer Drug Discovery/ Development Conference November 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com

Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgicalspecialties-2014s306

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians

19th Annual Meeting of the Society for Neuro-Oncology November 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org

3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

November

11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org

Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org

American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/ CourseDetail.aspx/80028747

European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl RSNA 2014: Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

December American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org

UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

February 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11 - 15 • San Diego, California For more information: www.asbmt.org

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Journal Spotlight Thoracic Oncology

Lung Cancer Mutation Consortium Finds Oncogenic Drivers in Majority of Metastatic Lung Adenocarcinomas Genotype-Directed Therapy Shown to Prolong Survival By Matthew Stenger

he Lung Cancer Mutation Consortium (LCMC) was formed to test adenocarcinomas of the lung for 10 oncogenic drivers in order to enable clinicians to select targeted treatments and enroll patients into suitable clinical trials. As recently reported in JAMA by Mark G. Kris, MD, William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center, New York, and colleagues in the LCMC, oncogenic drivers were identified in nearly two-thirds of patients with metastatic disease.1 Median overall survival was extended by more than 1 year in patients with an oncogenic driver who received genotype-directed therapy vs those who did not.

Study Details From 2009 through 2012, 14 U.S. LCMC sites enrolled patients with metastatic lung adenocarcinoma and Southwest Oncology Group (SWOG) performance status of 0 to 2 and attempted to test their tumors for 10 oncogenic drivers. The drivers consisted of alterations in EGFR, KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, PIK3CA, ALK, and MET. Sites performed multiplex genotyping for mutation detection using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, multiplexed single-nucleotide extension sequencing, or Sanger sequencing with peptide nucleic acid probes. All sites performed sizing electrophoresis to detect

The survival of patients was associated with the type of oncogenic driver detected in their tumor specimen, giving doctors a powerful tool to select therapies and estimate prognosis. —Mark G. Kris, MD, and colleagues

ERBB2 insertions and EGFR deletions. Results were used to select matched targeted therapies. LCMC clinical committee members solicited industrysponsored trials for nine drivers, with these trials subsequently being reviewed

and approved by representatives from the 14 LCMC sites. Treating physicians decided whether to recommend a targeted therapy to a patient with a tumor with an oncogenic driver. continued on page 64

Importance of Using Multiplex Testing for Oncogenic Drivers to Select Targeted Drugs in Lung Cancer By Paul A. Bunn, Jr, MD

ung cancer is the leading cause of cancer death in the world as well as in the United States, where it is the leading cancer killer in both men and women. The majority of lung cancer patients present with metastatic (stage IV) disease that cannot be cured with current therapies. Standard cytotoxic chemotherapy prolongs life by an average of a few months but at a cost of considerable toxicity. In 2004, investigators reported that mutations in the epidermal growth factor receptor (EGFR) oncogene could activate the receptor, causing uncontrolled cell growth, but also rendered the cells susceptible to oral EGFR tyrosine kinase inhibitors. Several such EGFR tyrosine kinase inhibitors were shown to produce superior outcomes compared to cytotoxic chemotherapy with much reduced toxicity. In subsequent years, other genetic alterations were shown to activate certain oncogenes, and these alterations also drove the growth of those cancers.

Dr. Bunn is Distinguished Professor of Medicine and the James Dudley Chair in Cancer Research at the University of Colorado Cancer Center Denver, Aurora, and is a past ASCO President.

Tyrosine kinase inhibitors specific for these altered oncogenes were also superior to cytotoxic chemotherapy.

Consortium Aims The Lung Cancer Mutation Consortium (LCMC) was formed to determine the frequency of driver genetic alterations in 10 oncogenes, identify the clinical features and outcomes associated with these on-

studies. The recently published JAMA article reviewed in this issue of The ASCO Post describes the results from the first study, funded by the National Cancer Institute and conducted at 11 institutions.1 (In the ongoing second study, there are 14 institutions studying a larger number of genes.) Those 11 institutions performed the panel testing of the 10 oncogenes in small biopsies from 1,000 patients with stage IV ad-

The LCMC findings … demonstrate the critical importance of simultaneous testing for multiple genetic driver alterations before instituting therapy for patients with advanced lung cancer. —Paul A. Bunn, Jr, MD

cogenic changes and the outcome, determine whether multiple genetic tests could be performed on the same small biopsy, and assess whether specific oral tyrosine kinase inhibitors could improve outcomes for patients with these genetic changes. Thus far, the LCMC has had two

enocarcinoma of the lung. The study found that 64% of the patients had one or more genetic driver alterations (3% had more than one). Specific oral tyrosine kinase inhibitors were given to about half of the patients with a genetic driver. The median survival was 3.5 years for patients with

a driver who were treated with a driver-specific tyrosine kinase inhibitor, 2.4 years for patients who had a driver change but did not receive a specific tyrosine kinase inhibitor, and 2.0 years for those without a driver treated with conventional therapies.

Conclusions The LCMC findings demonstrate the critical importance of simultaneous testing for multiple genetic driver alterations before instituting therapy for patients with advanced lung cancer. Such multiplex testing can be performed on small biopsies in many academic and commercial laboratories and results in a personalized or precision therapy that improves outcomes and reduces toxicity compared to standard chemotherapy for advanced lung cancer patients. n

Disclosure: Dr. Bunn is a Lung Cancer Mutation Consortium investigator and author of the Lung Cancer Mutation Consortium study published in JAMA and reviewed in this issue of The ASCO Post.

Reference 1. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014.

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. REVLIMID is not indicated and not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

For patients with

RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS™ program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma receiving REVLIMID with dexamethasone. For more information, please visit www.REVLIMID.com or call 1-888-423-5436. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on the following pages.

Efficacy and safety of REVLIMID were evaluated in pretreated patients with advanced disease1 • In a multicenter, single-arm, single-agent, open-label study (N=134)* • 92% (124/134) of patients had stage III-IV disease; 78% (105/134) of patients had received ≥3 prior systemic therapies; 60% (81/134) of patients were refractory to prior bortezomib; 55% (74/134) of patients were refractory to last prior therapy • Refractory disease was defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen; relapsed disease was defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen† • Patients received REVLIMID 25 mg orally, once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent *134 patients evaluated for safety; 133 patients evaluated for efficacy.1 † Had received prior treatment with anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination.1

REVLIMID may help continue the fight against relapsed or refractory MCL1‡

26 ORR %

(34/133)

Overall response rate (CR + CRu + PR) (95% CI: 18.4, 33.9)

7 CR %

(9/133)

Complete response rate (CR + CRu) (95% CI: 3.1, 12.5)

median

16.6 months DOR (n=34)

Median duration of response (95% CI: 7.7, 26.7) • Median time to response was 2.2

months (range: 1.8 to 13 months)

CI=confidence interval; CR=complete response; CRu=complete response unconfirmed; DOR=duration of response; ORR=overall response rate; PR=partial response. ‡ §

Based on all evaluable patients who received ≥1 dose of REVLIMID.1 Response was determined based on review of radiographic scans by an independent review committee, according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999); ORR was defined as: CR + CRu + PR.1,2

CONTRAINDICATIONS

Pregnancy: • REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide is contraindicated in females who are pregnant. 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 Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

ADVERSE REACTIONS

Mantle Cell Lymphoma • Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%) • Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia • Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%) • Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients References: 1. Revlimid [package insert]. Summit, NJ: Celgene Corp; 2013. 2. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17(4):1244-1253.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS™ Program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndrome (MDS) had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma (MM) who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicated that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide 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 REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID 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 REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the “RevAssist®” Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Patients may require dose interruption and/or dose reduction. MCL: Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. Venous Thromboembolism: Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MCL treated with lenalidomide monotherapy. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism.

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41], consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Second Primary Malignancies: Patients with MM treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Tumor Flare Reaction: Tumor flare reaction (TFR) occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

ADVERSE REACTIONS

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. Any suspected fetal exposure to REVLIMID must be reported 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 whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established. Geriatric Use: Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr <30 mL/min) and in patients on dialysis. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on the following pages.

The ASCO Post | JULY 10, 2014

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Journal Spotlight Lung Cancer Mutation Consortium continued from page 59

The primary objective of the study was to determine the frequency of the 10 oncogenic drivers. Secondary objectives were to assess as many tumors as possible for all 10 genes to define the co-occurrence of drivers in a single tumor, docu-

ment the ability to use the data to select treatment or a clinical trial targeting the identified driver, and assess survival.

Oncogenic Drivers in Majority Overall, tumors from 1,007 patients were tested for at least 1 gene and 733 were tested for 10 genes. The primary reason for the inability to test for all 10

genes was insufficient tissue. Among all 1,007 patients, median age was 63 years, 60% were women, SWOG performance status was 0 or 1 in 89%, 34% were never smokers and 58% were former smokers, stage at diagnosis was I in 10%, II in 7%, III in 17%, and IV in 64%, and prior therapy included surgery in 43%, radiotherapy in 20%, and chemotherapy in 59%.

REVLIMID [lenalidomide] capsules, for oral use The following is a brief summary for mantle cell lymphoma; refer to full prescribing information for complete product information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2). Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s tollfree number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)]. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.3 Mantle Cell Lymphoma REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. 1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)]. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.3 Mantle Cell Lymphoma The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to REVLIMID.

An oncogenic driver was identified in 466 (64%) of the 733 patients with full genotyping: 182 tumors (25%) had the KRAS driver, 122 (17%) had sensitizing EGFR mutations, 57 (8%) had ALK rearrangements, 29 (4%) had other EGFR mutations, 24 (3%) had aberrations in two or more genes, 19 (3%) had ERBB2 alterations, 16 (2%) had BRAF mutations, 6

Platelet counts Thrombocytopenia during treatment in MCL When Platelets Recommended Course Fall to <50,000/mcL Interrupt REVLIMID treatment and follow CBC weekly Return to ≥50,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Absolute Neutrophil counts (ANC) Neutropenia during treatment in MCL When Neutrophils Recommended Course Fall to <1000/mcL for at least 7 days Interrupt REVLIMID treatment and follow OR CBC weekly Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C OR Falls to < 500 /mcL Return to ≥1,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Other Grade 3 / 4 Toxicities in MCL For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MCL: 2.4 Starting Dose for Renal Impairment in MCL Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MCL are as follows: Table 1: Starting Dose Adjustments for Patients with Renal Impairment in MCL Category Renal Function Dose in MCL (Cockcroft-Gault) Moderate Renal CLcr 30-60 mL/min 10 mg Impairment Every 24 hours Severe Renal CLcr < 30 mL/min 15 mg Impairment (not requiring dialysis) Every 48 hours End Stage CLcr < 30 mL/min 5 mg Renal Disease (requiring dialysis) Once daily. On dialysis days, administer the dose following dialysis. After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described elsewhere (see section 2). 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)]. 4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)]. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of Cosmos Communications K

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Journal Spotlight

(< 1%) had PIK3CA mutations, 5 (< 1%) had MET amplifications, 5 (< 1%) had

NRAS mutations, 1 (< 1%) had MEK1 mutations, and 0 had AKT1 mutations.

Oncogenic Drivers in Lung Cancer ■■ An oncogenic driver was identified in 64% of patients tested for all 10 drivers. ■■ Overall survival was significantly longer in patients with an oncogenic driver who did vs did not receive genotype-directed therapy.

female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID 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 REVLIMID 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 Lenalidomide 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 REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with REVLIMID 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 REVLIMID. 5.2 REVLIMID REMS™ program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber 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 REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration (2.1, 2.2, 2.3)]. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration (2.2)]. In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)].

Genotype-Directed Therapy Results were used to select a targeted therapy or clinical trial for 275 (28%) of the total 1,007 patients and for 44% of patients with identified drivers. Of the 175 patients with EGFR sensitizing mutations, 146 (83%) were treated with targeted therapy, including 130 with erlotinib alone and 16

In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous Thromboembolism Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors. 5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. 5.6 Second Primary Malignancies Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. 5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to Cosmos Communications K

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with another EGFR inhibitor alone or in combination. Of the 35 patients with other EGFR mutations, 23 (66%) were treated with an EGFR inhibitor alone, another targeted agent, or a combination. Of 80 patients with ALK rearrangements, 52 (65%) were treated with crizotinib continued on page 66

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Journal Spotlight Lung Cancer Mutation Consortium continued from page 65

(Xalkori). Of the 23 patients with ERBB2-mutant disease, 11 (48%) received an ERBB2-targeted agent. Of the 245 with KRAS mutations, 22 (9%) were treated with investigational targeted agents.

Survival Data Among the 1,007 patients tested for at least one driver, 93% had sufficient information to be included in the survival analysis, at which time 456 were alive and 482 had died; in this group, median follow-up was 1.7 years. Median overall survival for all 938 patients with adequate data was 2.7 years (95% confidence interval [CI]

= 2.4–2.9 years). The median survival of individuals with each of the five most common oncogenic drivers ranged from 2.0 years (mutations in two genes) to 4.3 years (ALK), with a significant difference across groups (P < .001). Median overall survival was 3.49 years (interquartile range [IQR] = 1.96–7.70) among the 260 patients with an onco-

withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor lysis syndrome [see Warnings and Precautions (5.9)] • Tumor flare reactions [see Warnings and Precautions (5.10)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.3 Clinical Trials Experience in Mantle Cell Lymphoma In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years. Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events. Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) General disorders and administration site conditions Fatigue 45 (34) 9 (7) Pyrexia$ 31 (23) 3 (2) Edema peripheral 21 (16) 0 Asthenia$ 19 (14) 4 (3) General physical health deterioration 3 (2) 2 (1) Gastrointestinal disorders Diarrhea$ 42 (31) 8 (6) Nausea$ 40 (30) 1 (<1) Constipation 21 (16) 1 (<1) Vomiting$ 16 (12) 1 (<1) Abdominal pain$ 13 (10) 5 (4) Musculoskeletal and connective tissue disorders Back pain 18 (13) 2 (1) Muscle spasms 17 (13) 1 (<1) Arthralgia 11 (8) 2 (1) Muscular weakness$ 8 (6) 2 (1) Respiratory, thoracic and mediastinal disorders Cough 38 (28) 1 (<1) Dyspnea$ 24 (18) 8 (6) Pleural Effusion 10 (7) 2 (1) Hypoxia 3 (2) 2 (1) Pulmonary embolism 3 (2) 2 (1) Respiratory distress$ 2 (1) 2 (1) Oropharyngeal pain 13 (10) 0 Infections and infestations Pneumonia@ $ 19 (14) 12 (9) Upper respiratory tract infection 17 (13) 0 Cellulitis$ 3 (2) 2 (1) Bacteremia$ 2 (1) 2 (1) Staphylococcal sepsis$ 2 (1) 2 (1) Urinary tract infection$ 5 (4) 2 (1) (continued)

genic driver and genotype-directed therapy, 2.4 years (IQR = 0.88–6.20) among the 318 patients with any oncogenic driver who did not receive genotypedirected therapy, and 2.08 years among the 360 patients with no driver (P < .001 overall). For the comparison of patients with an oncogenic driver who did vs did not receive genotype-directed therapy,

Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) Skin and subcutaneous tissue disorders Rash + 30 (22) 2 (1) Pruritus 23 (17) 1 (<1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia% $ 48 (36) 37 (28) Anemia$ 41 (31) 15 (11) Leukopenia$ 20 (15) 9 (7) Lymphopenia 10 (7) 5 (4) Febrile neutropenia$ 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (<1) Hypokalemia 17 (13) 3 (2) Dehydration$ 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure$ 5 (4) 2 (1) Vascular disorders Hypotension@ $ 9 (7) 4 (3) Deep vein thrombosis$ 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin$ 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects @ - AEs where at least one resulted in a fatal outcome % - AEs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed + - All PTs under HLT of Rash will be considered listed The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma. General disorders and administration site conditions: Chills Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysguesia, headache, neuropathy peripheral Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma. Respiratory, Thoracic and Mediastinal Disorders: Chronic obstructive pulmonary disease Infections and Infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (incl cysts and polyps): Basal cell carcinoma Cardiac Disorder: Supraventricular tachycardia 6.4 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. 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 [see Warnings and Precautions Section (5.5 to 5.8)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of Cosmos Communications K

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Journal Spotlight

propensity score-adjusted analysis adjusting for sex, age, performance status, smoking history, stage, prior therapy, and time from diagnosis of metastatic disease to enrollment yielded a hazard ratio of 0.69 (P = .006). Among patients with the five most common oncogenic drivers who received genotype-directed therapy, median over-

all survival was 2.69 years in patients with oncogenic drivers in two genes, 2.70 years in those with other EGFR mutations, 3.78 years in those with EGFR sensitizing mutations, 4.85 years in those with KRAS mutations, and not reached in those with ALK mutations. There was no significant difference in overall survival across the groups (P = .32).

treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions. In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp). 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 7.3 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone [see Warnings and Precautions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1)] Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID 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. Lenalidomide caused thalidomide-type limb defects in monkey offspring. 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. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the

The investigators concluded, “Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.” n

rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 8.3 Nursing mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, 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 in pediatric patients below the age of 18 have not been established. 8.5 Geriatric use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age. Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two 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 one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID 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 REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. 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. REVLIMID treatment must be discontinued during this evaluation. Cosmos Communications K

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Disclosure: The study was entirely supported by a grant from the National Cancer Institute. For full disclosures of the study authors, visit jama. jamanetwork.com.

Reference 1. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014.

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Announcements

Patricia M. LoRusso, DO, to Join Yale Cancer Center

atricia M. LoRusso, DO, a leading expert on drug development through clinical trials, will join Yale Cancer Center in August as a Professor of Medicine and Associate Director of Innovative Medicine at Yale Cancer Center in New Haven, Connecticut.

Dr. LoRusso brings more than 25 years of expertise in medical oncology, drug development, and early phase clinical trials. Prior to her Yale appointment, Dr. LoRusso served in numerous leadership roles at Wayne State University’s Barbara Karmanos

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)]. 8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route. 10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg. In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats. A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility. 17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindicatons (4.1)]. REVLIMID is a thalidomide analog and can 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 REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID 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 two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. 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 REVLIMID 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 REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID 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 REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Cancer Institute in Detroit, most recently as Director of the Phase I Clinical Trials Program and of the Eisenberg Center for Experimental Therapeutics. “Pat LoRusso is a preeminent leader in early-phase drug develop-

REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product. Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)]. Venous Thromboembolism Inform patients that REVLIMID/dexamethasone has demonstrated significant increased risk of DVT and PE in patients with multiple myeloma [see Boxed Warnings and Warning and Precautions (5.4)]. Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)]. Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation. 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. Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, 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 REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for: Celgene Corporation Summit, NJ 07901 REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,281,230; 6,315,720; 6,555,554; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 7,119,106; 7,189,740; 7,468,363; 7,465,800; 7,855,217; 7,968,569 ©2005-2013 Celgene Corporation, All Rights Reserved. REV_MCL_HCP_BSv18 11_2013

Cosmos Communications K

1 js

ment, and she joins the cancer center at a time during which we have committed to accelerating the process of getting new drugs to patients,” said Thomas J. Lynch, MD, Director of Yale Cancer Center and Physicianin-Chief at Smilow Cancer Hospital at Yale New Haven. “She will help the center continue to make significant contributions to the global cancer problem.”

Patricia M. LoRusso, DO

Dr. LoRusso has served as cochair of the National Cancer Institute (NCI) Cancer Therapy Evaluation Program Investigational Drug Steering Committee. She also served on the scientific committee of the American Association for Cancer Research, the education and scientific committees of the ASCO, numerous peer- reviewed study sections, and NCI committees. “My primary mission is to make a difference in human lives, and one of the ways to do this is by bringing the very latest therapies to patients through clinical trials,” Dr. LoRusso said. “Yale Cancer Center has great research, great leadership, and a passionate group of scientists and physicians dedicated to fighting cancer, and this is where I want to apply my skills and passion.”

‘Transformational’ Leader Roy S. Herbst, MD, PhD, Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, and Associate Director of the Cancer Center’s Translational Research Program, called Dr. LoRusso a “truly transformational” leader. “Bringing new drugs into clinical trials, and ultimately to FDA approval, is no easy feat, and Pat has the proven ability to do this. The global cancer community has seen her achieve this time and again,” Dr. Herbst said. “Pat joining our team is going to make a huge impact on how we grow our research program and help our patients.” n

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Future of Oncology ASCO Convenes Think Tank to Tackle Disparities in Cancer Care A Conversation With Blase N. Polite, MD, MPP By Jo Cavallo

Blase N. Polite, MD, MPP

espite advances in cancer screening and in more effective therapies to treat the disease, which have led to improved outcomes and increased survival rates for millions of people with cancer, not every American is reaping the benefits of these advances. Disparities in health-care access, quality of care, and cancer outcomes remain stubbornly prevalent among minority populations, and the result is higher rates of both cancer incidence and death from cancer compared to non-Hispanic whites. According to the American Cancer Society, the death rate for cancer among African American men is 33% higher than it is among their white counterparts, and for African American women, the death rate is 16% higher than it is among white women.1 For specific diseases like breast cancer, black women are 40% more likely to die of their cancer than white women.2 To address the current state of disparities in cancer care, ASCO recently hosted a 3-day meeting with three other leading national cancer organizations, including the American Association for Cancer Research (AACR), the American Cancer Society (ACS), and the National Cancer Institute (NCI). It was the first-ever collaboration among these groups, with the specific goal of guiding future research that better examines the disparities in health-care access and outcomes in minority populations. The meeting brought together experts in cancer research, epidemiology, public health, and health-care policy, as well as patient advocates charged with reviewing the state of the science, discussing the needs and priorities in cancer disparities research, and developing a set of key recommendations. The recommendations developed by the ASCO/AACR/ACS/NCI think tank will become the basis of a joint

statement the group will issue later this year. The Executive Summary will describe the group’s findings on the state of cancer health disparities research and identify the top research needs, with a specific emphasis on funding priorities. The ASCO Post talked with Blase N. Polite, MD, MPP, Immediate Past Chair of ASCO’s Health Disparities Committee, Chair of ASCO’s Government Relations Committee, and Assistant Professor of Medicine and co–principal investigator of the Center for Interdisciplinary Health Disparities Research at The University of Chicago Medicine, about the formation of this joint partnership and its mission and goals.

Powerful Partnership Please describe how the formation of the ASCO/AACR/ACS/NCI cancer disparities think tank came about, and why it is necessary to have such a think tank. Forming a partnership of this type had been in the works for many years. The effort was originally led by Worta McCaskill-Stevens, MD, MS, Past Chair of ASCO’s Health Disparities Committee and Chief of NCI’s Community Oncology and Prevention Trials Research Group, and the idea was that we were really at a point in healthcare disparities where we needed to get the ball rolling.

Worta McCaskill-Stevens, MD, MS

There had been some really good work done over the past 15 to 20 years documenting the extent of disparities in cancer care, but we thought the science had matured to the point where it needed to move on to the intervention phase. We needed to solidify the science and take it to the next level if we were ever going to achieve a decrease and eventual elimination of cancer health disparities. Originally the idea was to produce a position paper on cancer health disparities research. But as ASCO considered the enormity of the problem, we began

moving into a much larger concept of bringing the four major players in cancer care together. ASCO, NCI, AACR, and ACS were all in alignment with this issue, and we thought what a powerful voice we would have collectively to discuss this topic and produce a joint statement declaring where we think the field of health-care disparities research should go.

Underlying Problems What are some of the reasons for health disparity in cancer research and in cancer care? The reasons differ depending on the type of cancer you are talking about. The reasons for health disparities in breast cancer are not the same as they are in colon cancer, although there is some commonality among all the cancer types. The main reason for dispari-

Finally, there are issues of “competing comorbidities.” We know, for example, in the African American community there are higher rates of obesity, diabetes, and hypertension. The question is, how do all these factors play into survival?

Potential Solutions What are some possible recommendations being considered by the committee members to reduce or eliminate disparities in cancer care? The executive committee is now working on a detailed recommendation statement that encompasses several areas, and it is still a work in progress. But some of our recommendations will include standardizing how we do this research. For example, we may recommend a CONSORT [Consolidated Standards of Reporting Trials]-like

ASCO, NCI, AACR, and ACS were all in alignment with this issue, and we thought what a powerful voice we would have collectively to discuss this topic and produce a joint statement declaring where we think the field of health-care disparities research should go. —Blase N. Polite, MD, MPP

ties in cancer care is limited access to high-quality care throughout the cancer continuum. For example, in colon cancer we know that the lower rates of colon cancer screening among minority groups probably accounts for between 50% and 60% of the disparities we see in survival rates in that cancer. In breast cancer the reasons are not as clear. The rates of mammography screening between African American and white women appear to be fairly similar, yet disparities in survivorship exist. In breast cancer survivorship differences may have to do with several factors, including economic resources, the quality of the mammography, lack of prompt follow-up care, and access to high-quality treatment. I also think differences in tumor biology in black women are contributing to lower survival rates. We know that African American woman are more likely to get more aggressive triple-negative breast cancer than white women, so obviously that will change outcome.

statement for researchers and journal editors on how health disparities research should be conducted and reported. I think there will be some recommendations on the science of how we use ancestral informative markers, the types of information we should be collecting, and questions on how diet and exercise and the genome all play into the development of different cancers. There will likely be recommendations for how we do community-based participatory research. One problem that has been clearly identified as contributing to difficulties in conducting community research is the impact of grant cycles on relationships with a community. Having a 5-year community participatory research grant and then leaving the community once the funding has ended leaves the community feeling abandoned, so we need to think about how to sustain a baseline level of community engagement. That will have to come from the comprehensive cancer centers, which need to invest in a continued on page 70

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Future of Oncology Disparities in Cancer Care continued from page 69

baseline level of research infrastructure within a community, so that there is never complete disengagement. There may be recommendations at the academic promotions level to encourage the next generation of researchers to stay in the field. One of the issues we identified at the meeting is that academics doing research in the community often have to spend 2 or 3 years building relationships within the community before they can even put the first research questions into the field to collect the first piece of data. That puts scientists on a typical 7-year promotions clock already behind the eight ball compared to scientists doing laboratory research or retrospective database reviews. Our feeling is that perhaps we should extend the promotions clock by a couple of years so more young researchers are encouraged to go into the field to produce the kind of intervention data that we need. We are also looking at the possibility of forming disparity-based research

networks in multiple institutions, so if people have research questions on disparities in cancer care, they can go to a network and see if there is interest in launching a study to answer those questions. It would help move us out of our individual silos and start connecting us with researchers throughout the country.

question we have is, are we setting up eligibility criteria that are perhaps excluding groups unnecessarily? Much of the design of clinical trials has built-in legacy eligibility—for example, issues regarding blood pressure. But if you have African American patients with slightly elevated blood

We are looking closely at eligibility criteria to determine what is necessary and what is not, and how groups are being excluded based on things like comorbidities and age. —Blase N. Polite, MD, MPP

Trial Eligibility Is the group considering changing the eligibility criteria for enrollment into clinical trials? We had an entire session devoted to this question of enrollment into clinical trials. The one issue that has clearly been on everyone’s mind for a long time, and one that ASCO’s Cancer Research Committee has been working on, is eligibility criteria for clinical trials. The big

pressure, should that be enough to exclude them from a clinical trial? We are looking closely at eligibility criteria to determine what is necessary and what is not, and how groups are being excluded based on things like comorbidities and age. One of the other issues we are considering, which is probably somewhat controversial, is should clinical trials be designed with racial and ethnic en-

rollment targets? For example, in order for a clinical study to be powered to answer disparity questions, you may need 20% of the study participants to be African American or members of other minority groups. The way clinical trial enrollment is done now, if our target goal is 1,200 people, once we reach that target, we’re done, and we try to answer whatever disparity questions we can with the number of minority participants we have. An alternative would be to set specific enrollment goals for racial and ethnic groups such that the trial could close for non-Hispanic whites, but remain open for minority groups. This will likely become increasingly important as we start looking at genomic differences by race and ethnicity, which may impact response to therapy or toxicity.

Underrepresentation of Black Patients African Americans are particularly underrepresented in cancer clinical trials. Is the legacy of the Tuskegee syphilis study3 preventing more African Americans from enrolling in clinical studies?

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Future of Oncology If you look at the research on that question, it’s not clear if that is the reason keeping African Americans from participating in clinical trials in greater numbers. In the detailed studies we have done, when minority patients are offered clinical trials, they are just as likely, or even more likely to go on a clinical trial than non- Hispanic whites. I think the problem lies with our clinical trial infrastructure and not with our patients.

Achievable Goals The think tank is charged with providing a model for cooperation among various research groups and reaching a diverse audience, including public and private funders, as well as all members of the cancer community. How might those goals be achieved? Those goals are accomplished by the powerful voice of the four organizations that are well represented in the public and private world. Each of the think tank organizations is a major funder of research, and we are all funding good research in health-care disparities, but

we need to change how we do that research. Members of our organization sit on the research review boards of many private foundations, including Stand Up To Cancer, the LIVESTRONG Foundation, and Susan G. Komen, and we have a lot of influence. If these foundations want to fund research in healthcare disparities, we can say, “Here are some questions that need to be answered, and here are recommendations that we believe you should be structuring into your review process and review criteria.” I’m hoping that the integrity and the reputation of our four groups and our broad involvement throughout the cancer-funding world will give the recommendations included in our Executive Summary the credibility and impetus to encourage their use as the model for designing cancer disparities research.

Incredible Passion What impressed you most about the meeting’s outcome? What really impressed me at our initial meeting was the incredible pas-

THE SIDE OF CANCER YOU’RE NOT SEEING

sion everyone brought to confronting the racial and economic-based disparities that affect many of our cancer patients and improving their outcomes. We were all on the same page in identifying the problems and developing solutions. That to me was the most encouraging result of the meeting, because we really are ready to take this initiative to the next level in testing and implementing solutions to reduce, if not eliminate, cancer health disparities. n

Don’t Miss in This Issue Paul A. Bunn, Jr, MD, on selection of targeted drugs in lung cancer see page 59

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

References 1. American Cancer Society: Cancer Facts & Figures 2013. Available at www. cancer.org. Accessed June 19, 2104. 2. Centers for Disease Control and Prevention: Health Disparities in Cancer. Available at www.cdc.gov/cancer/healthdisparities. Accessed June 19, 2014. 3. Centers for Disease Control and Prevention: U.S. Public Health Service Syphilis Study at Tuskegee. Available at www.cdc.gov/tuskegee. Accessed June 19, 2014.

Stuart M. Lichtman, MD, FACP, on advances in geriatric oncology see page 72

Amy P. Abernethy, MD, PhD, on discontinuing statins near end of life see page 90

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The ASCO Post | JULY 10, 2014

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ASCO Annual Meeting B.J. Kennedy Lecture

‘Physician Education Is Key’ to Continued Advances in Geriatric Oncology By Charlotte Bath

everal times during his lecture at the 2014 ASCO Annual Meeting, Stuart M. Lichtman, MD, FACP, the recipient of the B.J. Kennedy Award for Scientific Excellence in Geriatric Oncology, emphasized, “Physician education is the key” to continued advances in geriatric oncology. He specified that physician education is critical to overcoming ageism and barriers to treatment for older patients, to increasing participation of older patients in clinical trials, and to obtaining and applying data from clinical trials to optimize treatment for geriatric oncology patients. Dr. Lichtman is an attending physician at Memorial Sloan

In advancing the cause of geriatric oncology, “one of the things we’ve always had to fight is the negative perception of aging—the whole issue of ageism—and I think it is still pervasive today to some degree,” Dr. Lichtman said. Ageism is exemplified by the derogatory terms sometimes used to describe older people, such as biddy or geezer, and by stereotypes of older people as helpless victims or bizarre and comical. Ageism “is why we have such difficulty getting older patients on clinical trials,” Dr. Lichtman said. He acknowledged that positive images are “fortunately becoming more common.”

Physician education is to me truly the key to overcoming ageism, to overcoming the barriers to treatment. —Stuart M. Lichtman, MD, FACP

Kettering Cancer Center and former Chair of that institution’s 65+ Clinical Geriatric Group, and Professor of Medicine at Weill Cornell Medical College, New York. Dr. Lichtman was recognized for “outstanding leadership and scientific contributions in the field of geriatric oncology and for his dedication and commitment to mentoring young geriatric oncologists,” former ASCO President Sandra M. Swain, MD, FACP, noted in presenting the award. “For more than 2 decades, Stu Lichtman has devoted his career to providing quality care to underserved and under-

Sandra M. Swain, MD, FACP

treated older patients with cancer,” Dr. Swain stated. She is Medical Director of the Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.

Start of the Movement “Some people believe that the real start of the cancer and aging movement was in 1983,” he said, at a meeting entitled Perspectives on Prevention and Treatment of Cancer in the Elderly. Among the driving forces of that meeting were B.J. Kennedy, MD, and Rosemary Yancik, PhD. “In the summary of that meeting, Rosemary Yancik identified a number of pervasive issues, the issues that we are still talking about today,” Dr. Lichtman noted.1 Those issues involve discrepancies between physiologic and calendar age, changes in the population’s age structure and cancer control in the elderly, and the roles of physicians and the older people in cancer prevention and treatment. “She also identified a number of approaches to increase the knowledge base,” Dr. Lichtman continued. These included prospective clinical trials, epidemiologic and longitudinal studies, as well as assessments of the pharmacokinetics and drug sensitivity of older patients with cancer. The conference participants concluded that there were several pressing needs: the need to examine factors unique to older persons, the need to obtain baseline data on the

clinical interface of cancer and aging, and “particularly important” in Dr. Lichtman’s view, the need for an “interdisciplinary team approach far greater than an occasional collaboration.” In 1989, provoked by two trials of adjuvant breast cancer treatment that excluded patients over 65 for arbitrary reasons, Dr. Lichtman and Daniel R. Budman, MD, at the time colleagues at North Shore University Hospital, Manhasset, New York, wrote a letter to The New England Journal of Medicine arguing that “patients over 65 should be given due consideration in terms of receiving adjuvant therapy and participating in clinical trials.”2 “This is really where my cancer in the elderly career started,” Dr. Lichtman said. In 1991, he wrote an article in the New York State Journal of Medicine noting that elderly patients were underserved in cervical cancer screening.3 Many other articles followed. Dr. Lichtman has published more than 100 articles, although not all related to cancer in the aging population, in peer-reviewed journals.

“We were talking about the ASCO curriculum today actually,” Dr. Lichtman noted, “and we really have to improve upon it, update it. But when you think back on all the issues about cancer and ageism and how to do the things we want to do, physician education is to me truly the key to overcoming ageism, to overcoming the barriers to treatment.”

Optimize Data on Older Patients “Probably one of the most important studies to come out of the last couple of years,” Dr. Lichtman stated, was on adjuvant chemotherapy in older women with early-stage breast cancer, led by Hyman B. Muss, MD, Director of UNC Lineberger Comprehensive Cancer Center’s Geriatric Oncology Program, and published in The New England Journal

Meeting Milestones In 1994, the Cancer in the Elderly meeting in Genoa, Italy, had “a truly international focus” and was the progenitor of the International Society of Geriatric Oncology (SIOG), Dr. Lichtman reported. That meeting also established “geriatric oncology as we know it,” he added. “ASCO got on board in the year 2000,” with the educational symposium, Cancer Care in the Elderly: An Integrated Approach. “This was truly important to me in terms of my journey through geriatric oncology because this is where I started my collaboration with Arti Hurria,” Dr. Lichtman related. Arti Hurria, MD, received the B.J. Kennedy Award last year and is Director of the Cancer and Aging Program at the City of Hope Comprehensive Cancer Center in Duarte, California. In 2002, ASCO issued a curriculum for cancer care in the older population.

Hyman B. Muss, MD

of Medicine in 2009.4 “One of the strong points of that study was that physician/ patient preference was allowed to be part of the therapeutic decision-making.” The study also pointed out that “welldesigned databases can provide a huge amount of important information if designed in a prospective, well-thought-out model,” Dr. Lichtman added. Database studies have shown that compared to younger women, older women with metastatic breast cancer or ovarian cancer who take paclitaxel have increased risk of neurotoxicity. The lessons learned from this, Dr. Lichtman said, are that “while randomized studies are preferable, observational studies are important. We need to do longitudinal assessment, and the analysis of well-constructed databases is a gold mine of data. It has much to teach us, and some of it lies still hidden.”

Can Toxicity Be Predicted?

Arti Hurria, MD

A study led by Dr. Hurria “looking at various clinical predictors of toxicity has become an important component of multiple clinical trials and is embedded now in the assessment of older patients with cancer,” Dr. Lichtman noted.5 “One of the highlights of this was the idea that

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ASCO Annual Meeting we could possibly make very important predictions of toxicity with really very simple and straightforward clinical parameters—hemoglobin, creatinine clearance, and very simple history-taking and geriatric assessments. I think it points out to clinicians that you don’t have to do a 12-hour comprehensive assessment.” This study and others have shown that an assessment of toxicity predictors can be worked into a physician’s busy schedule and “can be very valuable in terms of helping us to make clinical decisions,” Dr. Lichtman said. “The model was highly predictive of grade 3+ toxicity,” Dr. Lichtman noted, and particularly improved on the Karnofsy performance score. “Clinical judgment is limited and is often misleading. We need these aids.” Predictive models need to be evaluated in different clinical situations. “In a targeted-therapy environment in which we are giving less chemotherapy, does [a predictive model] have the same importance? We really have to think about how we are going to assess patients who are getting targeted therapy alone, which is going to become more popular.”

Older patients constitute “the largest group of cancer survivors because of all we are doing.” n

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

References 1. Yancik R, Carbone PP, Patterson WB, et al (eds): Perspectives on Prevention and

Now

OAK

Good Position to Advance The field of geriatric oncology is in a good position to advance, according to Dr. Lichtman. “ASCO plays an important role in the future of geriatric oncology, particularly as publisher of the Journal of Clinical Oncology.” Dr. Lichtman stated. Other organizations such as the International Society of Geriatric Oncology, the Cancer and Aging Group, and the Alliance also continue to make valuable contributions. “We’ve come a long way,” in geriatric oncology, Dr. Lichtman concluded.

4. Muss HB, Berry DA, Cirrincione CT, et al: Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360: 2055-2065, 2009. 5. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 29:3457-3465, 2011.

Enrolling

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

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

MPDL3280A1

What’s Needed in Clinical Trials? Elder-specific trials are still needed, he said, “because the current system we have doesn’t seem to be working, if over 30 years, we are still decrying the fact that older persons are still underrepresented in clinical trials.” Studies looking at the barriers to participation in clinical trials have shown that in some cases, the barriers “are us—the physicians—to a large extent,” Dr. Lichtman said. “Again, it points out that physician education is really the key.” For large randomized trials that are not elder-specific, but in which older persons may make up 15% to 20% of patients, Dr. Lichtman proposed that authors “set up the trial to optimize the amount of data that we can obtain from older patients.” Currently, he said, the data on older patients are not always readily available.

Treatment of Cancer in the Elderly, Aging, vol 24. New York, Raven Press, 1983. 2. Lichtman SM, Budman: Adjuvant therapy for node-negative breast cancer (correspondence). N Engl J Med 321:469473, 1989. 3. Lichtman SM: B:7.75” Geriatric oncology: cervical cancer screeningT:7” in elderly women. S:6.5”1991. NY State J Med 91:147-149,

(an engineered anti-PDL1 antibody)

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

N=850

Randomized 1:1

Docetaxel

Primary Endpoint: • Overall survival

Secondary Endpoints: • Safety: incidence of adverse events • Overall response rate • Progression-free survival • Duration of response

Key Inclusion Criteria2: • Locally advanced or metastatic NSCLC • • • •

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

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

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

The ASCO Post | JULY 10, 2014

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Announcements

UC Davis Comprehensive Cancer Center Tailors Pilot Program to Help Patients Adhere to Oral Chemotherapy

University of California, Davis, Comprehensive Cancer Center program designed to better manage cancer patients taking oral chemotherapy drugs has demonstrated that one-on-one counseling, education, and monitoring can improve adherence to therapy.

Issues in Adherence The rise in oral chemotherapy use has heightened the need for coordinated cancer care. Oncology pharmacists and physicians worked together at UC Davis Comprehensive Cancer Center to create the Medication Adherence Pilot Program to ensure that patients stick to their regimens to safely maximize the drugs’ effectiveness and minimize or manage side effects. Oral chemotherapy prescriptions are on the rise because many newer drugs, which target individual genes involved in tumor growth, are being developed in oral formulations, said Ted Wun, MD, a medical oncologist and Chief of the Division of Hematology and Oncology. In addition, oral chemotherapy agents are created to allow for more continuous exposure of the drug in the patient over time, which can be more effective and may be less toxic. When oral treatment is prescribed exclusively, patients require fewer office visits and may get a greater sense of control over their treatment, Dr. Wun said. Patients taking oral chemotherapy may experience potentially life-threatening side effects without the immediate support they need. Or, patients may stop taking the medication or not follow the directions correctly, which can affect treatment efficacy, produce misleading treatment results, and cause higher mortality. “Patients are monitored when they’re here, but when they go home, it’s harder to monitor,” said Josephine Lai, PharmD, the cancer center’s pharmacy supervisor, who has been assessing oral chemotherapy adherence rates since 2012. “Unlike other chronic care medications, oral chemotherapy drugs can be more complicated.

to monitor patients’ progress, notify oncologists of any issues and offer practical tips, such as how to maintain a medication calendar or handle a missed dose. Early indications suggest the pro-

rolled in the program. Beginning this fall, the Cancer Center will employ a full-time pharmacist dedicated to the program, offering the services to all UC Davis cancer patients. n

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Pilot Program Dr. Lai and colleagues in the UC Davis Departments of Pharmacy and Internal Medicine, and the Division of Hematology and Oncology launched the Cancer Center Medication Adherence Pilot Program in September 2013. Patients enrolled in the program can make an appointment with a pharmacist or a nurse practitioner anytime they have a question about their drug regimen. Pharmacists also check in regularly each month

gram is working. In one assessment of 44 patients enrolled in the pilot program, 92% adhered to their drug regimens. Today, 80 patients at UC Davis Comprehensive Cancer Center are en-

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News

Life: Magnified

A new exhibit brings the beauty and promise of science to the public By Jo Cavallo

n June 10, Life: Magnified, an eyecatching photo exhibit of scientific images, opened at Washington Dulles International Airport’s Gateway Gallery in Chantilly, Virginia. The exhibit features 46 high-resolution backlit images of cells from the body, including the brain, blood, eye, skin, liver, and muscle, as well as cells from bacteria and viruses magnified 50,000 times using the latest microscopy techniques. The brilliant colors in the images show cells that have been dyed with chemicals to allow scientists to study structures within the cells. Each image is accompanied by a descriptive caption, and the result is a stunning display of scientific research and the medical advances it produces (see below). Cosponsored by the National Institutes of Health’s National Institute of General Medical Sciences (NIGMS), the American Society for Cell Biology, and the Metropolitan Washington Airports Authority Arts Program, the 46 images

Skin Cancer Cells

1. Skin Cancer Cells—This image shows the uncontrolled growth of cells in squamous cell carcinoma, the second most common form of skin cancer. Photo created by Markus Schober, PhD, and Elaine Fuchs, PhD, The Rockefeller University, New York, New York. Five of the images and their captions from Life: Magnified are published here. To view the full exhibit, visit the NIGMS’ website at www.nigms.nih.gov/education/ life-magnified/pages/default.aspx.

in the exhibit were culled from more than 600 submitted by researchers from 17 states across the United States and also include images submitted by researchers from Germany, Singapore, and Spain. Each of the images depicts how the study of different cell types contributes to the understanding of human health and show in detail how abnormal cell growth can

Making Science Exciting “The idea of the exhibit was to find a way to bring science to the public to draw them into science through its beauty and give people a chance to stop and think about the relevance of the images they are seeing and the research that created them to eventually curing diseases,” said Jon R. Lorsch, PhD, Di-

We wanted to show the importance of basic, fundamental science in creating the foundation that leads to new therapies and other medical advances. — Jon R. Lorsch, PhD

lead to diseases like cancer. The exhibit represents research funded by NIGMS and nine other NIH institutes.

Bone Cancer Cells

2. Bone Cancer Cell (nucleus in light blue)—This image shows an osteosarcoma cell with DNA in blue, mitochondria in yellow, and actin filaments, part of the cellular skeleton, in purple. One of the few cancers that originate in the bones, osteosarcoma is extremely rare, with less than 1,000 new cases diagnosed each year in the United States. Photo created by Dylan Burnette, PhD, and Jennifer Lippincott-Schwartz, PhD, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

rector of NIGMS. “We wanted to show the importance of basic, fundamental science in creating the foundation that

Skin Cancer Cells From A Mouse

3. Skin Cancer Cells From a Mouse Show How Cells Attach at Contact Points— These skin cancer cells come from a mouse. The two cells shown here are connected by actin (green), a protein in the cellular skeleton. Actin is required by many cells for normal movement, but it also enables cancer cells to spread to other parts of the body. Photo created by Catherine Galbraith, PhD, and James Galbraith, PhD, Oregon Health and Science University, Knight Cancer Institute.

leads to new therapies and other medical advances.” The display of Life: Magnified is located along Concourse C at Washington Dulles International Airport, a two-level walkway that accommodates about 2.5 million passengers each year. “I am particularly eager to see young people get excited about science when they see the exhibit,” said Dr. Lorsch. “I have an image of a young girl with a suitcase walking with her parents and stopping at the photos and asking, ‘What’s that?’ and becoming excited about science and medicine. It would be terrific if Life: Magnified could have that catalyzing effect on people, especially young people.” Life: Magnified is on display through November 2014. Once the exhibit closes at Washington Dulles International Airport, some of the images may go on display at the National Institutes of Health, according to Dr. Lorsch. n

Chromosomes Lined Up

4. Chromosomes (Blue) Lined Up for Cell Division—This cell is preparing to divide. Two copies of each chromosome (blue) are lined up next to each other in the center of the cell. Next, protein strands (red) will pull apart these paired chromosomes and drag them to opposite sides of the cell. The cell will then split to form two daughter cells, each with a single, complete set of chromosomes. Photo created by Jane Stout, Indiana University.

Dividing Cells

5. Dividing Cells Showing Chromosomes (Purple) and Cell Skeleton (Green)—This pig cell is in the process of dividing. The chromosomes (purple) have already replicated and the duplicates are being pulled apart by fibers of the cell skeleton known as microtubules (green). Studies of cell division yield knowledge that is critical to advancing understanding of many human diseases, including cancer and birth defects. Photo created by Nasser Rusan, PhD, National Heart, Lung, and Blood Institute, National Institutes of Health.

The ASCO Post | JULY 10, 2014

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FDA Update

FDA Launches ‘OpenFDA’ Initiative to Ease Access to Public Health Data

he U.S. Food and Drug Administration (FDA) has launched openFDA, a new initiative designed to make it easier for web developers, researchers, and the public to access large, important public health datasets collected by the Agency. In alignment with the recent Presidential Executive Order on Open Data and the Department of Health and Human Services Health Data Initiative, openFDA will make the FDA’s publicly available data accessible in a structured, computer readable format. This will make it possible for technology specialists, such as mobile application creators, web developers, data visualization artists, and researchers to quickly search, query, or pull massive amounts of public information instantaneously and directly from FDA datasets on an as-needed basis. OpenFDA utilizes a search-based Application Program Interface (API) to collect large amounts of existing

search, the FDA decided to phase in openFDA beginning with an initial pilot program involving the millions of reports of drug adverse events and medication errors that have been submitted to the FDA from 2004 to 2013. Previously, the data was only available

through difficult to use reports or Freedom of Information Act requests. The adverse events data made available under this initiative do not contain any data that could potentialS:6.875” ly be used to identify individuals or other private information. The pilot

will later be expanded to include the FDA’s databases on product recalls and product labeling. “Through this new and novel approach to data organization, these reports will be available in their entirety so that software developers can build

THE STORM FROM Exploring the connections between the microenvironment and intracellular signals

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publicly available data, offering developers the ability to search through text within that data, ranking results much like a search using Google would do. This method then allows them to build their own applications on top of openFDA, giving them a large amount of flexibility to determine what types of data they would like to search and how they would like to present that data to end-users. This enables a wide variety of applications to be built on one common platform. “The openFDA initiative leverages new technologies and methods to unlock the tremendous public data and resources available from the FDA in a user-friendly way,” said Walter S. Harris, the FDA’s Chief Operating Officer and Acting Chief Information Officer. “OpenFDA is a valuable resource that will help those in the private and public sectors use FDA public data to spur innovation, advance academic research, educate the public, and protect public health.” The initiative is the result of extensive research with internal officials and external developers to identify those datasets that are in recurrent demand and are traditionally fairly difficult to use. Based on this re-

BTK

B-cell malignancies include Hodgkin lymphomas, 85% of non-Hodgkin lymphomas, and some leukemias and myelomas. These diseases can present with nonspecific symptoms and can be difficult to diagnose and treat. Recently, emerging science has revealed the essential role of signaling pathways in B-cell malignancies. These pathways, which normally help to regulate B-cell function and interactions within the microenvironment, may become dysregulated in these diseases. The result can be malignant B-cell survival and disease progression. Pharmacyclics, Inc., and Janssen Biotech, Inc., are committed to uncovering new insights into this critical connection between intracellular signaling and the tumor microenvironment.

For more information, visit www.BCellSignals.com

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FDA Update

tools to help signal potential safety information, derive meaningful insights, and get information to consumers and health care professionals in a timely manner,” said Taha Kass-Hout, MD, FDA’s Chief Health Informatics Officer. “OpenFDA offers a scalable platform that can be easily searched and queried across many distinct datasets,

and can be easily redeployed or altered to fit a variety of purposes, and provides an innovative public data search and analytics solution.” In addition to providing datasets, openFDA will encourage the innovative use of the S:6.875” agency’s publicly available data by highlighting potential data applications and providing, a place for

community interaction with each other and with FDA domain experts. The FDA will continually work to identify additional public datasets to make available through openFDA. More information can be found at open.FDA.gov or you can email the FDA for more information at open@fda.hhs.gov. n

WITHIN

Diagnostic Imaging Agent Approved for Use in Patients With Head and Neck Cancer

he U.S. Food and Drug Administration (FDA) recently approved a new use for technetium 99m tilmanocept (Lymphoseek Injection), a radioactive diagnostic imaging agent used to help doctors determine the extent to which squamous cell carcinoma has spread in the body’s head and neck region.

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In 2013, tilmanocept was approved to help identify lymph nodes closest to a primary tumor in patients with breast cancer or melanoma. With the recent approval, the agent can now be used to guide sentinel lymph node biopsy in patients with cancer of the head and neck. This new indication will allow for the option of more limited lymph node surgery in patients with sentinel nodes negative for cancer. “For some patients with head and neck cancer, removal and pathological examination of lymph nodes draining a primary tumor is an important diagnostic evaluation,” said Libero Marzella, MD, PhD, Director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “To use [tilmanocept], doctors inject the drug into the tumor area and later, using a handheld radiation detector, find the sentinel lymph nodes that have taken up [tilmanocept]’s radioactivity.”

Clinical Trial Results BTK

Creative representation of select simplified signaling pathways. Illustration not to scale.

PRC-00251

For this new indication, tilmanocept’s safety and effectiveness were established in a clinical trial of 85 patients with squamous cell carcinoma of the lip, oral cavity, and skin. All patients were injected with tilmanocept. Surgeons subsequently removed suspected lymph nodes—those identified by the imaging agent and those based upon tumor location and surgical practice—for pathologic examination. Results showed that tilmanocept–guided sentinel lymph node biopsy accurately determined if the cancer had spread through the lymphatic system. The most common side effect identified in the clinical trial was pain or irritation at the injection site. n

The ASCO Post | JULY 10, 2014

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Health-Care Policy IOM Workshop

‘Financial Toxicity’

continued from page 1

S. Yousuf Zafar, MD, Associate Professor of Medicine, Duke University, Durham, North Carolina, used the phrase “financial toxicity” to refer to outof-pocket costs: an average of $4,800 per year (even more for oral drugs) for cancer patients compared to $450 for others. He related the story of a patient with pancreatic cancer who did well on a first course of chemotherapy but refused ongoing treatment. When Dr. Zafar asked

for commercial health plans by 2018. To control spending, many payers have established requirements for high costsharing that result in some patients having to eschew beneficial but expensive drugs. Dr. Fendrick noted three points concerning ensuring consumer access to specialty medicines: • For many patients and clinical indications, they represent money well spent.

Patients care about high out-ofpocket costs, but they want highquality and compassionate care—and they want it close to home. —Bruce Gould, MD

• Indiscriminate high cost-sharing can be harmful to patients and employers. • A variety of tactics—including value-based insurance design, can ensure that the right patients have access to the right drugs. For many patients and clinical indications, they represent money well spent, but indiscriminate high cost sharing can be harmful to patients and employers. However, a variety of tactics can ensure that the right patients have access to the right drugs. Bruce Gould, MD, Vice President, Community Oncology Alliance, Washington, DC, said that both practice and drug costs are increasing, even as reimbursement for administrative services has decreased by a third in the past decade. “And sequestration hit us hard,” he said. According to Dr. Gould, oncology practice is in crisis. As of 2013, he said, 131 practices have merged because they cannot go it alone, 288 have closed their doors, 407 are struggling financially, and 469 have aligned with hospitals, where the cost of care is 20% to 80% higher. Dr. Gould noted that payers recognize that cancer treatment is managed care’s fastest growing driver. “They want standardized treatment at the lowest cost and are particularly concerned about the high cost of hospital-based care. In many cases, the payers have limited negotiating power with hosptials because they need the full ‘basket’ of hospital services,” he said. “Patients care about high out-of-pocket costs, but they want high-quality and compassionate care—and they want it close to home.”

him why, the patient said that he had already spent thousands of dollars and didn’t want to leave his wife and children saddled with huge debt after his death. Cancer has effects beyond the disease itself. About 46% of patients have spent savings that were meant for other things, 46% had to cut down on basics such as groceries and clothing, and 68% cancelled a vacation. Further, the risk of bankruptcy is 2.65 times as high for cancer patients as for those without cancer. “Large out-of-pocket expenses mean that the likelihood of nonadherence to prescribed regimens increases by 42%. Does this affect survival? I don’t know,” said Dr. Zafar, “but the possibility warrants investigation.” Dr. Fendrick explained why out-ofpocket costs are unnecessarily high. First, cost-effectiveness varies. Many specialty medicines provide variable benefits depending on the circumstances in which they are used. Second, until 2002, most prescription drug plans had one or two tiers with corresponding methods of payment. The lower tier had a flat copayment, and the higher had a percentage co-insurance (usually 10%). Now plans have three or more tiers, some four or five. Specialty medicines sit at the highest tiers and require coinsurance of 30% to 50%. The greater the cost-sharing, by whatever formula is used, the more likely it is that a patient will not begin or continue to take a particular medication. This is a serious, potentially lifethreatening, problem. Sometimes certain savings (reduced emergency room visits and hospitalizations) can offset the high cost of a drug,

but there is no way to accurately predict this. Moreover, for many employers, the cost of medical care may be secondary to the cost of absenteeism. Dr. Fendrick quoted a 2009 study that showed that lost productivity due to poor health cost 2.3 times more than the cost of medical and pharmacy spending combined.

and Scotland to determine if they value delivering health benefits to cancer patients more highly than to others. The majority (64%) did not. They wanted fair allocation, regardless of disease. “There was a consistent message that cancer is no more special than other diseases. However current policy does not reflect this.”

Keynote on Drug Pricing

Kalipso Chalkidou, MD, PhD

Differing Perspectives Kalipso Chalkidou, MD, PhD, Director of NICE (National Institute for Health and Care Excellence) International, London, noted that big pharma is the most profitable international industry, second only to tobacco. “In the United States, investors bet huge amounts of money on winning drugs, as a result of great profitability not necessarily linked to clinical results nor what payers are willing to pay. It is hard to control cancer drug prices internationally.” The National Health Service has moved to value-based drug pricing. Patients in the United Kingdom have the right to drugs and treatments if, based

Alex Bastian, MBA, Vice President, Market Access, Health, Gf K Custom Research, LLC, San Francisco, described the oncology drug market. The effective lifespan of a drug is the time between approval and loss of exclusivity. “The more time it spends at peak [potential maximum usage], the more money it makes, and the faster it reaches peak, the better.” This seems straightforward, but consider the following: • The time a drug takes to reach peak depends on a number of variables: the speed and breadth of coverage, physicians’ willingness to prescribe it, patients’ urgency to take it, and the demand built up during development. • Price has an impact on perceived value, the speed and breadth of coverage, and patients’ willingness or reluctance to take a new drug. • Loss of patent exclusivity marks the end of a product’s life. Manufacturers of biologics have not yet faced

Large out-of-pocket expenses mean that the likelihood of nonadherence to prescribed regimens increases by 42%. Does this affect survival? I don’t know, but the possibility warrants investigation. —S. Yousuf Zafar, MD

on evidence of benefit, their physicians believe they are clinically appropriate. Decisions are made nationally, by NICE, but there is room for local discretion based on clinical opinion. “No evidence has been found,” said Dr. Chalkidou, “to prioritize cancer above other severe conditions or to prioritize drug treatments above any other interventions. Despite the fact that there is little evidence to support this, England has set up a Cancer Drugs Fund to pay for drugs—on a case by case basis—to which NICE has said no or which have not been reviewed by NICE yet.” She described a survey of more than 4,000 people across Wales, England,

this phenomenon, and the price of biosimilars is not as low as expected. • If the drug was approved under accelerated or other exceptional approval, pricing also is exceptional. • If a manufacturer cannot get a drug to market quickly, it must make up for lost commercial potential by extending its lifespan and/or increasing peak sales. “Clinicians do not have to use new therapies,” added Mr. Bastian. “They can wait for clinical guidelines or choose alternatives. Also, a number of states have enacted laws (concerning oral drugs, step therapy, clinical trials, continued on page 80

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Health-Care Policy IOM Workshop continued from page 78

cost-sharing, and out-of-pocket maximums) that protect and define coverage boundaries or limit payers’ ability to manage oncology practice.” Further, the number of oncology drugs that have companion biomarkers has doubled from 20% to 40% over the past 13 years, thus decreasing the size of the eligible patient population. Between 2001 and 2013, the average treatment population for oncology manufacturers has decreased by 242 patients per year. This adds up eventually. “Conflicting incentives affect prescribing habits,” said Mr. Bastian. First, the site of care affects drug costs. For example, daunorubicin costs 975% more in a hospital than in the community, and mitoxantrone is 372% more expensive [in a hospital]. Second, academic physicians believe that cost should not be a factor in choice of drugs. In fact, 78% of them would prescribe effective therapy regardless of cost. Physicians in private practice, though, say that cost is a more important factor. Oncology drugs are the most expensive in the pharmacopeia, but manufacturers keep looking for new, ever-pricier ones, and patients demand whatever they perceive as hope-affirming. The United States invests about $60 billion each year in medical research, only 40% of which is federally funded. Oncology is by far the largest slice of this pie. “A permanent 1% reduction in mortality from cancer has a value to current and future Americans of $500 billion, and improvement in quality of life can be even more valuable,” said Mr. Bastian. “Is this worth it?” he asked.

Paradoxes of Cancer Drug Reimbursement An afternoon panel discussed some of the ins and outs of access to and payment for cancer drugs. Rena M. Conti, PhD, Assistant Professor of Health Policy and Economics, Departments of Pediatrics and Health Studies, The University of Chicago, described the Medicare 340B Drug Pricing Program, which allows certain underfinanced providers to purchase outpatient drugs at a discount. It does not depend on patients’ insurance. As of October 2013, 11,000 providers participate. The 340B program is a drug dis-

count program. It used to be a small program used by safety net clinics and selected hospitals taking care of uninsured and underinsured patients to acquire drugs at 50% off list prices. It has now ballooned into an enormous program; one-third of all hospitals in the U.S. now participate, with $7.5 billion in annual drug sales. “Our research suggests the hospi-

amount of money we all pay for these drugs,” Dr. Conti explained. Lee N. Newcomer, MD, MHA, Senior Vice President, U nitedHealthcare, talked about oral vs intravenous drugs. “The most important decision should be which drug is best for the disease, but toxicity, dosing, compliance, reimbursement, and distribution channels all play a role,” he said.

These trends complicate efforts by payers to control spending and implement new payment methods for oncologic care. —Eric Hammelman, MBA

The most important decision should be which drug is best for the disease, but toxicity, dosing, compliance, reimbursement, and distribution channels all play a role. —Lee N. Newcomer, MD, MHA

tals that qualify for the program based on the vulnerability of their patients treated in the inpatient setting alone, are likely pushing the envelope on the program’s intent by affiliating with outpatient clinics, which largely serve well insured and affluent patient populations. This is a major policy concern for two reasons,” Dr. Conti said. “First, the discounts available to hospitals and affiliated medical providers do not get passed onto patients or their insurers,” she continued. “Instead, hospitals can keep the revenue generated when they acquire the drug at deep discounts and are reimbursed by patients and insurers at full price. There is very little oversight on how much revenue is being generated by these providers through these activities or whether this revenue is actually being used to provide cancer care to vulnerable patients,” she noted. “Secondly, drug manufacturers know that hospitals and medical providers are pushing the envelope on the program’s intent in oncology and are baking these discounts into the list prices of new and existing cancer drugs. This raises the

Toxicity does not go away with oral drugs and in some cases is worse than with intravenous drugs. According to Dr. Newcomer, oral dosing is fraught with poor tolerability, as well as fixed and arbitrary adjustments due to pill size, and this constraint often causes unbalanced clinical trials. Compliance is poor with oral drugs—only 58% overall, he said. In short, he commented, oral agents are neither superior nor inferior to intravenous drugs, both have clinical trade-offs, and cost remains an issue regardless of route of administration. Private practice vs hospital-based care is fast becoming a major issue— with hospitals winning because physicians are moving there, and hospitals are making a concerted effort to increase their share of the market, said Eric Hammelman, MBA, Vice President, Avalere Health, LLC, Washington, DC. In theory, Medicare reimburses hospitals and physicians the same for the same drug, but utilization differences result in bottom-line payment differences, so hospitals make more money. (There is, however, evidence that hospi-

tals are reimbursed at a higher rate for the same drugs by private payers.) “These trends complicate efforts by payers to control spending and implement new payment methods for oncologic care,” Mr. Hammelman said.

Value-Based Insurance Design Dr. Fendrick described value-based insurance design. “It reduces barriers to high-value clinical services and providers and discourages use of services and providers that are of lower value. Value-based insurance design is driven by clinical nuance, which recognizes that medical services differ in the benefit provided. Benefit derived from a specific service depends on three factors: characteristics of the patient receiving it, the provider, and where the service is delivered. Plans incorporating value-based insurance design establish lower cost-sharing on high-value services, drugs, providers, and settings as a means to increase utilization that represents worthwhile investment in health.” Value-based insurance design can be applied to drugs by ensuring that cost-sharing is related to clinical value, not simply acquisition cost. It works by imposing no more than modest cost-sharing in high-value medicines and abolishing four- and five-tier rankings to promote access to all medically necessary treatments. This approach limits clinical differentiation among treatments but provides access to all potentially important ones. Payers can be more selective by lowering high costsharing for drugs that consistently deliver outstanding value, which can then be moved from higher to lower tiers. Moreover, value-based insurance design reduces cost-sharing in accordance with patient- or disease-specific characteristics. Therapies are then readily available to those who will benefit from them, and less accessible to those unlikely to benefit. Value-based insurance design also relieves patients of high cost-sharing after failure on a different medicine. If a patient does not respond well to first-line treatment, that “good soldier” can be “rewarded” with a second line of specialty medicine without high cost-sharing. Finally, this approach offers lower cost-sharing for patients who choose cost-effective, efficient providers. n Disclosure: Drs. Fendrick, Gould, Chalkidou, Conti, and Newcomer, and Mr. Hammelman reported no potential conflicts of interest.

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Announcements

ASTRO Names Three Radiation Oncologists as Recipients of Society’s 2014 Gold Medal

he American Society for Radiation Oncology (ASTRO) has announced the names of three recipients of the Society’s highest honor, the ASTRO Gold Medal. Mary K. Gospodarowicz, MD, FASTRO, Leonard L. Gunderson, MD, MS, FASTRO, and Nancy J. Tarbell, MD, FASTRO, will receive the ASTRO Gold Medal during the Awards Ceremony on September 16, 2014, at ASTRO’s 56th Annual Meeting in San Francisco. ASTRO’s Gold Medal is bestowed annually on esteemed ASTRO members who have made exceptional contributions to the field of radiation oncology, including work in research, clinical care, teaching and service. “Congratulations to my distinguished colleagues, Drs. Gospodarowicz, Gunderson, and Tarbell for being recognized with the ASTRO Gold Medal,” said ASTRO Chair Colleen A.F. Lawton, MD, FASTRO. “They have each greatly impacted the field of radiation oncology through their research, clinical work, and passion for providing high-quality care. Their contributions to our specialty will continue to improve the lives of cancer patients worldwide.”

treating cancer patients worldwide.” Dr. Gospodarowicz’s research has focused on radiation therapy for lymphomas and genitourinary cancers, including prostate cancer, bladder can-

cer, and seminoma, as well as studies of secondary cancers and other late effects of treatment. Dr. Gospodarowicz and her colleagues at the Princess Margaret Cancer Centre pioneered system-

atic studies of surveillance in place of routine use of abdominal and thoracic radiation for early-stage seminoma. This change has helped reduce the risk continued on page 82

Trim: 7.625 X 10.5

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

Go with FASLODEX.

Mary K. Gospodarowicz, MD, FASTRO Dr. Gospodarowicz is a radiation oncologist at Princess Margaret Cancer Centre in Toronto and a 33-year ASTRO

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

Secondary Endpoint: Overall Survival (OS)1

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

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

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

• Not statistically signifcant as no adjustments were made for multiplicity2

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

Important Safety Information About FASLODEX Mary K. Gospodarowicz, MD, FASTRO

member who has had a major impact on several areas of radiation oncology, including the treatment of malignant lymphomas and genitourinary cancers, global health, and the use of radiation treatment worldwide, and the mentoring of trainees. “My career has been very eclectic, and to be recognized by my peers and colleagues is extremely meaningful,” Dr. Gospodarowicz said. “Throughout my career and my roles as clinician, researcher, teacher, administrator and leader, I have focused on promoting radiation therapy as an integral tool for

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

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

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

The ASCO Post | JULY 10, 2014

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Announcements ASTRO Gold Medal continued from page 81

of these patients developing complications and the risk of secondary cancer. In addition to her research, Dr. Gospodarowicz’s more recent work has focused on global health and the role of radiation therapy in treating cancer patients worldwide. She is currently the

president of the Union for International Cancer Control (UICC), an international organization dedicated to helping reduce the worldwide cancer burden, promote greater equity in cancer control, and place cancer on the global health and development agenda. In this role, Dr. Gospodarowicz created the Global Task Force on Radiotherapy for Cancer

Control (GTFRCC) to determine what it would take to close the gap between what exists today and equitable access to radiotherapy for cancer globally. Dr. Gospodarowicz is the Medical Director of the Princess Margaret Cancer Centre at the University Health Network in Toronto and the Regional VicePresident of Cancer Care Ontario.

Trim: 7.625 X 10.5

Leonard L. Gunderson, MD, MS, FASTRO As a 38-year ASTRO member and former Chair of ASTRO’s Board of Directors (2011-2012), Dr. Gunderson has made significant contributions to radiation oncology through research and clinical practice in gastrointestinal (GI) cancers, as well as service to ASTRO

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

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

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

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

Additional Important Safety Information About FASLODEX (continued)

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

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

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

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

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

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

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

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

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

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

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

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Announcements

Leonard L. Gunderson, MD, MS, FASTRO

through his dedication to numerous committees and his 9 years serving on ASTRO’s Board of Directors. “I have had the fortunate opportunity to conduct clinical research and to accomplish scholarly contributions in the area of GI cancers that have significantly impacted patient care,” Dr. Gunderson said. In the 1970s, Dr.X Gunderson pubTrim: 7.625 10.5

FASLODEX® (fulvestrant) Injection

lished a definitive study, “Areas of failure found at reoperation (second of symptomatic look) following ‘curative surgery’ for adenocarcinoma of the rectum. Clinicopathologic correlation and implications for adjuvant therapy,” in Cancer on the relapse patterns found by second-look surgery in patients treated for rectal cancer. The analysis of this

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

Fulvestrant 250 mg N=374

Injection Site Pain

42 (11.6)

34 (9.1)

Headache

28 (7.8)

25 (6.7)

DOSAGE AND ADMINISTRATION

Back Pain

27 (7.5)

40 (10.7)

Recommended Dose

Fatigue

27 (7.5)

24 (6.4)

Pain in Extremity

25 (6.9)

26 (7.0)

Asthenia

21 (5.8)

23 (6.1)

24 (6.6)

22 (5.9)

Nausea

35 (9.7)

51 (13.6)

Vomiting

22 (6.1)

21 (5.6)

Anorexia

22 (6.1)

14 (3.7)

Constipation

18 (5.0)

13 (3.5)

Bone Pain

34 (9.4)

28 (7.5)

Arthralgia

29 (8.0)

29 (7.8)

Musculoskeletal Pain

20 (5.5)

12 (3.2)

Cough

19 (5.3)

20 (5.3)

Dyspnea

16 (4.4)

19 (5.1)

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

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

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

Administration Technique

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

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

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

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

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

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

and Adverse Reaction Body as a Whole

Vascular System Hot Flash Digestive System

Musculoskeletal System

Respiratory System

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

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

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

study led to radiation oncologists tailoring radiation fields to the particular sites where disease did recur, rather than estimating where the risk existed. “It has been a privilege and an opportunity to mentor many residents and staff colleagues within the field of radiation oncology and associated disciplines. continued on page 84

The ASCO Post | JULY 10, 2014

PAGE 84

Announcements ASTRO Gold Medal continued from page 83

I feel strongly about the advantages of a team approach in the triad of patient care, research and education, and in having successful shared-leadership within institutional departments, organizations and families. Effective mentoring helps achieve these goals,” said Dr. Gunderson,

an Emeritus Professor and Consultant in the Department of Radiation Oncology at the Mayo Clinic.

Nancy J. Tarbell, MD, FASTRO Dr. Tarbell, a Radiation Oncologist at Massachusetts General Hospital and 29-year ASTRO member, has had a major Trim: 7.625influence X 10.5 on pediat-

ric oncology and radiation therapy, and has worked to expand the role of women faculty in radiation oncology and beyond. She specializes in pediatric brain tumors and has made significant contributions in cancer biology and radiation physics. “I feel fortunate to be able to take care of children with cancer, and I am

FASLODEX® (fulvestrant) Injection Body System and Adverse Reactiona

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

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

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

Post-Marketing Experience For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria. Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered. Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONS There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.

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

Hepatic Impairment FASLODEX is metabolized primarily in the liver. The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (ChildPugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C). A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (ChildPugh class B) [see Dosage and Administration and Warnings and Precautions].

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

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

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

Pediatric Use A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCuneAlbright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8). The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26. Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known. Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died. Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis. In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.

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

Nancy J. Tarbell, MD, FASTRO

proud of the multidisciplinary team approach, which has included medical physicists, biologists and clinicians that provided me with the opportunity to help improve the treatment of children with cancer,” she said. “Studying the long-term effects of treatment allowed me to move precision radiation techniques forward.” An internationally recognized expert in pediatric oncology and radiation therapy, Dr. Tarbell’s research has examined ways to provide curative treatment programs for children with malignant disease and to develop effective strategies to decrease the late effects of treatment. For more than 20 years, Dr. Tarbell has been an active member of the Brain Tumor Committee of the Children’s Oncology Group and served as the principal investigator on medulloblastoma protocols. She is credited with establishing the current standard of care for children with highrisk medulloblastoma. More recently, her research has focused on the use of proton-beam therapy in pediatric brain tumors and sarcomas, examining the feasibility, effectiveness, and dosimetric and physics aspects of particle radiation therapy. She is a member of the Institute of Medicine of the National Academies of Science. “I grew up in a house of six girls. This was a wonderful environment for true ‘division of labor’ without gender bias. In addition, I benefited greatly from the mentorship of Sam Hellman, MD, F ASTRO, while he was Chair of the Harvard Joint Center for Radiation Therapy. He mentored deeply and intuitively and continues to be an extraordinary leader today. He gave me opportunities when there were few women role models. I hope that I have shared like-opportunities with the many young men and women whom I have taught, particularly women,” said Dr. Tarbell, the Dean for Academic and Clinical Affairs at Harvard Medical School in Boston and the C.C. Wang Professor of Radiation Oncology at Harvard Medical School and Massachusetts General Hospital in Boston. n

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In the Clinic

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

n April 23, 2014, the anti–interleukin (IL)-6 monoclonal antibody siltuximab (Sylvant) was approved for the treatment of patients with multicentric Castleman’s disease (a rare lymphoproliferative disorder) who are human immunodeficiency virus (HIV)-negative and human herpes virus (HHV)-8– negative.1,2 Approval was based on the finding of durable tumor and symptomatic response and complete resolution or stabilization of disease symptoms in an international phase II study.2 Siltuximab has not been studied in patients who are HIV-positive or HHV-8–positive because it did not bind to virally produced IL-6 in a preclinical study.

Pivotal Study In the study, 79 patients were randomly assigned 2:1 to receive siltuximab at 11 mg/kg via intravenous infusion every 3 weeks plus best supportive care (n = 53) or placebo plus best supportive care (n = 26). Patients had a median age of 48 years (range = 20–78 years), 66% were male, 48% were Asian, and 39% were white. Histologic disease subtypes, which were similar in both groups, consisted of hyaline vascular subtype in 33%, plasmacytic in 23%, and mixed in 44%. Treatment was continued until treatment failure (defined as disease progression based on increase in symptoms, radiologic progression, or deterioration in performance status) or unacceptable toxicity. Tumor response was assessed by independent review. A durable response was defined as a tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. For symptom response, 34 prospectively identified multicentric Castleman’s disease-related symptoms were graded by investigators.

OF NOTE Siltuximab carries warnings/precautions for concurrent active severe infection, vaccinations, infusion-related reactions, and gastrointestinal perforation.

Durable tumor and symptomatic response rates were 34% in the siltuximab group vs 0% in the placebo group (P = .0012). With regard to other prespecified endpoints, tumor response rates were 38% vs 4% (P < .05), median time to treatment failure after median followup of 422 days was not reached vs 134 days (hazard ratio = 0.418, P < .05). An increase in hemoglobin level of ≥ 1.5 g/ dL at week 13 in patients who were anemic at study entry was observed in 19 vs 0 patients (P < .05).

How It Works Siltuximab is a human-mouse chimeric anti–IL-6 monoclonal antibody. It binds to IL-6 and prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors. IL6 is a cytokine with both proinflammatory and anti-inflammatory activities and is involved in numerous normal physiologic processes, such as induction of immunoglobulin secretion. Overproduction of IL-6 has been linked to systemic manifestations in patients with multicentric Castleman’s disease.

How It Is Given Siltuximab is given at 11 mg/kg via 1-hour infusion every 3 weeks until treatment failure. The dose of siltuximab should not be reduced. Hematology tests must be performed prior to

Since CYP450 enzymes are downregulated by infection and inflammation stimuli including cytokines such as IL-6, inhibition of IL-6 by siltuximab may restore CYP450 activities to higher levels, leading to increased metabolism of drugs that are CYP450 substrates (eg, amiodarone, diazepam, omeprazole). In patients receiving CYP450 sub-

OF NOTE Siltuximab prevents the binding of IL-6 to IL-6 receptors. Overproduction of IL-6 has been linked to systemic manifestations in patients with multicentric Castleman’s disease.

strates with a narrow therapeutic index, therapeutic monitoring of effect (eg, warfarin) or drug concentration (eg, cyclosporine or theophylline) should be performed. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.

Safety Profile In the pivotal trial, siltuximab patients received a median of 19 infusions (range = 1–50 and placebo patients received a median of 8 (range = 2–32). Adverse event data reflect events occurring through the first eight infusions in the two groups. The most common adverse events of any grade in the siltuximab group were rash

Siltuximab in Castleman’s Disease ■■ The anti–IL-6 monoclonal antibody siltuximab (Sylvant) was approved for the treatment of patients with multicentric Castleman’s disease who are HIV-negative and HHV-8–negative. ■■ Siltuximab is given at 11 mg/kg via 1-hour infusion every 3 weeks until treatment failure; the dose of siltuximab should not be reduced.

each dose for the first 12 months and every three dosing cycles thereafter. The absolute neutrophil count must be ≥ 1.0 × 109/L prior to initial administration and for retreatment, platelet count must be ≥ 75 × 109/L for initial treatment and ≥ 50 × 109/L for retreatment, and hemoglobin must be < 17 g/L for initial administration and retreatment. If hematologic criteria are not met, delay of treatment can be considered. No initial dosage adjustment is necessary in patients with creatinine clearance ≥ 15 mL/min or mild-to-moderate hepatic impairment. The drug has not been studied in patients with end-stage renal disease or severe hepatic impairment.

(28% vs 12% in the placebo group), pruritus (28% vs 8%), upper respiratory tract infection (26% vs 15%), edema (26% vs 27%), weight increase (19% vs 0%), and hyperuricemia (11% vs 0%). The most common grade 3 or 4 adverse events were edema (8% vs 0%), thrombocytopenia (4% vs 4%), and lower respiratory tract infection (4% vs 4%). The safety of long-term administration in patients with multicentric Castleman’s disease was examined in 19 patients from an initial dose-finding study who benefited from continued treatment with 11 mg/kg every 3 to 6 weeks. Median exposure to siltuximab in these patients was 5.1 years (range = 3.4–7.2 years).

The most common adverse events of any grade were upper respiratory tract infection (63%), diarrhea (32%), pain in extremities, arthralgia, and fatigue (21% each). No patient discontinued therapy due to adverse events, there were no deaths, and no cumulative toxicities were identified. In overall experience with siltuximab, an anaphylactic reaction occurred in 1 of approximately 750 patients. Among 249 receiving siltuximab monotherapy, 4.8% have experienced infusion-related reactions. The immunogenicity of siltuximab has been evaluated using an antigenbridging enzyme immunoassay and an electrochemiluminescence-based immunoassay. Overall, anti-siltuximab antibodies have been found in 1 (0.2%) of 411 patients, with no neutralizing capability observed in the one case. Siltuximab carries warnings/precautions for concurrent active severe infection, vaccinations, infusion-related reactions, and gastrointestinal perforation. Patients with severe infection should not receive siltuximab until the infection resolves, and all patients should be monitored closely for infection. Patients should not receive live vaccines, since IL-6 inhibition may interfere with the normal immune response. The drug should be permanently discontinued in patients with severe infusion-related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. n References 1. U.S. Food and Drug Administration: Approved drugs. Siltuximab. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm394675.htm. 2. SYLVANTTM (siltuximab) for Injection prescribing information, Janssen Biotech, Inc, April 2014. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2014/125496s000lbl.pdf.

Now Approved New Indication

(ofatumumab)

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

Important Safety Information for ARZERRA WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)]. • Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)]. Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, ﬂushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the ﬁrst 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment. Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms

of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is deﬁned as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, ie, increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufﬁcient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation.

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

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

CLL=chronic lymphocytic leukemia.

Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%). In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. Laboratory Abnormalities In the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with ≥5% incidence in patients receiving ARZERRA plus chlorambucil and also ≥2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%). Reference: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

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

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; JULY 10, 2014

PAGE 88

Announcements

Three Physician-Scientists Join St. Jude Childrenâ&#x20AC;&#x2122;s Research Hospital

fficials at St. Jude Childrenâ&#x20AC;&#x2122;s Research Hospital have announced the appointment of three physician-scientists to leadership positions. Mitchell Weiss, MD, PhD, has been named Chair of the St. Jude Department of Hematology. He was recruited to the

institution from the University of Pennsylvania Perelman School of Medicine and the Childrenâ&#x20AC;&#x2122;s Hospital of Philadelphia, where he is currently Professor of Pediatrics and holds an endowed chair. J. Paul Taylor, MD, PhD, who joined the St. Jude Department of Developmental

Neurobiology in 2008, has been appointed Chair of the new St. Jude Department of Cell and Molecular Biology. He will also hold the Edward F. Barry Endowed Chair in Cell and Molecular Biology. Kim Nichols, MD, has been selected to launch the new Division of He-

reditary Cancer Predisposition in the St. Jude Department of Oncology. She currently directs the Childrenâ&#x20AC;&#x2122;s Hospital of Pennsylvania Pediatric Hereditary Cancer Predisposition Program. She is also an Associate Professor of Pediatrics at the University of Pennsyl-

BRIEF SUMMARY

discontinue ARZERRA andBRIEF any concomitant institute SUMMARY chemotherapy, discontinue and ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRAappropriate in patients whose HBVResumption of ARZERRA in patients whose HBV treatment. ÂŽ ARZERRAÂŽ (ofatumumab) Injection, for intravenous infusion reactivation resolves should be discussed with physicians expertise in be discussed with physicians with expertise in ARZERRA (ofatumumab) Injection, for intravenous infusion reactivationwith resolves should managing hepatitis B. InsufďŹ cient data exist regarding the hepatitis safety of B. resuming managing InsufďŹ cient data exist regarding the safety of resuming The following is a brief summary only; see full prescribing information, The following is a brief summary only; see full prescribing information, ARZERRA in patients who develop HBV reactivation. (EPATITIS " 6IRUS ARZERRA in patients who develop HBV reactivation. (EPATITIS " 6IRUS including Boxed Warning, for complete product information. including Boxed Warning, for complete product information. Infection Fatal infection due to hepatitis B in patients whoFatal haveinfection not beendue to hepatitis B in patients who have not been Infection WARNING: HEPATITIS B VIRUS REACTIVATIONWARNING: AND PROGRESSIVE infectedAND hasPROGRESSIVE been observed with ARZERRA. Monitor patients HEPATITIS B VIRUSpreviously REACTIVATION previously infected has been observed with ARZERRA. Monitor patients MULTIFOCAL LEUKOENCEPHALOPATHY for clinical and laboratory signs of hepatitis. 5.4for Progressive MULTIFOCAL LEUKOENCEPHALOPATHY clinical andMultifocal laboratory signs of hepatitis. 5.4 Progressive Multifocal s (EPATITIS " 6IRUS ("6 REACTIVATION CAN OCCUR IN PATIENTS ,EUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy (PML) s (EPATITIS " 6IRUS ("6 REACTIVATION CAN OCCUR IN PATIENTS ,EUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy (PML) ÂŽ receiving CD20-directed cytolytic antibodies, receiving including CD20-directed ARZERRAÂŽ, cytolytic resultingantibodies, in death has occurredARZERRA with ARZERRA. Consider in any including , resulting PML in death haspatient occurred with ARZERRA. Consider PML in any patient IN SOME CASES RESULTING IN FULMINANT HEPATITIS HEPATIC FAILURE with new onset of or changes in pre-existing neurological signs or symptoms. IN SOME CASES RESULTING IN FULMINANT HEPATITIS HEPATIC FAILURE with new onset of or changes in pre-existing neurological signs or symptoms. and death [see Warnings and Precautions (5.2)]. If PML is suspected, discontinue ARZERRA and initiate evaluation fordiscontinue PML and death [see Warnings and Precautions (5.2)]. If PML is suspected, ARZERRA and initiate evaluation for PML s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY 0-, RESULTING including neurology consultation. 5.5 Tumor Lysis Syndrome Tumorconsultation. lysis s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY 0-, RESULTING including neurology 5.5 Tumor Lysis Syndrome Tumor lysis IN DEATH CAN OCCUR IN PATIENTS RECEIVING #$ DIRECTED syndrome (TLS), including the need for hospitalization, has(TLS), occurred in the need for hospitalization, has occurred in IN DEATH CAN OCCUR IN PATIENTS RECEIVING #$ DIRECTED syndrome including cytolytic antibodies, including ARZERRA [seecytolytic Warnings patients treated [see with ARZERRA. tumor burden high antibodies, including ARZERRA WarningsPatients with highpatients treatedand/or with ARZERRA. Patients with high tumor burden and/or high and Precautions (5.4)]. greater risk for developing and Precautions (5.4)]. circulating lymphocyte counts (>25 x 109/L) are at circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of prior to infusion of ARZERRA. For treatment of beginning 12 to 24 hours 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE TLS, administer aggressive intravenous andadminister anti-hyperuricemic aggressive intravenous hydration and anti-hyperuricemic 0REVIOUSLY 5NTREATED #HRONIC ,YMPHOCYTIC ,EUKEMIA ARZERRA 0REVIOUSLY 5NTREATED #HRONIC ,YMPHOCYTIC ,EUKEMIA ARZERRA hydrationTLS, agents, correct electrolyte abnormalities, and monitor renal function. agents, correct electrolyte abnormalities, and monitor renal function. (ofatumumab) is indicated, in combination with (ofatumumab) chlorambucil, for the is indicated, in combination with chlorambucil, for the Severelymphocytic cytopenias,leukemia including neutropenia, thrombocytopenia, #YTOPENIAS Severe cytopenias, including neutropenia, thrombocytopenia, treatment of previously untreated patients with treatment chronic lymphocytic leukemia of previously untreated #YTOPENIAS patients with chronic and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and (CLL) for whom ďŹ&#x201A;udarabine-based therapy is considered inappropriate [see (CLL) for whom ďŹ&#x201A;udarabine-based therapy is considered inappropriate [see fatal neutropenic sepsis occurred in patientsfatal whoneutropenic received ARZERRA in occurred in patients who received ARZERRA in sepsis have Clinical Studies (14.1) of full prescribing information]. Refractory Clinical1.2 Studies (14.1) CLL of full prescribing information]. 1.2 have Refractory CLL combination with with chlorambucil. Gradeto3 or 4 late-onset neutropenia (onset at Grade 3 or 4 late-onset neutropenia (onset at combination with chlorambucil. ARZERRA is indicated for the treatment of patients with CLL refractoryfor to the treatment ARZERRA is indicated of patients CLL refractory 42 days after(14.2) last treatment dose) and/or prolonged neutropenia least 42 days after last(not treatment dose) and/or prolonged neutropenia (not ďŹ&#x201A;udarabine and alemtuzumab [see Clinical Studies (14.2) ofand full alemtuzumab prescribing [seeleast ďŹ&#x201A;udarabine Clinical Studies of full prescribing resolved between 24 and 42 days after last treatment dose) were 24 reported resolved between and 42 days after last treatment dose) were reported information]. information]. in patients who received ARZERRA [see AdverseinReactions (6.1)]. MonitorARZERRA [see Adverse Reactions (6.1)]. Monitor patients who received complete blood counts at regular intervals during and after conclusion 4 CONTRAINDICATIONS complete blood counts of at regular intervals during and after conclusion of 4 CONTRAINDICATIONS therapy, and increase the frequency of monitoring in patients who develop therapy, and increase the frequency of monitoring in patients who develop None. None. Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of 4immunization Grade 3 or cytopenias. 5.7 Immunizations The safety of immunization 5 WARNINGS AND PRECAUTIONS of ARZERRA 5 WARNINGS AND PRECAUTIONSwith live viral vaccines during or following administration with live viral vaccineshas during or following administration of ARZERRA has 5.1 Infusion Reactions ARZERRA can cause serious, including fatal, ARZERRAnot studied. Doincluding not administer to studied. patients Do whonothave 5.1 Infusion Reactions canbeen cause serious, fatal, live viral vaccines not been administer live viral vaccines to patients who have infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, as bronchospasm, recently receiveddyspnea, ARZERRA. The ability to generate an immune response to The ability to generate an immune response to infusion reactions manifesting laryngeal edema, recently received ARZERRA. pulmonary edema, ďŹ&#x201A;ushing, hypertension, hypotension, syncope, any vaccine following syncope, administration of ARZERRA not been studied. pulmonary edema,cardiac ďŹ&#x201A;ushing, hypertension, hypotension, cardiac anyhas vaccine following administration of ARZERRA has not been studied. events (e.g., myocardial ischemia/infarction, acute coronary syndrome, ischemia/infarction, acute coronary syndrome, events (e.g., myocardial arrhythmia, bradycardia), back pain, abdominal arrhythmia, pain, pyrexia, rash, urticaria, 6 ADVERSE bradycardia), back pain, abdominalREACTIONS pain, pyrexia, rash, urticaria, 6 ADVERSE REACTIONS angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic The following serious adverse reactions are discussed in greater detailadverse in angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic The following serious reactions are discussed in greater detail in reactions. Infusion reactions occur more frequently with the ďŹ rst 2 reactions infusions.occurother of the reactions. Infusion moresections frequently withlabeling: the ďŹ rst 2 infusions. other sections of the labeling: These reactions may result in temporary interruption withdrawal s )NFUSION 2EACTIONS [see Warnings (5.1)] Theseorreactions mayofresult in temporary interruption or withdrawal of and Precautions s )NFUSION 2EACTIONS [see Warnings and Precautions (5.1)] treatment [see Adverse Reactions (6.1)]. Premedicate with[see acetaminophen, (EPATITIS " 6IRUS 2EACTIVATION [see Warnings and Precautions (5.2)] treatment Adverse Reactions s (6.1)]. Premedicate with acetaminophen, s (EPATITIS " 6IRUS 2EACTIVATION [see Warnings and Precautions (5.2)] an antihistamine, and a corticosteroid [see Dosage and Administration s (EPATITIS " 6IRUS )NFECTION [see Warnings Precautions (5.3)] an antihistamine, and a(2.1, corticosteroid [see Dosage and Administration (2.1, ands (EPATITIS " 6IRUS )NFECTION [see Warnings and Precautions (5.3)] 2.4) of full prescribing information]. Infusion reactions occur despite s Infusion 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY [see Warnings and 2.4) of may full prescribing information]. reactions may occur despite s 0ROGRESSIVE -ULTIFOCAL ,EUKOENCEPHALOPATHY [see Warnings and premedication. Interrupt infusion with ARZERRApremedication. for infusion reactions of infusion withPrecautions (5.4)] Interrupt ARZERRA for infusion reactions of Precautions (5.4)] any severity. Institute medical management for severe infusion reactions s 4UMOR ,YSIS 3YNDROME [see Warnings and Precautions (5.5)] any severity. Institute medical management for severe infusion reactions s 4UMOR ,YSIS 3YNDROME [see Warnings and Precautions (5.5)] including angina or other signs and symptoms ofincluding myocardial ischemia #YTOPENIAS [see Warnings and Precautions (5.6)] angina or other signs ands symptoms of myocardial ischemia s #YTOPENIAS [see Warnings and Precautions (5.6)] [see Dosage and Administration (2.3) of full prescribing information]. If an Previously Untreated CLL: The mostIfcommon adverse reactions (â&#x2030;Ľ10%) [see Dosage and Administration (2.3) of full prescribing information]. an Previously Untreated CLL: The most common adverse reactions (â&#x2030;Ľ10%) anaphylactic reaction occurs, immediately and permanently were infusion reactions anddiscontinue neutropenia (Table 1). Refractory The and neutropenia (Table 1). Refractory CLL: The anaphylactic discontinue reaction occurs, immediately and permanently were infusion CLL: reactions ARZERRA and initiate appropriate medical treatment. (EPATITIS " common adverse reactions (â&#x2030;Ľ10%) were neutropenia, pneumonia, ARZERRA and initiate appropriate most medical treatment. (EPATITIS " most common adverse reactions (â&#x2030;Ľ10%) were neutropenia, pneumonia, Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases pyrexia, diarrhea, anemia, fatigue, dyspnea, rash,cough, nausea, bronchitis, Virus Reactivation Hepatitis B virus (HBV)cough, reactivation, in some cases pyrexia, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, resulting in fulminant hepatitis, hepatic failure, and death,inhas occurred in and upper respiratory tract 3). The serious resulting fulminant hepatitis, hepatic failure, and death, hasinfections occurred (Table in and most uppercommon respiratory tract infections (Table 3). The most common serious patients treated with ARZERRA. Cases have been reported in patients who adverse were infections pneumonia and sepsis), patients treated with ARZERRA. Cases havereactions been reported in patients(including who adverse reactions were infections (including pneumonia and sepsis), are hepatitis B surface antigen (HBsAg) positiveare andhepatitis also in patients who neutropenia, Infectionswho were the most common and adverse B surface antigen (HBsAg) positiveand andpyrexia. also in patients neutropenia, pyrexia. Infections were the most common adverse are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. reactions drug discontinuation. are HBsAg negative but are hepatitis B coreleading antibodyto(anti-HBc) positive. #LINICAL 4RIALS %XPERIENCE reactions leading to drug discontinuation. #LINICAL 4RIALS %XPERIENCE Reactivation also has occurred in patients who appear to have resolved Because who clinical trialstoare conducted varying conditions, Reactivation also has occurred in patients appear have resolvedunder widely Because clinical trials are conducted under widely varying conditions, hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B adverseanti-HBc reaction positive, rates observed in the clinical trials of a reaction drug cannot hepatitis B infection (i.e., HBsAg negative, and hepatitis B adverse ratesbeobserved in the clinical trials of a drug cannot be surface antibody [anti-HBs] positive). HBV reactivation is deďŹ ned an abruptpositive). directly compared with rates in clinical trialsdirectly of another drug and surface antibodyas[anti-HBs] HBV reactivation is deďŹ ned asthe an abrupt compared withmay rates in the clinical trials of another drug and may increase in HBV replication manifesting as a rapid increase in serum HBV manifesting not reďŹ&#x201A;ect rates observed in practice. Untreated CLL: observed The increase in HBV replication as a the rapid increase in serum HBV Previously not reďŹ&#x201A;ect the rates in practice. Previously Untreated CLL: The DNA level or detection of HBsAg in a person whoDNA waslevel previously HBsAgof HBsAg insafety of ARZERRA evaluated in an open-label, parallel-arm, or detection a person who waswas previously HBsAg safety of ARZERRArandomized was evaluated in an open-label, parallel-arm, randomized negative and anti-HBc positive. Reactivation of HBV replication is oftenpositive. Reactivation trial (Studyof1)HBV in 444 patients iswith previously untreated CLL.1)Patients were with previously untreated CLL. Patients were negative and anti-HBc replication often trial (Study in 444 patients followed by hepatitis, i.e., increase in transaminase levelsbyand, in severe to receive infusion everyeither ARZERRA as an intravenous infusion every followed hepatitis, i.e., increaserandomized in transaminase levelseither and, ARZERRA in severe as an intravenous randomized to receive cases, increase in bilirubin levels, liver failure, and death. Screeninall patients in combination with chlorambucil or chlorambucil as with a chlorambucil (n = 217) or chlorambucil as a cases, increase bilirubin levels, 28 liverdays failure, and death. Screen all patients(n = 217) 28 days in combination for HBV infection by measuring HBsAg and anti-HBc before initiating singleand agent (n = 227). In initiating both arms, patients received chlorambucil for HBV infection by measuring HBsAg anti-HBc before single agent (n = 227). In both arms, patients received chlorambucil 2 schedule treatment with ARZERRA. For patients who showtreatment evidencewith of hepatitis B For patients 10 mg/m ARZERRA. who 2show hepatitis orallyevidence on Days of 1 to 7 everyB28 days. The infusion 10 mg/m orally on Days 1 to 7 every 28 days. The infusion schedule infection (HBsAg positive [regardless of antibodyinfection status] or HBsAgpositive negative (HBsAg [regardless of antibodywas status] or HBsAg negativeon Cyclefor1 ARZERRA for ARZERRA 300 mg administered Day 1, 1,000 wasmg 300 mg administered on Cycle 1 Day 1, 1,000 mg but anti-HBc positive), consult physicians with expertise in managing but anti-HBc positive), consult physicians with expertise managing administered on Cycle in 1 Day 8, and 1,000 mg administered 1 of1 Day 8, and 1,000 mg administered on Day 1 of administeredon onDay Cycle hepatitis B regarding monitoring and consideration for HBV antiviral therapy. hepatitis B regarding monitoring and consideration forcycles. HBV antiviral therapy. subsequent 28-day The median numbersubsequent of cycles of 28-day ARZERRA cycles. The median number of cycles of ARZERRA Monitor patients with evidence of current or prior HBV infection clinical Monitor patientsfor with evidence of completed current or prior HBV for clinical was 6. Theinfection data described in Table 1completed include relevant was 6.adverse The data described in Table 1 include relevant adverse and laboratory signs of hepatitis or HBV reactivation during andsigns for several and laboratory of hepatitis orreactions HBV reactivation anddays for several occurringduring up to 60 after the last dose of study medication; reactions occurring up to 60 days after the last dose of study medication; months following treatment with ARZERRA. HBVmonths reactivation has been following treatment with ARZERRA. HBV reactivation has been laboratoryTable Table 2 includes relevant hematologic abnormalities. 2 includes relevant hematologic laboratory abnormalities. reported for at least 12 months following completion of therapy. In patients reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receivingwho ARZERRA, developimmediately reactivation of HBV while receiving ARZERRA, immediately (contâ&#x20AC;&#x2122;d)

(contâ&#x20AC;&#x2122;d)

ASCOPost.com | JULY 10, 2014

PAGE 89

Announcements

Mitchell Weiss, MD, PhD

J. Paul Taylor, MD, PhD

Kim Nichols, MD

vania Perelman School of Medicine. “These gifted physician-scientists will enhance and expand our ability to translate discoveries and insight gained in the laboratory into clinical advances against diseases that continue to devastate children and families,” said William E. Evans, MD, St. Jude Director and Chief Executive Officer.

The announcement comes as St. Jude takes steps to broaden its basic and translational research programs and capitalize on its discoveries from the St. Jude Children’s Research Hospital - Washington University Pediatric Cancer Genome Project, said James Downing, MD, St. Jude Scientific Director. n

Table 1. Adverse Reactions With ≥5% Incidence in 1. Patients Receiving receivedinall 12 infusions. The median and age was years (range: 41 Table Adverse Reactions With and ≥5%55% Incidence Patients Receiving 55%63 received all 12 infusions. The median age was 63 years (range: 41 ARZERRA Plus Chlorambucil and Also ≥2% More Than Plus Patients 86 years), 72% Than were Patients male, and 97% were white. ARZERRA Chlorambucil andtoAlso ≥2% More to 86 years), 72% were male, and 97% were white. Receiving Chlorambucil Receiving Chlorambucil Table 3. Incidence of All Adverse Reactions Occurring in ≥5% ofofPatients Table 3. Incidence All Adverse Reactions Occurring in ≥5% of Patients ARZERRA Plus ARZERRA Plus and in the Fludarabine- and Alemtuzumab-refractory and in theSubset Fludarabine- and Alemtuzumab-refractory Subset Chlorambucil Chlorambucil Chlorambucil Chlorambucil Fludarabine- and (N = 217) (N = 227) Fludarabine- and (N = 217) (N = 227) AlemtuzumabAlemtuzumabAll All All All refractory 4OTAL 0OPULATION refractory 4OTAL 0OPULATION Grades Grade ≥3 Grades Grade ≥3 (N = 59) (N =≥3 154) Grades Grade ≥3 Grades Grade (N = 59) (N = 154) Adverse Adverse Reactions % % Reactions % % % % % Grade All All % Grade Grade All Grade All ≥3 Grades ≥3 Adverse Grades0 ≥3 Grades ≥3 Grades Infusion reactionsa 67 10 Infusion 0reactionsa 0 67 Adverse10 0 % % % Reaction % Reaction % % % % Neutropenia 27 26 Neutropenia 18 14 27 26 18 14 Pneumoniaa 23 14 Pneumonia 25 a 15 23 14 25 15 Asthenia 8 <1 Asthenia5 0 8 <1 5 0 Pyrexia 20 3 25 5 Pyrexia 20 3 25 5 Headache 7 <1 Headache 3 0 7 <1 3 0 Cough 19 0 0 Cough19 19 0 19 0 Leukopenia 6 3 Leukopenia 2 <1 6 3 2 <1 Diarrhea 18 0 19 0 Diarrhea 18 0 19 0 b 6 0 Herpes simplex 4 <1 Herpes simplexb 6 0 4 <1 Anemia 16 5 17 8 Anemia 16 5 17 8 Lower respiratory tract 5 1 Lower respiratory 3 <1 tract 5 1 3 <1 Fatigue 15 0 15 0 Fatigue 15 0 15 0 infection infection Dyspnea 14 2 19 5 Dyspnea 14 2 19 5 Arthralgia 5 <1 Arthralgia3 0 5 <1 3 0 b 14 0 <1 5 Rash 0 3 a <1 a infusion or within Includes events which occurred on the day of an Includes events which occurred onBronchitis the day of an infusion or within11 24 hours of the end of an infusion and resulted 24 in an interruption or of an infusion and hours of the end resulted in an interruption 11 or Nausea 0 discontinuation of treatment. Infusion reactions discontinuation may include, butofare not treatment. Infusion reactions may include, but are not respiratory tractpain, pruritus, 11 0 limited to, chills, dyspnea, ﬂushing, hypotension,limited nausea, to,pain, chills,pruritus, dyspnea, ﬂushing,Upper hypotension, nausea, infection pyrexia, rash, and urticaria. pyrexia, rash, and urticaria. b b Includes oral herpes, herpes, herpes virus infection, genital Includes oralherpes, herpes,and herpes, herpes virus peripheral infection, genital herpes,9 and Edema <1 herpes simplex. herpes simplex. Back pain 8 1 Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring Chills 8 0 With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil 8 0 and Also ≥2% More Than Patients Receivingand Chlorambucil Also ≥2% More Than PatientsNasopharyngitis Receiving Chlorambucil

Upper abdominal pain

0 Upper abdominal 3 pain0

ARZERRA Plus Chlorambucil (N = 217)

8 8 Chlorambucil (N = 227)7

19 Bronchitis

12 Nausea

0 Upper 3respiratory tract infection

Edema8peripheral 2

12 Back pain

Chills 10

8 Nasopharyngitis c Sepsis10

5 Urticaria

10 Insomnia

Grade All≥3 Grades Headache Grade ≥3 All Grades Grade ≥3 0 6 7 0 Headache 6 0 7 0 % % % % % Herpes zoster 6 1 7 2 Herpes zoster 6 1 7 2 Leukopenia 67 23 28 4 67 Leukopenia 23 28 4 Hyperhidrosis 5 0 5 0 Hyperhidrosis 5 0 5 0 Neutropenia 66 29 56 24 66 Neutropenia 29 56 24 Hypertension 5 0 8 0 Hypertension 5 0 8 0 Lymphopenia 52 29 20 7 52 Lymphopenia 29 20 7 Hypotension 5 0 3 0 Hypotension 5 0 3 0 Infusion Reactions: Overall, 67% of patients whoInfusion received ARZERRAOverall, in Reactions: 67% of patients who received ARZERRA in Muscle spasms 5 0 3 0 Muscle spasms 5 0 3 0 combination with chlorambucil experienced onecombination or more symptoms of with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal).(10% Infusion 5 2 3 2 infusion reactions were Grade Sinusitis 3 or greater; none were fatal). Infusion Sinusitis 5 2 3 2 reactions that were either Grade 3 or greater, serious, or led treatment reactions thattowere either Grade 3 or greater, serious, or led to treatment Tachycardia 5 <1 7 2 Tachycardia 5 <1 7 2 interruption or discontinuation occurred most frequently during Cycle 1 (56% occurred most frequently during Cycle 1 (56% interruption or discontinuation a a on Day 1 [6% were Grade 3 or greater] and 23%ononDay Day1 8[6% [3%were wereGrade Grade3 3or greater] and 23% on Day 8lung [3%infection, were Grade Includes pneumonia, lobar3 pneumonia, andpneumonia, lung infection, lobar pneumonia, and Includes or greater]) and decreased with subsequent infusions. Infusion or greater]) andreactions decreasedledwith subsequent infusions. Infusion reactions led bronchopneumonia. bronchopneumonia. b to discontinuation of treatment in 3% of patients. adverse of events to Serious discontinuation treatment in 3% of patients. adverseand events Includes rash,Serious rash macular, rash vesicular.b Includes rash, rash macular, and rash vesicular. c of patients. Neutropenia: Overall, 3% c and septic shock. of infusion reactions occurred in 2% of patients.ofNeutropenia: Overall,occurred 3% infusion reactions in 2% Includes sepsis, neutropenic sepsis, bacteremia, Includes sepsis, neutropenic sepsis, bacteremia, and septic shock. of patients had neutropenia as a serious adverseofevent, reported up to patients had neutropenia as a serious adverse event, reported up to Infusion Reactions: Infusion reactions occurred in 44% patients onInfusion the reactions occurred in 44% of patients on the InfusionofReactions: 60 days after the last dose. One patient died with sepsis 60neutropenic days after the last and dose. One patient died with neutropenic sepsis and day of the first infusion (300 mg), 29% on the day of the second infusion day of the first infusion (300 mg), 29% on the day of the second infusion agranulocytosis. Prolonged neutropenia occurred in 6% of patients receivingneutropenia occurred in 6% of patients receiving agranulocytosis. Prolonged (2,000 mg), and less frequently during subsequent infusions. Infections: A (2,000 mg), and less frequently during subsequent infusions. Infections: A ARZERRA in combination with chlorambucil compared within 4% of patientswith chlorambucil ARZERRA combination compared with 4% of patients total of 108 patients (70%) experienced bacterial,total viral,ofor108 fungal infections. Aexperienced bacterial, viral, or fungal infections. A patients (70%) receiving chlorambucil. Late-onset neutropenia receiving occurred chlorambucil. in 6% of patients Late-onset neutropenia occurred in 6% of patients total of 45 patients (29%) experienced Grade 3 ortotal greater of which of 45infections, patients (29%) experienced Grade 3 or greater infections, of which receiving ARZERRA in combination with chlorambucil compared within 1% receiving ARZERRA combination with chlorambucil compared with 1% 19 (12%) were fatal. The proportion of fatal infections in thewere fludarabine19 (12%) fatal. Theand proportion of fatal infections in the fludarabine- and of patients receiving chlorambucil alone. Refractory CLL: The safety of of patients receiving chlorambucil alone. Refractory CLL: The safety of alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with monotherapy with ARZERRA was evaluated in 181 patients with or was evaluated monotherapy withrelapsed ARZERRA in 181 patients with relapsed or normal neutrophil counts at baseline, 45 (42%) developed Grade 3 counts or greater normal neutrophil at baseline, 45 (42%) developed Grade 3 or greater refractory CLL in 2 open-label, non-randomized,refractory single-arm studies. In these non-randomized, CLL in 2 open-label, single-arm studies. In these neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Nineteen Some patients (18%) developed Grade 4 neutropenia. Some patients studies, ARZERRA was administered at 2,000 mg beginning with the second studies, ARZERRA was administered at 2,000 mg beginning with the second experienced new onset Grade 4 neutropenia >2 weeks in duration. experienced new onset Grade 4 neutropenia >2 weeks in duration. dose for 11 doses (Study 2 [n = 154]) or 3 dosesdose (Study 3 [ndoses = 27]). The data for 11 (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]). The data 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic described in Table 3 and other sections below are derived in from 1543 patients described Table and other sections below are derived from 154 patients proteins such as ofatumumab. Serum samples from moresuch thanas 300 patients Serum samples from more than 300 patients proteins ofatumumab. in Study 2. All patients received 2,000 mg weekly from the second dose in Study 2. All patients received 2,000 mg weekly from the second dose with CLL were tested during and after treatment with for antibodies ARZERRA. CLL were to tested during and after treatment for antibodies to ARZERRA. onward. Ninety percent of patients received at least 8 infusions of ARZERRA onward. Ninety percent of patients received at least 8 infusions of ARZERRA All Grades %

Grade ≥3 %

Chlorambucil (N = 227)

Sepsisc ARZERRA Plus Urticaria Chlorambucil (N = 217) Insomnia

Rashb17

All Grades %

(cont’d)

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; JULY 10, 2014

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Discontinuing Statins Near the End of Life Is Safe, Can Reduce Symptom Burden, and Is Generally Acceptable to Patients By Charlotte Bath

iscontinuing statins for patients near the end of life is safe, saves money, spares patients from swallowing yet another pill and from the symptoms

associated with statins, and is generally welcomed by patients. That last bit might come as a surprise to some physicians who worry that discontinuing statins or

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and speciďŹ city, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading. 0OSTMARKETING %XPERIENCE The following adverse reactions have been identiďŹ ed during post-approval use of ARZERRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda. 7 DRUG INTERACTIONS Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or wellcontrolled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential beneďŹ t to the mother justiďŹ es the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufďŹ cient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 2ENAL )MPAIRMENT No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. (EPATIC )MPAIRMENT No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA. 13 NONCLINICAL TOXICOLOGY #ARCINOGENESIS -UTAGENESIS )MPAIRMENT OF &ERTILITY No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

other medications might signify that the physician is giving up on the patient. But most patients donâ&#x20AC;&#x2122;t see it that way, according to a survey conducted as part of

2EPRODUCTIVE AND $EVELOPMENTAL 4OXICOLOGY Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the ďŹ nal dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared with control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological signiďŹ cance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals. 17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: s 3IGNS AND SYMPTOMS OF INFUSION REACTIONS INCLUDING FEVER CHILLS RASH or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)] s 3YMPTOMS OF HEPATITIS INCLUDING WORSENING FATIGUE OR YELLOW DISCOLORATION of skin or eyes [see Warnings and Precautions (5.2, 5.3)] s .EW NEUROLOGICAL SYMPTOMS SUCH AS CONFUSION DIZZINESS OR LOSS OF balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.4)] s "LEEDING EASY BRUISING PETECHIAE PALLOR WORSENING WEAKNESS OR FATIGUE [see Warnings and Precautions (5.6)] s 3IGNS OF INFECTIONS INCLUDING FEVER AND COUGH [see Warnings and Precautions (5.6), Adverse Reactions (6.1)] s 0REGNANCY OR NURSING [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: s -ONITORING AND POSSIBLE NEED FOR TREATMENT IF THEY HAVE A HISTORY of hepatitis B infection (based on the blood test) [see Warnings and Precautions (5.2)] s 0ERIODIC MONITORING FOR BLOOD COUNTS [see Warnings and Precautions (5.6)] s !VOIDING VACCINATION WITH LIVE VIRAL VACCINES [see Warnings and Precautions (5.7)] ARZERRA is a registered trademark of the GSK group of companies. Manufactured by: GLAXO GROUP LIMITED Brentford, Middlesex, TW8 9GS, United Kingdom U.S. License 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 ÂŠ2014, the GSK group of companies. All rights reserved. Revised: 04/2014 ARZ:8BRS ÂŠ2014 GSK group of companies. All rights reserved. Printed in USA. AZA438R0 May 2014

a randomized study on continuing vs discontinuing statins for patients with a life expectancy of less than 1 year. Presented at the 2014 ASCO Annual Meeting in Chicago by Amy P. Abernethy, MD, PhD, Professor of Medicine and Palliative Care Specialist at Duke University Medical Center in Durham, North Carolina, the study found that the rate of death within 60 days, the primary endpoint of the study, was not significantly different among those who discontinued statins and those who continuedâ&#x20AC;&#x201D;20.3% vs 23.8%. The group discontinuing statins even had a longer median time to deathâ&#x20AC;&#x201D;229 days vs 190 for those continuing statinsâ&#x20AC;&#x201D;but it was not statistically significant, and there were several confounding factors, Dr. Abernethy noted. â&#x20AC;&#x153;The number of pills in our pill cup doubles at the end of life: medicines to treat the illness, medicines for comorbidities that we have been taking for a very long time, medicines for symptom control, and other burdens,â&#x20AC;? Dr. Abernethy said at a press briefing held during the Annual Meeting. In an interview with The ASCO Post, she explained that patients in the palliative care setting â&#x20AC;&#x153;commonly specify that they like taking fewer medicines. Getting full early, bloating, and nausea are very common concerns. So when you donâ&#x20AC;&#x2122;t have to take as many pills, that is valuable.â&#x20AC;?

Patient and Physician Concerns Diverge The study included 381 patients, 49% with cancer, with a life expectancy of no more than 1 year, recruited from 15 sites across the country. All patients were taking statin medications for primary or secondary prevention for at least 3 months, and 69% had used statins for more than 5 years. Before patients were randomized, they were surveyed to see if they were worried about possibly having statins discontinued. â&#x20AC;&#x153;Some of the things that are commonly concerns for physicians are not concerns for patients,â&#x20AC;? Dr. Abernethy said. â&#x20AC;&#x153;For example, as physicians, we worry about stopping medicines because it might signify that the doctor is giving up on the patient, but less than 5% of patients said that that was a concern to them.â&#x20AC;? Asked if stopping statins would signify that the previous use of statins had been a wasted effort, less than 15% agreed it would. â&#x20AC;&#x153;We asked them whether they

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worried about unintended consequences of discontinuing the medicine,” Dr. Abernethy said, and only 11% said yes. “Physicians get anxious about having this conversation,” Dr. Abernethy noted, but the survey showed that for patients it wasn’t such a big concern. An article that Dr. Abernethy coauthored for the British Medical Journal2 in 2004 “was really the starting point for this study,” she explained. “We described the need to more properly manage medicines in the palliative care setting.” This included basing decisions to adjust drugs on whole-body changes that occur in lifelimiting illness, rather than just adverse events, and monitoring those changes with ongoing clinical assessments. At the editors’ request, the authors developed a table listing patients’ potential perceptions and clinicians’ potential responses when discussing changes in drug regimens near the end of life. Those questions formed the basis of the survey.

scription drugs but not nonprescription drugs or complementary medicine. “Discontinuing statins led to the discontinuation of other medicines, too. We clearly saw this in the data,” Dr. Abernethy said. “The number of medicines in the pill cup other than statin medicines significantly decreased” for those who discontinued statins (10.1 vs 10.8, P = .034). “We don’t know what the impetus was” for discontinuing other medicines, she acknowledged. “We don’t know if patients did it with or without their doc-

patients would be amenable to discontinuing medications that were no longer necessary. “I’m always asking myself: Do I need to take whatever it is that I am taking right now? As my grandmother’s pill cup got more full with different types of medicines, I was more attentive to which ones we could get rid of.”

Sense of Relief A previous study Dr. Abernethy coauthored in 2007 noted, “There is abundant literature about starting

As physicians, we worry about stopping medicines because it might signify that the doctor is giving up on the patient, but less than 5% of patients said that that was a concern to them. —Amy P. Abernethy, MD, PhD

Discontinuation of Other Drugs Before the study began, Dr. Abernethy and her colleagues had estimated that the average number of medicines the patients would be taking would be about 10. “When we originally said that, we got lots of pushback that the estimate was too high—people don’t take that many medicines—but it was exactly what the average was,” she noted. That included routine and as-needed pre-

tor’s input. But we do know that polypharmacy is quite detrimental, especially over time, as people start losing more and more weight and have more decline in their kidney and liver functions. The concoction of drugs becomes more potent and potentially harmful, just due to drugdrug interaction.” Reflecting on her own situation, Dr. Abernethy said that it makes sense that

Expect Questions but Not a Lot of Resistance

topping statin therapy is safe for patients with cancer who have a life expectancy of no more than a year, according to a randomized study reported at the 2014 ASCO Annual Meeting. Discontinuing statins did not shorten survival, reduced symptom burden, improved overall quality of life, and led many patients to discontinue other medicines as well. The clinical question of whether to continue or discontinue statins in the last year of life remains “a patient-centered decision, where clinicians and patients together talk about what to do,” noted the study’s lead author, Amy P. Abernethy, MD, PhD, Professor of Medicine and Palliative Care Specialist at Duke University Medical Center in Durham, North Carolina. “As clinicians, however, we can now feel confident we are not harming the patient by making this decision.”

‘Safe Language’ “Physicians get anxious about having this conversation,” about discontinuing medications for patients at the end of life, Dr. Abernethy told The ASCO Post. But a survey conducted before patients in the study were randomly assigned found that most patients would not interpret negatively a physician’s recommendation to discontinue statins. Less than 5% of patients surveyed said a recommendation to discontinue statins would signify their physician giving up on them, and only 11% were worried about unintended consequences of stopping statins. “I always try to think about what is safe language for a conversation with a patient,” Dr. Abernethy said. “A good way to bring this up with patients is around the burden of taking so many pills.” Working in partnership, the physician and patient can discuss the medicines the patient is currently taking, and the physician can suggest, “let’s take a look at your list and see what we can do differently.” n

medications for comorbid illnesses but little guidance on reducing or stopping medications, especially in the setting of a life-limiting illness.”3 Before conducting the current study about discontinuing medicines for patients with a life expectancy ≤ 1 year, “we surveyed the palliative care community and asked if this was an important question, and we got a resounding yes. We asked, if we were going to study medication simplification, which medicines should we study? That is where we learned we should study statins. We also asked, do you use any statins in your own practice, and half said that they continued them and half discontinued them. So it was a place of great equipoise, where clinically, nobody knew what to do.” Dr. Abernethy said that the study results and subsequent news reports about discontinuing medicines near the end of life were well received by her palliative care colleagues. “Among the palliative care physicians, I think there is a sense of relief,” she noted. “In the oncology community, there has been a general sense of, ‘Okay, as long as you don’t stop the chemotherapy,’” she added. “We set this study up to be essentially a platform where we can now conduct a sequence of studies of additional medicines,” Dr. Abernethy said, nothing that the next study would probably be about stopping anticoagulants. “We originally were going to do bisphosphonates next,” she said, but she and her colleagues learned that the rheumatology community would likely be studying that issue, and they wanted to avoid duplication of effort.

Dr. Abernethy noted that the statin investigation “was the first study conducted by the Palliative Care Research Cooperative Group, which is a new national research network funded by funded by the National Institute of Nursing Research.”

Big Cost Savings The study included overall cost estimates on how much money could be saved if all people with a life expectancy of 1 year or less—similar to the group involved in this study (49% with cancer and the remainder with heart disease, chronic obstructive pulmonary disease, and other illnesses)—were to discontinue statins. For 2014, an estimated $603 million could potentially be saved in the United States. This estimate was based on an average survival on the study of 212 days and $3.37 saved per patient day. Applying these results to 2040 population estimates, the potential savings would total $1 billion. Dr. Abernethy said that when she brings up cost concerns with physicians, especially cardiologists, many respond that statins are so cheap. But that may not be true for brand name statins and for individual patients. Physicians may feel uncomfortable talking about cost-effectiveness “because they think that patients will assume doing something that is costeffective is somehow slighting them of something that they need. In fact, patients make decisions about cost-effectiveness all day long,” she said. “We work a lot with this concept of ‘financial toxicity’ and the decisions people make because of the financial implications of their health care. People are constantly making judgments and decisions about going to the doctor, what to do with their pills, and the trade-offs. For us to assume that they don’t want to be able to discuss it with us is paternalistic. The neat thing about this statin study is that we actually can talk about something that is good for patients and is cheaper.” n

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

References 1. Abernethy AP, Kutner, Blatchford PJ: Managing comorbidities in oncology: A multisite randomized controlled trial of continuing versus discontinuing statins in the setting of life-limiting illness. ASCO Annual Meeting. Abstract LBA9514. Presented June 3, 2014. 2. Stevenson J, Abernethy AP, Miller C, et al: Managing comorbidities in patients at the end of life. BMJ 329:909-912, 2004. 3. Currow DC, Stevenson JP, Abernethy AP, et al: Prescribing in palliative care as death approaches. J Am Geriatr Soc 55:590-595, 2007.

The ASCO Post | JULY 10, 2014

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Emerging Clinical Data on Cancer Management BREAST CANCER Underuse of Trimodality Treatment for Patients With Inflammatory Breast Cancer Negatively Impacts Survival

Analysis of data for 10,197 women treated for nonmetastatic inflammatory breast cancer treated over a 12-yearperiod found that the use of trimodality treatment (chemotherapy, surgery, and radiation therapy) fluctuated annually

between 58.4% and 73%. “Underutilization of trimodality therapy negatively impacted survival for patients with [inflammatory breast cancer],” Natasha M. Rueth, MD, and colleagues from The University of Texas MD Anderson

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Cancer Center, Houston, concluded in the study report published in the Journal of Clinical Oncology.

Unsurprising Findings “Not surprising, 5- and 10-year survival rates were highest among patients receiving trimodality treatment (55.4% and 37.3%, respectively) compared with any other treatment group,” the researchers wrote. Survival rates for patients who received the combination of surgery plus chemotherapy were 42.9% at 5 years and 28.5% at 10 years, and for those receiving surgery plus radiation therapy, 40.7% at 5 years and 23.5% at 10 years. The 10year survival rate for patients receiving surgery alone was 16.5%. “Current [inflammatory breast cancer] treatment guidelines published by the National Comprehensive Cancer Network recommend anthracyclinebased neoadjuvant chemotherapy followed by modified radical mastectomy and postmastectomy radiation therapy to the chest wall and draining lymphatics (trimodality treatment),” the investigators noted. Over the course of the study, they found that the use of trimodality treatment “increased steadily until it reached a maximum of 73.4% in 2004. In the years that followed, use varied; by 2010, only 65.9% of patients received trimodality treatment for [inflammatory breast cancer].” Patients diagnosed earlier in the study period were significantly less likely to receive trimodality therapy, as were those who were older, lived in regions of the country outside of the Midwest, had lower incomes or public insurance, and had a higher comorbid score (all P < .05). “After adjusting for potential confounding variables, use of trimodality therapy remained a significant independent predictor of survival,” the authors noted. The majority of the patients, identified through the National Cancer Data Base, were white, insured, and had a low comorbidity score. Almost all women (93.4%) had unilateral or bilateral mastectomy, and the remainder had segmental mastectomy of an unknown or unreported breast operation.

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The authors noted that they were “surprised to find that 5.3% of women in the study were treated with substandard segmental mastectomy rather than total mastectomy, a surgical option associated with poor cosmetic outcomes and

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unacceptably high positive margin and local recurrence rates. We also found it notable that nearly one third of women did not have pathologic lymph node status reported, despite the knowledge that [inflammatory breast cancer] is associated with axillary lymph node involvement in 55% to 85% of cases and is a predictor of patient survival.” Although 93.5% of patients received chemotherapy in addition to surgery, 26.8% of those patients did not receive radiotherapy also, which had a significant detrimental impact on overall survival. “By focusing our study on the surgical population, we have created a cohort of women who had access to medical care; despite this, patients with lower incomes or public insurance were less likely to receive complete trimodality treatment than those with higher incomes or private insurance,” the researchers wrote. “Although it is quite likely that the reasons for noncompliance of treatment are multifactorial, clinicians must consider the individual impact of each patient’s social setting, recognizing that unique financial challenges including travel, childcare, and days away from work may influence a woman’s ability to fully adhere to her cancer treatment plan,” the authors advised. “Given that recurrence rates in [inflammatory breast cancer] are relatively high and take place within a shorter time period than in other forms of breast cancer, adherence to [radiotherapy] may play a greater role in locoregional control,” they continued. “The ongoing nationwide trends in underutilization of [radiotherapy] warrant further investigation into the specific patient and physician factors that preclude comprehensive cancer care.” Rueth NM, et al: J Clin Oncol. June 2, 2014 (early release online).

HEAD AND NECK CANCER Limited Public Awareness of Head and Neck Cancers Raises Concerns About Prevention and Detection Public awareness of head and neck cancer is limited, with the lack of awareness including the term head and neck cancer and common symptoms and risk factors, such as tobacco use and human papillomavirus (HPV), according to results of a cross-sectional online survey reported in JAMA Otolaryngology-Head & Neck Surgery. This lack of awareness “is concerning given the importance of risk factor avoidance and modification, as

well as early patient detection, as drivers of prevention and improved outcomes,” the study authors commented.

Study Details The online survey of 2,126 randomly selected adults in the United States was conducted in early January 2013. The mean age of those responding was 42 years (range, 15.2–18.92 years), and 30.2% identified as current or former smokers. Only 3.6% reported having more than four drinks per day. Most respondents identified as white (78.5%), and a slightly higher percentage were women (54.8%). The south was represented by a higher percentage of respondents (30.1%) than the midwest, northeast, and west. “Self-reported respondent knowledge of [head and neck cancer] was low, with 66.0% reporting that they were ‘not very’ or ‘not at all’ knowledgeable. This did not vary significantly with tobacco use (P = .92), education (P = .053), sex (P = .07), or race (P = .02),” the investigators stated. Most respondents lacked understanding of the organs or tissues affected by head and neck cancer, with 21% incorrectly identifying brain cancer as head and neck cancer. Among those correctly identifying head and neck cancer sites, 22.1% of respondents correctly identified throat cancer, 15.3% mouth cancer, and 2.0% cancer of the larynx. “Questions about symptoms of [head and neck cancer] revealed that almost all respondents lacked knowledge of common symptoms, with only 14.9% identifying ‘red or white sores that do not heal’ and even fewer identifying other important symptoms such as ‘sore throat’ (5.2%), ‘bleeding in the mouth or throat’ (0.5%), or ‘swelling or lump in the throat’ (1.3%),” the researchers reported. “Headache, a nonspecific symptom that is uncommon in [head and neck cancer], was the symptom most frequently identified as a symptom of [head and neck cancer] among survey participants (19.0%).”

reported. “The lack of awareness of the association between HPV infection and throat cancer and the greater awareness of the vaccine among women suggest that this knowledge is primarily due to awareness of the role of HPV in uterine cervical cancer,” the authors added. The researchers estimated that widespread HPV vaccination could prevent almost 9,000 cases of oropharyngeal cancer annually. “However, greater awareness of the role of HPV infection in oropharyngeal cancer is necessary to improve vaccine adherence, especially in men,” the authors noted. “In addition, greater awareness of the disease may prompt patients harboring symptoms of HPV-positive cancers to seek evaluation while also prompting dentists and physicians to consider this in the differential diagnosis of more common diseases such as pharyngitis, tonsillitis, and benign lymphadenopathy.” The authors noted that 5-year survival rates have improved only modestly, and the proportion of patients diagnosed in late stages of disease has remained essentially constant. “Given that routine screening for [head and neck cancer] by primary care physicians is rarely performed and currently not recommended by the U.S. Preventive Services Task Force, early detection depends on patient recognition. Similarly, primary prevention of [head and neck cancer] largely depends on awareness and avoidance of environmental risk factors. Public awareness of [head and neck cancer] is therefore necessary for both primary and secondary prevention.” Luryi AL, et al: JAMA Otolaryngol Head Neck Surg. June 5, 2014 (early release online).

UVEAL MELANOMA Modest Improvement in Progression-Free but Not Overall Survival With Selumetinib vs Chemotherapy Patients with uveal melanoma treated with selumetinib had modestly improved progression-free survival and response rate compared to patients treated with chemotherapy, but no improvement in overall survival, according to results of a randomized, openlabel, phase II trial. “Improvement in clinical outcomes was accompanied by a high rate of adverse events,” Richard D. Carvajal, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported in The Journal of the American Medical Association. “Arising from melanocytes within the choroid layer of the eye, uveal melanoma “is biologically distinct from cutaneous melanoma,” the investigators noted. Oncogenic mutations of the GNAQ and GNA11 genes “are observed in more than 80% of primary uveal melanomas and activate signaling pathways including the mitogen-activated protein kinase (MAPK) pathway. We and others demonstrated the genotypedependent antitumor effects of inhibition of the MAPK pathway at the level of the mitogen-activated protein kinase (MEK) enzymes MEK1 and MEK2 in preclinical models.”

Study Background Selumetinib is a selective, non– adenosine triphosphate competitive inhibitor of MEK1 and MEK2. In a

Role of HPV Smoking was identified as a risk factor by 54.5%, chewing or spitting tobacco by 32.7%, alcohol use by 4.8%, and prolonged sun exposure by 0.6%. “Only 0.8% of respondents identified HPV infection as a risk factor for mouth and throat cancer, but specific questioning revealed that 12.8% were aware of the association between HPV infection and throat cancer, whereas 70.0% of respondents were aware of the vaccine targeting HPV,” the researchers

continued on page 94

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In the Literature Emerging Clinical Data continued from page 93

subset analysis of 20 patients with advanced uveal melanoma, progressionfree survival time with selumetinib was double that achieved with chemotherapy. At last year’s ASCO Annual Meeting, Dr. Carvajal reported data on 96 patients showing that median

progression-free survival was significantly improved for patients treated with selumetinib (15.9 weeks) vs temozolomide (7 weeks) and that there was a trend toward improved overall survival. As described in the JAMA article, patients recruited at 15 academic oncology centers in the United States and

Canada were randomly assigned to receive selumetinib at 75 mg orally twice daily (n = 50), or chemotherapy (n = 51) with the investigator’s choice of temozolomide (Temodar), 150 mg/ m2 orally daily for 5 of every 28 days, or dacarbazine 1,000 mg/m2 intravenously every 21 days) until disease progression, death, intolerable adverse

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effects, or withdrawal of consent. Eligible patients could not have received prior treatment with a MEK inhibitor, temozolmide, or dacarbazine. “After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression,” the researchers noted. A total of 99 patients were ultimately treated, with 98 stopping therapy by December 2013. While no objective responses were observed with chemotherapy, 49%. of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Median progression-free survival was 7 weeks in the chemotherapy group (median treatment duration, 8 weeks) and 15.9 weeks in the selumetinib group (median treatment duration, 16.1 weeks). “The hazard ratio for progression-free survival was 0.46 [95% confidence interval = 0.30–0.71, P < .001] in favor of selumetinib,” the authors reported.

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Treatment-related adverse events were observed in 65 patients (97%) treated with selumetinib, with 25 patients (37%) experiencing grade 3/4 treatment-related adverse events vs 2 patients (4%) in the chemotherapy group. The treatment-related adverse events in the selumetinib group “were consistent with those observed with other inhibitors of MEK, including rash, creatinine kinase elevation, edema, and visual changes,” the authors stated. In the selumetinib group, 25 patients required at least one dose reduction vs 1 patient in the chemotherapy group. “In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival time and rate of response; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events.” the authors conclude. The clinical trials.gov identifier is NCT01143402. n Carvajal RD, et al: JAMA 311:23972405, 2014. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Patient’s Corner

Coping With the Aftermath of Cancer

Although I’m now cancer-free, the lingering effects of my breast cancer have impacted both my financial and physical well-being. By Marie Krejci, as told to Jo Cavallo

ven now, 3 years after I was diagnosed with breast cancer, I’m still struggling with how it is possible to have a normal mammogram and 6 months later be confronted with stage II estrogen/progesterone–positive, HER2-positive breast cancer. The news was especially devastating to hear because it arrived 6 weeks before my wedding, and at a time in my life when

our wedding date so it wouldn’t interfere with the start of my treatment. We were married the day before my surgery.

The Cost of Cancer My treatment was difficult. In addition to the 4½ months of chemotherapy and an additional year of trastuzumab, I underwent seven surgeries, including breast reconstruction surgeries. I was

Cancer changes everything: your outlook on life, your career goals, and your priorities. And while cancer has taken a lot away from me, it has also given me a lot, including a desire to help other survivors going through a similar experience. —Marie Krejci

I was the happiest I have ever been. In an instant, my whole world was turned upside down, and I knew I was going to be in for the fight of my life. Because the cancer was so aggressive, my oncologist recommended that I postpone the wedding and immediately undergo treatment: first a mastectomy, followed by a grueling chemotherapy regimen of carboplatin, trastuzumab (Herceptin), and docetaxel. Although the cancer was confined to my right breast, I also opted to have a contralateral prophylactic mastectomy. I could see the looks of concern on the faces of my medical team and knew I had to act fast. After talking it over with my fiancé, Scott, we decided to cancel the wedding festivities, but moved up

so sick most of that time, I had to take a medical leave from work. With the loss of my income, the bills began piling up, and I’m still recovering financially. So many things about having cancer are devastating. Certainly, the immediate fear that you could lose your life is at the top of the list. But what has been the most difficult to cope with is the aftermath of cancer. I’m thrilled to say that the treatment was successful and I’m now cancer-free, but it has not been easy trying to resume the life I had before my diagnosis—and I am realizing with every day that passes, I never will have that life again. The treatment has left me with serious cognition problems. I struggle at work to complete assignments, and my

ability to multitask—a skill I was so proficient at before—is now completely gone. Complex situations that I used to handle with ease now leave me feeling bewildered and overwhelmed. In addition to my cognitive issues, I also have a lot of joint pain from anastrozole, the aromatase inhibitor I’m taking to prevent a cancer recurrence, so I also have physical limitations to contend with as well. All of these problems have left me unable to continue my career in a fulltime capacity. Having to make such a drastic change in my profession is concerning. I’ve been with the same company for 29 years and love what I do, so having to curtail my workload and relinquish some of my responsibilities has been difficult. On a more basic level, I’m worried about how reducing my work hours will affect my retirement fund and my ability to recover financially from my treatment expenses.

Survivorship Support My treatment was difficult. In addition to the 4½ months of chemotherapy and an additional year of trastuzumab, I underwent seven surgeries, including breast reconstruction surgeries. I was so sick most of that time, I had to take a medical leave from work. With the loss of my income, the bills began piling up, and I’m still recovering financially. So many things about having cancer are devastating. Certainly, the immediate fear that you could lose your life is at the top of the list. But what has been the most difficult to cope with is the aftermath of cancer. I’m thrilled to say that the treatment was successful and I’m now cancer-free, but it has not been easy trying to resume the life I had be-

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship. Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

fore my diagnosis—and I am realizing with every day that passes, I never will have that life again. The treatment has left me with serious cognition problems. I struggle at work to complete assignments, and my ability to multitask—a skill I was so proficient at before—is now completely gone. Complex situations that I used to handle with ease now leave me feeling bewildered and overwhelmed. In addition to my cognitive issues, I also have a lot of joint pain from anastrozole, the aromatase inhibitor I’m taking to prevent a cancer recurrence, so I also have physical limitations to contend with as well. All of these problems have left me unable to continue my career in a fulltime capacity. Having to make such a drastic change in my profession is concerning. I’ve been with the same company for 29 years and love what I do, so having to curtail my workload and relinquish some of my responsibilities has been difficult. On a more basic level, I’m worried about how reducing my work hours will affect my retirement fund and my ability to recover financially from my treatment expenses..

Renewed Sense of Purpose Cancer changes everything: your outlook on life, your career goals, and your priorities. And while cancer has taken a lot away from me, it has also given me a lot, including a desire to help other survivors going through a similar experience. Cancer has also given me a renewed sense of purpose, and now I live every day to the fullest and never take anything for granted. That’s a valuable lesson for us all. 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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