TAP Vol 4 Issue 20 by Harborside Press LLC

Breast Cancer in YoungWomen 7 | Smoldering Myeloma

| Letters to the Editor

VOLUME 4, ISSUE 20

96, 109–110

DECEMBER 15, 2013

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

Chemotherapy Foundation Symposium

Consent Is Informed and Shared, But Is It Compassionate?

Call for Expanded Genetic Profiling in Colorectal Cancer By Alice Goodman

By Chandrakanth Are, MBBS, FRCS, FACS

esting for codons 12 and 13 on the KRAS gene and BRAF testing can predict whether patients with colorectal cancer will respond to anti–epidermal growth factor receptor (EGFR) therapies. However, genetic alterations not captured by testing for KRAS codon 12 and 13 mutations may play an important role in determining response to therapy for colorectal cancer.

‘Think Beyond KRAS Mutations’ “KRAS is the most dominant mutated RAS member in the tumors of patients with colorectal cancer, and it is commonly mutated in codons 12 and 13. But other mutations not routinely tested in KRAS or mutations in the NRAS gene may be present. Think beyond KRAS mutations,” said Scott Kopetz, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston. “These are important mutations biologically.

Genetic profiling should be expanded to include other KRAS mutations and NRAS mutations [ie, codons 12, 13, 59, 61, 117, and 146 in the KRAS and NRAS genes],” he told listeners at the Chemotherapy Foundation Symposium XXXI, Scott Kopetz, MD, PhD held recently in New York.1 “These extended KRAS and NRAS mutations are also transforming in vitro. These mutations are mutually exclusive with KRAS codons 12 and 13 mutations. If we can better define a responsive population, then everybody wins. We can provide therapy that is more effective with less toxicity, and it would ultimately be more cost-effective. We will better deploy our weapons against colorectal cancer,” Dr. Kopetz commented. continued on page 20

Issues in Oncology

Sharing Treatment Decision-Making With Patients: Where’s the Evidence of Value?

72-year-old, obese male patient and a poor operative candidate is diagnosed with esophageal carcinoma. He has multiple comorbidities and a past history of colon carcinoma. His staging workup, which included a colonoscopy, revealed recurrent colon carcinoma. Thus, we have a patient who we initially thought may not be fit enough for even one operation but now is looking at the prospect of two operations. A 92-year-old female patient presents to the emergency room with abdominal pain whose continued on page 107

Dr. Are is Associate Professor of Surgical Oncology, Vice Chair of Education, and Program Director of the General Surgery Residency Program at University of Nebraska Medical Center, Omaha. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO. Some details have been changed to protect patient privacy.

MORE IN THIS ISSUE

By Caroline Helwick

ASCOPost.com

hough certainly not new to oncologists, “shared decision-making” between doctors and patients is receiving increased attention in the medical community today. While it’s an idea with merit, Steven J. Katz, MD, MPH, a specialist in quality care issues, maintains that expectations about the potential value of shared decision-making may be too high. Dr. Katz is Professor of Medicine and Health Management and Policy at the University of Michi-

gan, Ann Arbor, and a member of ASCO. He heads up research projects on the quality of cancer care delivery, including a National Institutes of Health– funded study aimed at better understanding treatment decision-making. Dr. Katz recently authored a “Viewpoint” appearing in the Journal of the American Medical Association, questioning the quality of the evidence offered in support of shared decision-making and its benefits to patients, providers, and the healthcare system.1 Dr. Katz recently spoke with the The Ultimately, we ought to share ASCO Post to elaborate. “We have seen an overdecision-making, but the responsibility exuberance regarding the for cost-containment is in the hands of bang for the buck, with regard to increasing the the doctors. patient’s engagement in —Steven J. Katz, MD, MPH clinical encounters,” he

Oncology Meetings Coverage European Cancer Congress �� 8–12 Chemotherapy Foundation Symposium �� 20, 21 Quality Care Symposium �� 24 Autologous Transplantation as Consolidation in Aggressive Lymphoma �� 3 Richard I. Fisher, MD �� 26 Julie M. Vose, MD �� 27 Andrew D. Seidman, MD, on Adjuvant Trastuzumab Duration �� 30 Direct From ASCO �� 48–51 Brian J. Druker, MD, on Personalized Therapies �� 80 In Memoriam: Peter Jacobs, MD �� 106

continued on page 24

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Journal Spotlight Hematology

Autologous Transplantation as Consolidation Improves ProgressionFree Survival in Aggressive Non-Hodgkin Lymphoma By Matthew Stenger

he strategy of autologous stem-cell transplantation as consolidation in high-intermediate– or high-risk diffuse aggressive non-Hodgkin lymphoma (NHL) has not been specifically examined in the rituximab (Rituxan) era. In the phase III Southwest Oncology Group (SWOG)led intergroup 9704 trial reported in The New England Journal of Medicine, Patrick J. Stiff, MD, of Loyola University Medical Center, Maywood, Illinois, and colleagues compared three additional cycles of induction chemotherapy vs one additional cycle plus autologous stem cell transplantation in patients with response to induction CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab plus CHOP (R-CHOP).1 The study showed that early autologous transplantation resulted in greater progression-free survival but not overall survival, although an overall survival benefit was observed among patients with high–International Prognostic Index (IPI) disease.

disease. In addition, 36% had Eastern Cooperative Oncology Group performance status ≥ 2, 84% had elevated lactate dehydrogenase, 22% had bone marrow involvement, 66% had ≥ 1 extranodal site (≥ 2 in 26%), 62% had B symptoms, 32% had IPI high-risk disease, and 47% of those with B-cell lymphoma (156/330) received R-CHOP. Of the 370 patients, 117 did not enter the randomized phase, primarily due to disease progression (56%) and patient decision (20%). The remaining 253 patients were randomly assigned to the transplantation group (n = 125) or control group (n = 128). There were no significant dif-

Treatment of Relapse Of 62 control group patients with relapse (48% of group), 29 (47%) received salvage chemotherapy and transplantation; of these, 11 (38%) survived without disease progression and another 7 patients survived without progression after alternative salvage therapy. Thus, a total

Early transplantation and late transplantation achieve roughly equivalent overall survival in the combined risk groups. Early transplantation appears to be beneficial for the small group of patients presenting with high-risk disease. —Patrick J. Stiff, MD, and colleagues

Study Details In the trial, 370 eligible patients with NHL in Working Formulation groups D through H and J and age-adjusted IPI classification of high risk or high-intermediate risk received five cycles of CHOP or R-CHOP. Those with response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary endpoints were 2-year progression-free survival and overall survival. Among the 370 patients, median age was 51 years, 59% were male, 89% had Bcell lymphoma (diffuse large B-cell lymphoma–not otherwise specified in 67%), 11% had T-cell lymphoma, 31% had stage III disease, and 63% had stage IV

transplantation group (adjusted HR = 1.26, P = .30). Median overall survival was not reached in either group. Nine transplantation group patients who did not receive transplantation had a 2-year progression-free survival rate of 56% and overall survival rate of 78%.

ferences between groups in age, sex, risk group, initial stage, lactate dehydrogenase level, number of extranodal sites, or B symptoms. Of patients with B-cell lymphoma, 60% had received R-CHOP induction, indicating a higher dropout rate among those receiving CHOP induction.

Key Findings Two-year progression-free survival rates were 55% in the control group vs 69% in the transplantation group (hazard ratio [HR] in multivariate analysis adjusting for risk score = 1.72, P = .005). Median progression-free survival was not reached in the transplantation group vs 2.8 years in the control group. Two-year overall survival rates were 71% in the control group vs 74% in the

Role of Autologous Transplantation in NHL ■■ Early transplantation was associated with significantly improved progression-free survival but not overall survival. ■■ Transplantation was associated with a significant overall survival benefit among patients with high-risk disease. ■■ Overall survival results in the entire population may have been affected by the efficacy of salvage transplantation in the control group.

of 18 (29%) of the control group patients with relapse survived without disease. Of the 28 patients in the transplantation group with relapse, 23 (82%) died, most after salvage chemoimmunotherapy. Allogeneic stem-cell transplantation was performed in three patients, with two dying from toxic effects and one having a subsequent relapse but surviving.

Subgroup Analyses No differential treatment effect was found between the subgroup of patients with B-cell lymphoma and the subgroup with T-cell lymphoma for either progression-free survival (P = .46 for interaction) or overall survival (P = .56 for interaction). Among patients with B-cell lymphoma, the hazard ratios for control vs transplantation group were 1.84 (P = .004) for progression-free survival and 1.36 (P = .21) for overall survival. There was also no differential effect between patients with B-cell lymphoma treated with R-CHOP vs CHOP for either progression-free survival (P = .33 for interaction) or overall survival (P = .31 for interaction). Among those receiving RCHOP, 2-year progression-free survival

rates were 63% in the control group vs 73% in the transplantation group (HR = 1.56, P = .10) and 2-year overall survival rates were 73% vs 77% (HR = 1.09, P = .79).

Benefit in High-Risk Patients A significant treatment effect was observed according to risk category for both progression-free survival (P = .04 for interaction) and overall survival (P = .01 for interaction). Among randomized patients, 36% of those with B-cell lymphoma receiving R-CHOP, 32% of those with B-cell lymphoma receiving CHOP, and 36% of those with T-cell lymphoma were in the high-risk category. Among all 165 high-intermediate-risk patients, 2-year progression-free survival was 66% in transplantation patients vs 63% in control patients (P = .32), whereas rates were 75% vs 41% (P = .001) among all 88 highrisk patients. Two-year overall survival was 70% in the transplantation group vs 75% in the control group (P = .48) among those at intermediate-high risk and 82% vs 64% (P = .01) among those at high risk. Similar differential effects were found among patients with B-cell lymphoma for both progression-free survival (P = .05 for interaction) and overall survival (P = .03 for interaction).

Toxicities During the first five cycles of CHOP or R-CHOP, four patients died, three due to neutropenic infection and one due to hemorrhage. Among patients randomized to the transplantation group or the control group, grade 3 or 4 adverse events were more frequent in the transplantation group. These included infection (50% vs 13%), gastrointestinal effects (26% vs 5%), metabolic effects (13% vs 1%), lung effects (11% vs 2%), cardiovascular effects (10% vs 4%), neurologic effects (7% vs 5%), dyspnea (7% vs 2%), hyperglycemia (6% vs 0%), hypoxia (4% vs 0%), and hepatic effects (3% vs 0%). Six patients in the transplantation group (5%) died from toxic effects, consisting of lung damage in three and hemorrhage and renal failure, infection, and multiorgan failure in one each. Three control group patients died (2%), due to cardiovascular toxic effects, infection, and unknown factors in one each. continued on page 6

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Journal Spotlight

Autologous Transplantation continued from page 3

The investigators concluded: [A]lthough we found that progressionfree survival was superior with early transplantation among patients with high-intermediate-risk or high-risk nonHodgkin’s lymphoma who had a response

to induction therapy, we could not validate a benefit of consolidative transplantation with respect to overall survival. Thus, early transplantation and late transplantation achieve roughly equivalent overall survival in the combined risk groups. Early transplantation appears to be beneficial for the small group of patients presenting with high-risk disease. n

Disclosure: The study was supported by NCI grants, Canadian Cancer Society Research Institute grants, and Bristol-Myers Squibb. For full disclosures of the study authors, visit www. nejm.org.

Reference 1. Stiff PJ, Unger JM, Cook JR, et al: Autologous transplantation as con-

solidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369:16811690, 2013.

See related commentaries by Richard I. Fisher, MD (page 26) and Julie Vose, MD (page 27).

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European Cancer Congress Breast Cancer

Radiotherapy Benefit in Young Women With Node-Positive Breast Cancer May Vary by Intrinsic Subtypes By Caroline Helwick

adiation therapy appears to significantly decrease local recurrence in premenopausal women with node-positive and luminal A tumors, based on an

analysis of two small but independent randomized series reported at the 2013 European Cancer Congress in Amsterdam.1 “Though not definitive, our study

suggests that these biologically slowgrowing luminal A tumors may obtain the greatest benefit from regional radiotherapy. Thus, radiation should not be

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omitted in young patients with high-risk tumors,” said Tinne Laurberg, MD, of Aarhus University Hospital, Denmark.

Study Design Luminal A tumors are associated with good prognosis but carry substantial risk for late locoregional relapse. The study tested the predictive value of intrinsic subtypes (as defined by the PAM50 classifier) for benefit from adjuvant radiation therapy among premenopausal women with node-positive tumors. Tumors were classified as luminal A, luminal B, HER2enriched, basal-like, and normal-like. Tumor samples (n = 232) were derived from two independent postmastectomy randomized adjuvant radiation trials with more than 20 years of follow-up—the British Columbia Randomized Radiation Trial (1979–1986)2 and the Danish Breast Cancer Group protocol 82b (1982–1989).3 In both trials, patients received adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) and were randomly assigned to postmastectomy radiation therapy or no radiotherapy. In the British Columbia trial, patients with estrogen receptor–positive tumors were re-randomized to receive oophorectomy, and 42 of them were included in this correlative study. Both trials showed that radiation therapy lowered the incidence of locoregional recurrence and improved overall survival, in comparison to adjuvant chemotherapy alone. In the current analysis by intrinsic subtypes, patients with luminal A tumors had the greatest benefit for local control. Basallike tumors appeared to derive some benefit, which warranted further investigation. Luminal B and HER2-enriched subtypes

Radiotherapy Benefit by Breast Cancer Subtype ■■ In a PAM50 molecular analysis of breast cancer tumors from a subgroup of patients in two randomized radiotherapy trials in premenopoausal patients, the benefit of radiotherapy in reducing locoregional recurrence was greatest for patients with luminal A tumors. continued on page 8

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European Cancer Congress Breast Cancer

Most Benefit in Patients With Luminal A Tumors continued from page 7

had few patients, and therefore limited power excluded the potential benefit, Dr. Laurberg reported. In patients with luminal A tumors, locoregional recurrence-free rates were 90% with radiotherapy and 59% without (P = .04) in the British Columbia

currence among luminal A patients,” Dr. Laurberg concluded. “In this subanalysis within each subtype, the effect is clear, especially in luminal A tumors and maybe also in basal-like tumors. Radiotherapy is protective in luminal A tumors, with survival free of locoregional relapse in 90% of patients after 20 years, but for luminal B tumors there were no statistical significant differenc-

Radiotherapy is protective in luminal A tumors, with a 20-year locoregional disease–free survival at 90%, but for luminal B and HER2-enriched tumors, there were no statistically significant differences observed for locoregional recurrence after radiation therapy. —Tinne Laurberg, MD

trial and 92% vs 50%, respectively (P = .01), in the Danish trial. In patients with basal-like tumors, locoregional recurrence-free rates were 86% vs 36% (P = .03) and 60% vs 51%, respectively (P = .35), in the two trials. Differences between the treatment arms were not statistically significant for the other subtypes. No differences in overall survival were observed in any of the comparisons. “Intrinsic subtype based on PAM50 is predictive for radiation therapy benefit among premenopausal high-risk patients, with radiation therapy lowering the incidence of locoregional re-

es observed for locoregional recurrence after radiotherapy compared to the control arm. For basal-like breast cancer, the protective effect of radiotherapy was seen only in the British Columbia cohort,” she added. “Depending on confirmation, intrinsic subtyping may be useful to predict patients who may benefit from adjuvant radiation therapy,” Dr. Laurberg suggested. n

EXPERT POINT OF VIEW

lzbieta Senkus-Konefka, MD, PhD, of the Medical University of Gdansk, Poland, the formal discussant of the paper at the European Cancer Congress, took exception with the authors’ conclusion that radiotherapy may not be effective in all subtypes. “I don’t agree that luminal B and HER2-enriched subtypes have no benefit,” Dr. SenkusKonefka said, basing this conclusion largely on the small patient numbers. For example, in Elzbieta Senkus-Konefka, MD, PhD the HER2-enriched population, there was only one event seen in 10 patients in the radiotherapy arm. “You can’t draw conclusions from this,” she maintained. The patients in these studies also received, by today’s practice, suboptimal systemic therapy, including no trastuzumab (Herceptin) for HER2-positive patients. “We know that systemic therapy improves local control, and we don’t know the effect of modern systemic therapies in these patients.”

Importance of Local Control She also suggested that the largest benefit in the patients with the most favorable histology may partly be due to the relatively low risk of distant failure and proportionally larger effect of local control in this group. In other words, she said, “The largest benefit may be present in patients in whom the overall outcome is mostly determined by local control.” The findings pose an interesting hypothesis, Dr. Senkus-Konefka concluded, “but this needs further study.” Future research should evaluate gene expression in predicting locoregional control and benefit from postoperative radiotherapy in patients undergoing contemporary systemic treatment, with tailored patient selection. Other areas of research include the molecular prediction of tumor radiosensitivity and normal tissue tolerance and molecular prediction of tumor pattern spread, with radiotherapy technique and dose tailored, she suggested. n Disclosure: Dr. Senkus-Konefka reported no potential conflicts of interest.

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

References 1. Laurberg T, Tramm T, Gelmon K, et al:

2013 European Cancer Congress. Abstract 1850. Presented September 28, 2013. 2. Ragaz J, Jackson SM, Le N, et al: N Engl J

Med 337:956-962, 1997. 3. Marie Overgaard M, Hansen PS, Overgaard J, et al: N Engl J Med 337:949-955, 1997.

Global Oncology 2013: Disparities in Cancer Care

hile much progress has been made against cancer over the last century, a new report1 presented at the 2013 European Cancer Congress brings together evidence that not every patient benefits from it, nor even has the opportunity to benefit. The economics of cancer are daunting and the current model of financing is broken, said Professor Peter Boyle, in a presentation on “The State of Oncology.” Dr. Boyle is President of the International Prevention Research Institute (Lyon, France) and Director of the Institute of Global Public Health of the University of Strathclyde (Glasgow, United Kingdom, and Lyon, France). “Many parts of the world are already unable to cope and are totally unprepared for the future growth of cancer. In lower-resource countries, for many pa-

tients the stigma associated with cancer leads them to seek alternative care, and if they do present to medical services they do so frequently when the disease is advanced,” Professor Boyle said. “The rights of cancer patients can be achieved by implementing and adhering to what we call the four pillars of oncology: prevent all cancers that can be prevented; treat all cancers that can be treated; cure all cancers that can be cured; and provide palliation whenever palliation is required.” For more information, visit http:// bit.ly/IEdtIQ n Disclosure: The “State of Oncology 2013” report was based on the contributions of four overall project leaders, seven regional leaders, and over 100 medical scientists who described the state of oncology in over 50 countries. It is a noncommercial, editorially independent

work, which has been supported by the International Prevention Research Institute, the World Prevention Alliance, and an unrestricted educational grant from Roche.

Reference 1. Boyle P, et al: State of Oncology 2013. Abstract 1401. Presented at the 2013 European Cancer Congress, September 29, 2013.

Erratum

n the November 15 issue of The ASCO Post, the article, “Strong Showing for Ado-Trastuzumab Emtansine in Advanced HER2-Positive Heavily Pretreated Breast Cancer,” contained the following errors in the reported outcomes data for the TH3RESA trial: • The article incorrectly stated the median survival in the control arm at the first interim analysis; this finding was actually 14.9 months. • The any-grade adverse event rates

included in the article were incorrect. These should be 94% for those who received ado-trastuzumab emtansine (Kadcyla) vs 89% for the control arm. The ASCO Post regrets the errors. A corrected version of the article appears at www.ascopost.com. n

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European Cancer Congress Breast Cancer

PIK3CA-Mutant Tumors Not Likely to Respond to Neoadjuvant HER2 Blockade By Caroline Helwick

n early breast cancer patients receiving anti-HER2 therapy in the NeoALTTO trial, mutations in PIK3CA were associated with lower rates of pathologic complete response, according to a study reported at the 2013 European Cancer Congress by José Baselga, MD, Physician-in-Chief at Memorial Sloan-Kettering Cancer Center, New York.1 In patients treated with the combination of lapatinib (Tykerb) and trastuzumab (Herceptin), the pathologic

fore, investigated the influence of PI3K pathway mutations (PIK3CA, KRAS, BRAF, AKT1) on sensitivity to trastuzumab, lapatinib, or both agents in combination in early-stage HER2-positive breast cancer patients enrolled in the phase III NeoALTTO trial. NeoALTTO evaluated neoadjuvant dual HER2 blockade in 449 patients with primary HER2-positive breast cancer. Dual blockade achieved a pathologic complete response rate of 51.3%, vs 29.5% for trastuzumab alone (P = .0001). The pathologic complete response rate for lapatinib was 24.7%, which was not significantly different from trastuzumab (P = .34).2

those with mutant tumors (P = .02). By estrogen receptor status, both positive and negative tumors were less likely to respond in patients with mutations. To more rigorously determine the association, the investigators used a logistic regression model of pathologic complete response, which adjusts for treatment arm and estrogen receptor status. Again, significant differences in pathologic complete response were observed between those with and without the PIK3CA mutation (odds ratio = 0.45, P = .015). Dr. Baselga noted that these results are in line with those observed with pertuzumab (Perjeta) and trastuzumab in the NeoSphere and CLEOPATRA

Mutation Rates

José Baselga, MD

complete response rate was 55.8% in those lacking PIK3CA mutations but only 28.6% in those with mutant tumors (P = .02), Dr. Baselga noted. “The lower [pathologic complete response] rate in PIK3CA-mutant tumors is observed in all treatment arms and irrespective of estrogen receptor status. These findings are consistent with experimental data in our laboratories,” he said. The study provides further evidence of the role of PIK3CA mutations in resistance to trastuzumab- and lapatinibbased therapies, suggesting that the assessment of PIK3CA status might help identify patients unlikely to derive substantial benefit from these treatments.

NeoALTTO Details PIK3CA mutations are frequent in HER2-positive breast cancer. PIK3CA mutations and low PTEN expression are associated with poor prognosis after trastuzumab therapy, and PTEN lossof-function mutations and mutations in PIK3CA lead to lapatinib resistance in vitro, Dr. Baselga explained. The NeoALTTO investigators, there-

Genotyping was completed on biopsies from 355 patients. The primary efficacy endpoint was pathologic complete response at surgery, defined as the absence of tumor in the breast. Consistent with previous analyses, according to Dr. Baselga, PIK3CA mutations were found in 23% of patients. Only one patient (0.3%) had a KRAS mutation and none had a BRAF mutation. The PIK3CA mutation rate was similar among estrogen receptor–negative (22%) and estrogen receptor–positive patients (23%). Per treatment arm, mutations occurred in 23% of patients treated with lapatinib, 19% treated with trastuzumab, and 25% treated with the combination.

Effect of PIK3CA Mutations “PIK3CA mutations were associated with a lower [pathologic complete response] rate. This relationship was evident across the entire patient cohort, but was most pronounced in the lapatinib/ trastuzumab arm,” Dr. Baselga said. The rate of pathologic complete response was 34% in PIK3CA wild-type tumors, but dropped to 21% in PIK3CAmutant tumors (P = .03). In patients treated with the combination, the pathologic complete response rate was 55.8% in those lacking PIK3CA mutations and 28.6% in

Treatment Selection in Early Breast Cancer ■■ PIK3CA mutations were associated with a lower pathologic complete response rate to dual HER2 blockade, compared to PIK3CA wild-type tumors, in the NeoALTTO trial. ■■ After treatment with lapatinib/trastuzumab, patients with tumors lacking the mutation had a pathologic complete response rate of 55.8%, compared to 28.6% among those with tumors having the PIK3CA mutation.

trials. He added that his group has also begun exploring the relationship between PTEN status and achievement of pathologic complete response, and will be reporting these data in the future. n

Disclosure: Dr. Baselga has served in a consulting or advisory role for Novartis, Roche, and Chugai.

References 1. Baselga J, Majewski I, Nuciforo PG, et al. 2013 European Cancer Congress. Abstract 1859. Presented September 29, 2013. 2. Baselga J, Bradbury I, Eidtmann H, et al: Lapatinib with trastuzumab for HER2positive early breast cancer (NeoALTTO): A randomised, open-label, multicentre, phase 3 trial. Lancet 379:633-640, 2012.

EXPERT POINT OF VIEW

ibylle Loibl, MD, of the German Breast Group and the Klinikum Offenbach in Germany, discussed the NeoALTTO findings at the European Cancer Congress, noting that this trial is one of several studies that all point to one conclusion: Pathologic complete response rates are lower in HER2-positive patients with PIK3CA mutations. The GeparSixto study, for which Dr. Loibl was an investigator, found PIK3CA mutations in about 20% of HER2-positive tumors, including 22% of Sibylle Loibl, MD hormone receptor–positive patients and 16% in the negative group.1 The NeoSphere study found PIK3CA mutations in 32%, with no differences in frequency between the hormone receptor subgroups.2 In NeoSphere, however, the estrogen receptor–positive PIK3CA-mutant tumors had the lowest pathologic complete response rate, leading her to question whether the hormone subgroups do respond similarly, she said. “But clearly, there is homogeneity demonstrated between studies, in that [pathologic complete response] rates are higher in wild-type than in PIK3CA-mutant cohorts,” she concluded. The difference is greatest in groups of HER2-positive patients receiving dual blockade, vs single agents.

Pathway Interactions “The studies suggest the interaction of the different pathways, and the need to better select our HER2-positive patients for treatment,” Dr. Loible suggested, adding that other agents targeting PIK3CA might prove beneficial. The addition of a PIK3CA inhibitor to anti-HER2 treatment in patients prescreened for the mutation prior to randomization is currently being evaluated in the phase II NeoPHOEBE trial. n Disclosure: Dr. Loibl reported no potential conflicts of interest.

References 1. Loibl S, Denkert C, Loi S, et al: PIK3CA mutations in primary HER2-positive and triple negative breast cancer. 2013 ASCO Annual Meeting. Abstract 11061. Presented June 3, 2013. 2. Gianni L, Bianchini G, Kiermaier A, et al: Neoadjuvant pertuzumab and trastuzumab: biomarker analyses of a 4-arm randomized phase II study (NeoSphere) in patients with HER2-positive breast cancer. 2011 San Antonio Breast Cancer Symposium. Abstract S51. Presented December 9, 2011.

The ASCO Post | DECEMBER 15, 2013

PAGE 10

European Cancer Congress Gastrointestinal Oncology

Extended-Release Lanreotide Significantly Delays Disease Progression in Patients With Neuroendocrine Tumors in Large Phase III CLARINET Trial By Caroline Helwick

strong antiproliferative response was shown for the somatostatin analog lanreotide (subcutaneous, extended-release formulation, Somatuline Autogel [Somatuline Depot in the United States]) in patients with gastroenteropancreatic neuroendocrine tumors, in the large multinational prospective phase III CLARINET trial. Compared to placebo, lanreotide offered a highly significant advantage in progression-free survival, Philippe Ruszniewski, MD, Professor of Gastroenterology and Chief of the Division of Gastroenterology and Pancreatology at Beaujon Hospital in Clichy, France, reported at the 2013 European Cancer Congress.1

Growing Body of Evidence CLARINET (Controlled study of Lanreotide Antiproliferative Response In NeuroEndocrine Tumors) adds to a growing body of evidence for these agents in neuroendocrine tumors, and supports their use in nonfunctioning tumors. The study’s first author was Martyn Caplin, MD, Professor of

Gastroenterology and Gastrointestinal Neuroendocrinology, Royal Free Hospital, London. In 2009, the PROMID trial was the first study to show that somatostatin analogs, in this case octreotide (Sandostatin) LAR, have antiproliferative effects.2 In PROMID, octreotide improved progression-free survival from 6.0 months to 14.3 months—a 66% reduction in risk (P < .00072). PROMID, however, was a small study of only 85 patients with well-differentiated midgut neuroendocrine tumors, and only two-thirds of these were nonfunctioning. CLARINET was a larger international study of 204 patients with metastatic or locally advanced inoperable sporadic nonfunctioning gastroenteropancreatic neuroendocrine tumors (approximately 45% pancreas, 35% midgut). Patients with well- or moderately differentiated tumors with a low proliferative index (Ki67 < 10%)

EXPERT POINT OF VIEW

jell Oberg, MD, PhD, Professor in the Department of Medical Sciences at the University Hospital in Uppsala, Sweden, discussed the CLARINET paper at the Presidential Session during the European Cancer Congress in Amsterdam. Dr. Oberg noted the curious observation that median progression-free survival for the placebo arms was 18 months in CLARINET but only 6 months in PROMID. He questioned whether this might be due to the inclusion of a “special cohort” of patients in CLARINET. “The very long 18-month median progression-free survival in the placebo arm of CLARINET needs to be discussed,” he suggested. “Only patients who were stable for 6 months were included [progressive disease was allowed in PROMID]. The majority of patients were therapy-naive with a rather short medical history. The cell proliferation rate was low (78% grade 1, Ki67 < 2%), and the hepatic tumor load was < 25% in 67% of patients. The patient material is obviously different from PROMID.” Nevertheless, the benefit is clear, he said, concluding that previous restrictions on the use of somatostatin analogs to functioning tumors only is no longer justified. As a result of CLARINET, guidelines on this issue may change. n Disclosure: Dr. Oberg reported no potential conflicts of interest.

and naive to somatostatin analogs were randomized to receive lanreotide at 120 mg or placebo every 4 weeks for 96 weeks or until progression or death. Two baseline computed tomography (CT) scans at least 12 weeks apart were performed, followed by additional scans at intervals up to 96 weeks.

Primary and Secondary Endpoints For the lanreotide arm, 30 of 101 patients developed progressive disease and 2 patients died. For the placebo arm, 58 of 103 had disease progression and 2 died. In addition, there were 18 withdrawals for various reasons in the lanreotide arm and 21 in the placebo arm. Ultimately, 53 patients treated with lanreotide completed the study “without events” compared to 26 in the placebo arm. CLARINET met its primary endpoint, significantly improving progression-free survival at 2 years from 22% with placebo to 62% with lanreotide— a 53% reduction in risk (P = .0002). Median progression-free survival was not reached with lanreotide (after > 27 months) and was 18 months with placebo, Dr. Ruszniewski reported. In a subgroup (intent-to-treat) analysis, the researchers looked separately at midgut (n = 73) and pancreatic (n = 91) neuroendocrine tumors. In midgut tumors, risk of progression was reduced by 65% with lanreotide (P = .0091); median progression-free survival was not reached with lanreotide but was 21.1 months with placebo. For the pancreatic neuroendocrine tumors, the risk reduction was 42% (P =

.0637); again, median progression-free survival was not reached with lanreotide but was 12.1 months with placebo. “Progression-free survival was substantially prolonged with lanreotide Autogel 120 mg for metastatic, well- to moderately differentiated enteropancreatic [neuroendocrine tumors],” he concluded. “The effect was observed in patients with grade 1 and grade 2 tumors, and in patients with low and high hepatic tumor load.” Not surprisingly, overall survival was similar, with 19 deaths observed in the lanreotide arm and 17 in the placebo arm (P = .8791). The safety profile was consistent with previous studies. Dr. Ruszniewski said the benefit of lanreotide in CLARINET, a clear antiproliferative effect, “may support its place in the treatment algorithm for enteropancreatic [neuroendocrine tumors].” n References 1. Caplin M, Ruszniewski P, Pavel M, et al: A randomized, double-blind, placebo-Controlled study of Lanreotide Antiproliferative Response in patients with gastroenteropancreatic NeuroEndocrine Tumors (CLARINET). 2013 European Cancer Congress. Abstract 3. Presented September 28, 2013. 2. Rinke A, Müller HH, Schade-Brittinger C, et al: Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study Group. J Clin Oncol 27:4656-4663, 2009.

Lanreotide in Neuroendocrine Tumors ■■ The somatostatin analog lanreotide significantly prolonged progressionfree survival in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumors. ■■ Median progression-free survival was not reached (after 27 months) in the lanreotide arm and was 18 months in the placebo arm. ■■ The study adds to a growing body of data supporting the use of somatostatin analogs in patients with nonfunctioning neuroendocrine tumors.

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ASCOPost.com | DECEMBER 15, 2013

PAGE 11

European Cancer Congress Gynecologic Oncology

Continuous, Combined Hormone Replacement Therapy Protects Against Endometrial Cancer By Caroline Helwick

ccording to an analysis of the Women’s Health Initiative, continuous combined use of estrogen plus progestin reduces the risk of endometri-

al cancer among postmenopausal women. The study was reported at the 2013 European Cancer Congress by Rowan T. Chlebowski, MD, PhD, Professor

and Chief of Medical Oncology/Hematology at the David Geffen School of Medicine at UCLA and Harbor-UCLA Medical Center, Los Angeles.1

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and <1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and <2% thereafter [see Dosage and Administration (2)].

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother.

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm.

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

Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3-4, and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of Pre-Existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic

8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients <75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those <75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) >30mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr<30mL/min. [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6, and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA™ [obinutuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

Important Findings “In postmenopausal women with a uterus and nonproliferative endometrial histology [at baseline], continuous combined estrogen/progestin use reduces endometrial cancer incidence by 35%,” Dr. Chlebowski said. “According to our review, this is the first randomized clinical trial evidence that shows this.” A second important finding of the Estrogen-Progestin Trial was the association between obesity and endometrial cancer risk. Women with a body mass index (BMI) > 35 had approximately a sevenfold increased risk, the study found. “BMI > 35 could be a unique target for a cancer prevention intervention in the future,” he suggested.

Study Details The Women’s Health Initiative enrolled 16,608 postmenopausal women from 40 U.S. clinical centers into a randomized, double-blind placebo-controlled trial. Women aged 50 to 70 with an intact uterus and normal endometrial histology were assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate or to placebo. After 5.6 years of the intervention and 6.8 years of additional follow-up, 66 women in the combined hormone therapy group were diagnosed with en-

Estrogen/Progestin and Cancer Risk ■■ Continuous combined estrogen/ progestin use reduced the incidence of endometrial cancer by 35%. ■■ Estrogen/progestin use may have a protective effect in women in the highest BMI categories, who have a substantially increased risk of endometrial cancer. ■■ Although estrogen/progestin reduces endometrial cancer incidence, it increases breast cancer incidence and breast cancer–related deaths. Interventions that reduce the incidence of both cancers are needed. continued on page 12

The ASCO Post | DECEMBER 15, 2013

PAGE 12

European Cancer Congress Endometrial Cancer continued from page 11

dometrial cancer, compared with 95 in the placebo group, which translated to a 35% reduction in risk (P = .007). The analysis at 5.6 years had shown a 17% relative risk reduction that was not statistically significant.

Estrogen/Progestin Broadly Protective In the current analysis, women in the estrogen/progestin group who did develop cancer tended to have fewer poorly differentiated/anaplastic tumors and less regional and distant disease, he added. Although there were fewer endometrial cancers during the intervention period of the trial (25 vs 30), the difference between the arms largely emerged in the postintervention period, where there were 41 cases in the combined hormone group and 65 in the placebo group, a 41% reduction in risk (P = .008). “After about 5 years is when we see a separation of the curve,”

Dr. Chlebowski noted. In a sensitivity analysis that adjusted for adherence, the reduction in risk was 51% (P = .004). Adjusting for hysterectomy also did not change the results. There was no difference in the effect

the highest BMI categories, who have a substantially increased risk of endometrial cancer. “We saw a rapid and high-level rise of endometrial cancer in the obese women,” he said. Women with a BMI

In postmenopausal women with a uterus and nonproliferative endometrial histology [at baseline], continuous combined estrogen/ progestin use reduces endometrial cancer incidence by 35%. —Rowan T. Chlebowski, MD, PhD

according to age or time from menopause. Additionally, there was no significant interaction with race or ethnicity, smoking, physical activity, or prior estrogen alone or estrogen/progestin use. The favorable effects of estrogen/ progestin were broadly observed, including a protective effect in women in

≥ 40 had a relative risk of 7.40, and those with a BMI of 35–50 had a 6.66 relative risk (BMI < 25 served as the reference point). Women with BMI ≥ 40 had a 43% reduction in risk. Deaths were also reduced in the estrogen/progestin group—5 vs 11—but this was not statistically significant.

Breast Cancer Risk Dr. Chlebowski noted that combined estrogen/progestin use has “opposite effects on breast and endometrial cancers.” Estrogen/progestin reduces endometrial cancer incidence but increases breast cancer incidence and breast cancer–related deaths, he noted. The Women’s Health Initiative previously showed a 28% increased risk of breast cancer with combined hormone replacement therapy after 5.6 years of the intervention. “Interventions that reduce both endometrial cancer and breast cancer are needed,” he said. n

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

Reference 1. Chlebowski R, Anderson GL, Sarto G, et al: Continuous combined oestrogen plus progestin and endometrial cancer in postmenopausal women in the Women’s Health Initiative randomized clinical trial. 2013 European Cancer Congress. Abstract LBA13. Presented September 30, 2013.

Now Available: Communicating with Cancer Patients Endorsed by the European Society of Medical Oncology

he European Society of Medical oncology has endorsed the newly released book, Communicating with

John F. Smyth, MD

Cancer Patients, written by Professor John F. Smyth, MD, of the University of Edinburgh, and designed for trainee oncologists, oncology nurses, and other health-care professionals involved in explaining the complexities of cancer to patients in their care. Contents address different aspects of the challenges faced in communicating with patients with cancer, such as discussing the etiology of cancer, diagnosis and staging, and explaining the purpose of treatment, including

chemotherapy, hormone treatment, and immunological and gene-based therapies. Individual copies are available to purchase at www.crcpress.com, or email orders@crcpress.com. n Communicating with Cancer Patients was published October 14, 2013, by CRC Press. Author John F. Smyth, MD, is Emeritus Professor of Medical Oncology at the University of Edinburgh, Scotland, United Kingdom.

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In postmenopausal women with advanced HR+, HER2-negative breast cancer,

When your patients need MORE...

There is a treatment regimen that has more than doubled median PFS after failure of a nonsteroidal aromatase inhibitor1

Abbreviations: HR+, hormone receptor-positive; PFS, progression-free survival.

AFINITOR plus exemestane Combination Therapy Gives You More: Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

55%

HR=0.45 [95% CI, 0.38-0.54]

reduction in risk of progression or death1

Log-rank P value: <0.0001

PFS curves began to diverge

at 6 weeks

(the first tumor assessment) 1,2

PFS Probability (%)

Median PFS

7.8 months

[95% CI, 6.9-8.5] Median PFS

3.2 months

[95% CI, 2.8-4.1]

0 0

Time (months) AFINITOR plus exemestane (n/N=310/485)

Exemestane plus placebo (n/N=200/239)

Abbreviations: BOLERO-2, Breast Cancer Trials of Oral Everolimus-2.

62% reduction in risk of progression or death1

Independent central assessment confirmed benefit1 •

Median PFS was 11.0 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6] (HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

Overall survival (OS) results were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted (HR=0.77 [95% CI, 0.57-1.04]).1 AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information) Noninfectious Pneumonitis: •

•

• •

•

For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR The development of pneumonitis has been reported even at a reduced dose

MORE THAN DOUBLES MEDIAN PFS

over exemestane alone1

Proven PFS benefit across all preplanned patient subgroups1,2 Median PFS Across Preplanned Patient Subgroups2 AFINITOR plus exemestane

Placebo plus exemestane

Median PFS (months) 8.3 6.8

2.9 4.0

8.1 6.8

3.9 2.8

6.8 9.9

2.8 4.2

8.3 6.9

4.1 2.8

12.9 6.9

5.3 2.8

8.2 7.0

3.2 3.5

8.1 6.9 8.2

4.4 3.0 3.0

8.1 7.0

2.8 4.1

8.1 6.9

3.3 2.8

11.5 6.7 6.9

4.4 3.5 2.6

Subgroups (n) All (724)

Age <65 (449) ≥65 (275) Sensitivity to prior hormonal therapy YES (610) NO (114) Presence of visceral metastasis YES (406) NO (318) Baseline ECOG PS 0 (435) 1 or 2 (274) Bone-only lesions at baseline YES (151) NO (573) Prior chemotherapy YES (493) NO (231) No. of prior therapies used in the adjuvant setting or to treat advanced disease 1 (118) 2 (217) ≥3 (389) Prior hormonal therapya YES (398) NO (326) Progesterone receptor status Positive (523) Negative (184) No. of organs involved 1 (219) 2 (232) ≥3 (271)

Excluding anastrozole and letrozole.

Favors placebo plus exemestane

Favors AFINITOR plus exemestane

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Hazard Ratio

Abbreviation: ECOG PS, Eastern Cooperative Oncology Group Performance Status.

Prescribe AFINITOR plus exemestane upon first progression on letrozole or anastrozole therapy1 Important Safety Information) Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR •

Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment •

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

Important Safety Information. AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: •

Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed If symptoms are moderate, patients should be managed with dose interruption until symptoms improve The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR The development of pneumonitis has been reported even at a reduced dose

In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed •

Renal Failure: •

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR

Geriatric Patients:

Hepatic Impairment: Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended •

Vaccinations:

• The use of live vaccines and close contact with In the randomized advanced hormone those who have received live vaccines should receptor-positive, HER2-negative breast cancer be avoided during treatment with AFINITOR study, the incidence of deaths due to any cause within 28 days of the last AFINITOR Embryo-Fetal Toxicity: • dose was 6% in patients ≥65 years of age • Fetal harm can occur if AFINITOR is compared to 2% in patients <65 years of age administered to a pregnant woman. Women of • Adverse reactions leading to permanent childbearing potential should be advised to use discontinuation occurred in 33% of patients a highly effective method of contraception • ≥65 years of age compared with 17% in while using AFINITOR and for up to 8 weeks patients <65 years of age after ending treatment • • Careful monitoring and appropriate Adverse Reactions: dose adjustments for adverse reactions • The most common adverse reactions (incidence are recommended ≥30%) were stomatitis (67%), infections Laboratory Tests and Monitoring: (50%), rash (39%), fatigue (36%), diarrhea • (33%), and decreased appetite (30%) Elevations of serum creatinine, proteinuria, • glucose, lipids, and triglycerides, and • The most common grade 3/4 adverse reactions reductions of hemoglobin, lymphocytes, (incidence ≥2%) were stomatitis (8%), infections Infections: neutrophils, and platelets, have been reported (5%), hyperglycemia (5%), fatigue (4%), dyspnea • AFINITOR has immunosuppressive properties • Renal function (including measurement of blood (4%), pneumonitis (4%), and diarrhea (2%) and may predispose patients to bacterial, urea nitrogen, urinary protein, or serum Laboratory Abnormalities: fungal, viral, or protozoal infections (including creatinine), blood glucose, lipids, and • The most common laboratory abnormalities those with opportunistic pathogens). Localized hematologic parameters should be evaluated (incidence ≥50%) were hypercholesterolemia and systemic infections, including pneumonia, prior to treatment and periodically thereafter (70%), hyperglycemia (69%), increased aspartate mycobacterial infections, other bacterial • When possible, optimal glucose and lipid transaminase (AST) concentrations (69%), anemia infections, invasive fungal infections such as control should be achieved before starting a (68%), leukopenia (58%), thrombocytopenia aspergillosis or candidiasis, and viral patient on AFINITOR (54%), lymphopenia (54%), increased alanine infections, including reactivation of hepatitis B transaminase (ALT) concentrations (51%), and Drug-Drug Interactions: virus, have occurred hypertriglyceridemia (50%) • Avoid coadministration with strong CYP3A4 • Some of these infections have been severe (eg, • The most common grade 3/4 laboratory inhibitors (eg, ketoconazole, itraconazole, leading to respiratory or hepatic failure) or fatal abnormalities (incidence ≥3%) were clarithromycin, atazanavir, nefazodone, • Physicians and patients should be aware of the lymphopenia (12%), hyperglycemia (9%), saquinavir, telithromycin, ritonavir, indinavir, increased risk of infection with AFINITOR anemia (7%), decreased potassium (4%), nelfinavir, voriconazole) • Treatment of preexisting invasive fungal increased AST (4%), increased ALT (4%), • Use caution and reduce the AFINITOR dose to infections should be completed prior to and thrombocytopenia (3%) 2.5 mg daily if coadministration with a starting treatment moderate CYP3A4 and/or PgP inhibitor is • Be vigilant for signs and symptoms of infection Please see Brief Summary of Prescribing required (eg, amprenavir, fosamprenavir, and institute appropriate treatment promptly; Information on adjacent pages. aprepitant, erythromycin, fluconazole, interruption or discontinuation of AFINITOR verapamil, diltiazem) To learn more, please visit should be considered • Avoid coadministration with strong CYP3A4 www.AFINITOR.com. • Discontinue AFINITOR if invasive systemic inducers (eg, phenytoin, carbamazepine, fungal infection is diagnosed and institute rifampin, rifabutin, rifapentine, phenobarbital); appropriate antifungal treatment References: 1. AFINITOR [prescribing information]. East Hanover, however, if coadministration is required, NJ: Novartis Pharmaceuticals Corp; 2012. 2. Data on file. AFINITOR Oral Ulceration: CRAD001Y2301 Clinical Study Report. Novartis Pharmaceuticals increase the AFINITOR dose from 10 mg daily Corp; March 2012. • Mouth ulcers, stomatitis, and oral mucositis have up to 20 mg daily, using 5-mg increments occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients •

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

•

8/13

AFB-1066531

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

T:14”

B:14.25”

S:13”

Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 Pneumonitisd 19 4 0.2 0.4 0 0 Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 e Median duration of treatment 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

B:14.25” B:14.25” T:14” T:14” S:13” S:13”

A study A study in in healthy healthy subjects subjects demonstrated demonstrated that that co-administration co-administration of of anan oral oral dose dose of of mid mid azolam azolam (sensitive (sensitive CYP3A4 CYP3A4 substrate) substrate) with with everolimus everolimus resulted resulted in in a a and and a 30% a 30% increase increase in in midazolam midazolam AUC AUC . 25% 25% increase increase in in mid mid azolam azolam Cmax Cmax (0-inf) (0-inf). byby Coadministration Coadministration of of everolimus everolimus and and exemestane exemestane increased increased exemestane exemestane Cmin Cmin byby 64%. 64%. However, However, thethe corresponding corresponding estradiol estradiol levels levels at at steady steady 45% 45% and and C2hC2h state state (4 (4 weeks) weeks) were were notnot different different between between thethe two two treatment treatment arms. arms. NoNo increase increase in in adverse adverse events events related related to to exemestane exemestane was was observed observed in in patients patients with with hormone hormone receptor-positive, receptor-positive, HER2-negative HER2-negative advanced advanced breast breast cancer cancer receiving receiving thethe combination. combination. Coadministration Coadministration of of everolimus everolimus and and depot depot octreotide octreotide increased increased octreotide octreotide Cmin Cmin byby approximately approximately 50%. 50%. 8 8USE USE ININ SPECIFIC SPECIFIC POPULATIONS POPULATIONS Pregnancy Pregnancy Pregnancy Pregnancy Category Category D [see D [see Warnings Warnings and and Precautions] Precautions] . . There There areare nono adequate adequate and and well-controlled well-controlled studies studies of of AFINITOR AFINITOR in in pregnant pregnant women; women; however, however, based based onon thethe mechanism mechanism of of action, action, AFINITOR AFINITOR cancan cause cause fetal fetal harm harm when when administered administered to to a pregnant a pregnant woman. woman. Everolimus Everolimus caused caused embryo-fetal embryo-fetal toxicities toxicities in in animals animals at at maternal maternal exposures exposures that that were were lower lower than than human human exposures. exposures. If this If this drug drug is is used used during during pregnancy pregnancy or or if the if the patient patient becomes becomes pregnant pregnant while while taking taking thethe drug, drug, thethe patient patient should should bebe apprised apprised of of thethe potential potential hazard hazard to to thethe fetus. fetus. Women Women of of childbearing childbearing potential potential should should bebe advised advised to to useuse a highly a highly effective effective method method of of contraception contraception while while receiving receiving AFINITOR AFINITOR and and forfor upup to to 8 weeks 8 weeks after after ending ending treatment. treatment. In In animal animal reproductive reproductive studies, studies, oral oral administration administration of of everolimus everolimus to to female female rats rats before before mating mating and and through through organogenesis organogenesis induced induced embryo-fetal embryo-fetal toxicities, toxicities, including including increased increased resorption, resorption, pre-implantation pre-implantation and and post-implantation post-implantation loss, loss, decreased decreased numbers numbers of of livelive fetuses, fetuses, malformation malformation (e.g., (e.g., sternal sternal cleft), cleft), and and retarded retarded skeletal skeletal development. development. These These effects effects occurred occurred in in thethe absence absence of of matermaternalnal toxicities. toxicities. Embryo-fetal Embryo-fetal toxicities toxicities in in rats rats occurred occurred at at doses doses ≥ 0.1 ≥ 0.1 mg/kg mg/kg 2) 2with ) with resulting resulting exposures exposures of of approximately approximately 4%4% of of thethe exposure exposure (0.6 (0.6 mg/m mg/m ) achieved ) achieved in in patients patients receiving receiving thethe 1010 mgmg daily daily dose dose of of everolimus. everolimus. (AUC (AUC 0-24h 0-24h In In rabbits, rabbits, embryotoxicity embryotoxicity evident evident asas anan increase increase in in resorptions resorptions occurred occurred at at anan 2),2approximately ), approximately 1.61.6 times times either either thethe 1010 mgmg oral oral dose dose of of 0.80.8 mg/kg mg/kg (9.6 (9.6 mg/m mg/m daily daily dose dose or or thethe median median dose dose administered administered to to SEGA SEGA patients patients onon a body a body surface surface area area basis. basis. The The effect effect in in rabbits rabbits occurred occurred in in thethe presence presence of of maternal maternal toxicities. toxicities. In In a prea preand and post-natal post-natal development development study study in in rats, rats, animals animals were were dosed dosed from from 2),2there ), there implantation implantation through through lactation. lactation. At At thethe dose dose of of 0.10.1 mg/kg mg/kg (0.6 (0.6 mg/m mg/m were were nono adverse adverse effects effects onon delivery delivery and and lactation lactation or or signs signs of of maternal maternal toxicity; toxicity; however, however, there there were were reductions reductions in in body body weight weight (up(up to to 9%9% reduction reduction from from thethe control) control) and and in in survival survival of of offspring offspring (~5% (~5% died died or or missing). missing). There There were were nono drug-related drug-related effects effects onon thethe developmental developmental parameters parameters (morphological (morphological developdevelopment, ment, motor motor activity, activity, learning, learning, or or fertility fertility assessment) assessment) in in thethe offspring. offspring. Nursing Nursing Mothers Mothers It is It is notnot known known whether whether everolimus everolimus is is excreted excreted in in human human milk. milk. Everolimus Everolimus and/or and/or itsits metabolites metabolites passed passed into into thethe milk milk of of lactating lactating rats rats at at a concentration a concentration 3.53.5 times times higher higher than than in in maternal maternal serum. serum. Because Because many many drugs drugs areare excreted excreted in in human human milk milk and and because because of of thethe potential potential forfor serious serious adverse adverse reactions reactions in in nursnursinging infants infants from from everolimus, everolimus, a decision a decision should should bebe made made whether whether to to discondiscontinue tinue nursing nursing or or to to discontinue discontinue thethe drug, drug, taking taking into into account account thethe importance importance of of thethe drug drug to to thethe mother. mother. Pediatric Pediatric Use Use Pediatric Pediatric useuse of of AFINITOR AFINITOR Tablets Tablets is is recommended recommended forfor patients patients 1 year 1 year of of ageage and and older older with with TSC TSC forfor thethe treatment treatment of of SEGA SEGA that that requires requires therapeutic therapeutic interintervention vention butbut cannot cannot bebe curatively curatively resected. resected. The The safety safety and and effectiveness effectiveness of of AFINITOR AFINITOR Tablets Tablets have have notnot been been established established in in pediatric pediatric patients patients with with renal renal angiomyolipoma angiomyolipoma with with TSC TSC in in thethe absence absence of of SEGA. SEGA. The The effectiveness effectiveness of of AFINITOR AFINITOR in in pediatric pediatric patients patients with with SEGA SEGA was was demondemonstrated strated in in two two clinical clinical trials trials based based onon demonstration demonstration of of durable durable objective objective response, response, asas evidenced evidenced byby reduction reduction in in SEGA SEGA tumor tumor volume volume [see [see Clinical Clinical Studies Studies (14.5) (14.5) in in thethe fullfull prescribing prescribing information] information] . Improvement . Improvement in in diseasediseaserelated related symptoms symptoms and and overall overall survival survival in in pediatric pediatric patients patients with with SEGA SEGA hashas notnot been been demonstrated. demonstrated. The The long long term term effects effects of of AFINITOR AFINITOR onon growth growth and and puberpubertaltal development development areare unknown. unknown. Study Study 1 was 1 was a randomized, a randomized, double-blind, double-blind, multicenter multicenter trial trial comparing comparing AFINITOR AFINITOR (n=78) (n=78) to to placebo placebo (n=39) (n=39) in in pediatric pediatric and and adult adult patients. patients. The The median median ageage was was 9.59.5 years years (range (range 0.80.8 to to 2626 years). years). At At thethe time time of of randomization, randomization, a total a total of of 2020 patients patients were were < 3< years 3 years of of age, age, 5454 patients patients were were 3 to 3 to < 12 < 12 years years of of age, age, 2727 patients patients were were 1212 to to < 18 < 18 years years of of age, age, and and 1616 patients patients were were ≥ 18 ≥ 18 years years of of age. age. The The overall overall nature, nature, type, type, and and frequency frequency of of adverse adverse reactions reactions across across thethe ageage groups groups evaluated evaluated were were similar, similar, with with thethe exception exception of of a higher a higher perper patient patient inciincidence dence of of infectious infectious serious serious adverse adverse events events in in patients patients < 3< years 3 years of of age. age. A total A total of of 6 of 6 of 1313 patients patients (46%) (46%) < 3< years 3 years of of ageage had had at at least least one one serious serious adverse adverse event event due due to to infection, infection, compared compared to to 2 of 2 of 7 patients 7 patients (29%) (29%) treated treated with with placebo. placebo. NoNo patient patient in in anyany ageage group group discontinued discontinued AFINITOR AFINITOR due due to to infection infection [see [see Adverse Adverse Reactions Reactions (6.5) (6.5) in in thethe fullfull prescribing prescribing information] information] . Subgroup . Subgroup analyses analyses showed showed reduction reduction in in SEGA SEGA volume volume with with AFINITOR AFINITOR treatment treatment in in allall pediatric pediatric ageage subgroups. subgroups.

Study Study 2 was 2 was anan open-label, open-label, single-arm, single-arm, single-center single-center trial trial of of AFINITOR AFINITOR (N=28) (N=28) in in patients patients aged aged ≥ 3≥ years; 3 years; median median ageage was was 1111 years years (range (range 3 to 3 to 3434 years). years). AA total total of of 1616 patients patients were were 3 to 3 to < 12 < 12 years, years, 6 patients 6 patients were were 1212 to to < 18 < 18 years, years, and and 6 patients 6 patients were were ≥ 18 ≥ 18 years. years. The The frequency frequency of of adverse adverse reactions reactions across across thethe ageage [see [see Adverse Adverse Reactions Reactions (6.5) (6.5) in in thethe fullfull prescribprescribgroups groups was was generally generally similar similar . Subgroup . Subgroup analyses analyses showed showed reductions reductions in in SEGA SEGA volume volume with with inging information] information] AFINITOR AFINITOR treatment treatment in in allall pediatric pediatric ageage subgroups. subgroups. Everolimus Everolimus clearance clearance normalized normalized to to body body surface surface area area was was higher higher in in pediatric pediatric [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in in thethe fullfull patients patients than than in in adults adults with with SEGA SEGA .The .The recommended recommended starting starting dose dose and and subsequent subsequent prescribing prescribing information] information] requirement requirement forfor therapeutic therapeutic drug drug monitoring monitoring to to achieve achieve and and maintain maintain trough trough concentrations concentrations of of 5 to 5 to 1515 ng/mL ng/mL areare thethe same same forfor adult adult and and pediatric pediatric patients patients [see [see Dosage Dosage and and Administration Administration (2.3, (2.3, 2.4) 2.4) in in thethe fullfull prescribing prescribing with with SEGA SEGA . . information] information] Geriatric Geriatric Use Use In In thethe randomized randomized advanced advanced hormone hormone receptor receptor positive, positive, HER2-negative HER2-negative breast breast cancer cancer study, study, 40% 40% of of AFINITOR-treated AFINITOR-treated patients patients were were ≥ 65 ≥ 65 years years of of age, age, while while 15% 15% were were 7575 and and over. over. NoNo overall overall differences differences in in effectiveness effectiveness were were observed observed between between elderly elderly and and younger younger subjects. subjects. The The incidence incidence of of deaths deaths due due to to anyany cause cause within within 2828 days days of of thethe lastlast AFINITOR AFINITOR dose dose was was 6%6% in in patients patients ≥ 65 ≥ 65 years years of of ageage compared compared to to 2%2% in in patients patients < 65 < 65 years years of of age. age. Adverse Adverse reactions reactions leadleadinging to to permanent permanent treatment treatment discontinuation discontinuation occurred occurred in in 33% 33% of of patients patients ≥ 65 ≥ 65 [see [see Warnings Warnings years years of of ageage compared compared to to 17% 17% in in patients patients < 65 < 65 years years of of ageage and and Precautions] Precautions] . . In In two two other other randomized randomized trials trials (advanced (advanced renal renal cellcell carcinoma carcinoma and and advanced advanced neuroendocrine neuroendocrine tumors tumors of of pancreatic pancreatic origin), origin), nono overall overall differences differences in in safety safety or or effectiveness effectiveness were were observed observed between between elderly elderly and and younger younger subjects. subjects. In In thethe ranrandomized domized advanced advanced RCC RCC study, study, 41% 41% of of AFINITOR AFINITOR treated treated patients patients were were ≥ 65 ≥ 65 years years of of age, age, while while 7%7% were were 7575 and and over. over. In In thethe randomized randomized advanced advanced PNET PNET study, study, 30% 30% of of AFINITOR-treated AFINITOR-treated patients patients were were ≥ 65 ≥ 65 years years of of age, age, while while 7%7% were were 7575 and and over. over. Other Other reported reported clinical clinical experience experience hashas notnot identified identified differences differences in in response response between between thethe elderly elderly and and younger younger patients, patients, butbut greater greater sensitivity sensitivity of of some some older older [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in in thethe fullfull individuals individuals cannot cannot bebe ruled ruled outout . . prescribing prescribing information] information] NoNo dosage dosage adjustment adjustment in in initial initial dosing dosing is is required required in in elderly elderly patients, patients, butbut close close monitoring monitoring and and appropriate appropriate dose dose adjustments adjustments forfor adverse adverse reactions reactions is is recomrecom[see [see Dosage Dosage and and Administration Administration (2.2), (2.2), Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) mended mended . . in in thethe fullfull prescribing prescribing information] information] Renal Renal Impairment Impairment NoNo clinical clinical studies studies were were conducted conducted with with AFINITOR AFINITOR in in patients patients with with decreased decreased renal renal function. function. Renal Renal impairment impairment is not is not expected expected to to influence influence drug drug exposure exposure and and nono dosage dosage adjustment adjustment of of everolimus everolimus is is recommended recommended in in patients patients with with renal renal impairment impairment [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in in thethe fullfull prescribing prescribing . . information] information] Hepatic Hepatic Impairment Impairment The The safety, safety, tolerability tolerability and and pharmacokinetics pharmacokinetics of of AFINITOR AFINITOR were were evaluated evaluated in in a 34 a 34 subject subject single single oral oral dose dose study study of of everolimus everolimus in in subjects subjects with with impaired impaired hepatic hepatic function function relative relative to to subjects subjects with with normal normal hepatic hepatic function. function. Exposure Exposure was was increased increased in in patients patients with with mild mild (Child-Pugh (Child-Pugh class class A),A), moderate moderate (Child-Pugh (Child-Pugh class class B),B), and and severe severe (Child-Pugh (Child-Pugh class class C)C) hepatic hepatic impairment impairment [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in in thethe fullfull prescribing prescribing information] information] . . ForFor advanced advanced HR+ HR+ BC,BC, advanced advanced PNET, PNET, advanced advanced RCC, RCC, and and renal renal angiomyo angiomyo - lipoma lipoma with with TSC TSC patients patients with with severe severe hepatic hepatic impairment, impairment, AFINITOR AFINITOR may may bebe used used at at a reduced a reduced dose dose if the if the desired desired benefit benefit outweighs outweighs thethe risk. risk. ForFor patients patients with with mild mild (Child-Pugh (Child-Pugh class class A)A) or or moderate moderate (Child-Pugh (Child-Pugh class class B)B) hepatic hepatic impairment, impairment, a dose a dose reduction reduction is is recommended recommended [see [see Dosage Dosage and and AdministraAdministration tion (2.2) (2.2) in in thethe fullfull prescribing prescribing information] information] . . ForFor patients patients with with SEGA SEGA who who have have severe severe hepatic hepatic impairment impairment (Child-Pugh (Child-Pugh class class C),C), reduce reduce thethe starting starting dose dose of of AFINITOR AFINITOR Tablets Tablets byby approximately approximately 50%. 50%. ForFor patients patients with with SEGA SEGA who who have have mild mild (Child-Pugh (Child-Pugh class class A)A) or or moderate moderate (Child(ChildPugh Pugh class class B)B) hepatic hepatic impairment, impairment, adjustment adjustment to to thethe starting starting dose dose may may notnot bebe needed. needed. Subsequent Subsequent dosing dosing should should bebe based based onon therapeutic therapeutic drug drug monitoring monitoring [see [see Dosage Dosage and and Administration Administration (2.4, (2.4, 2.5) 2.5) in in thethe fullfull prescribing prescribing information] information] . . 1010OVERDOSAGE OVERDOSAGE In In animal animal studies, studies, everolimus everolimus showed showed a low a low acute acute toxic toxic potential. potential. NoNo lethality lethality or or severe severe toxicity toxicity was was observed observed in in either either mice mice or or rats rats given given single single oral oral doses doses of of 2000 2000 mg/kg mg/kg (limit (limit test). test). Reported Reported experience experience with with overdose overdose in in humans humans is is very very limited. limited. Single Single doses doses of of upup to to 7070 mgmg have have been been administered. administered. The The acute acute toxicity toxicity profile profile observed observed with with thethe 7070 mgmg dose dose was was consistent consistent with with that that forfor thethe 1010 mgmg dose. dose. Manufactured Manufactured by:by: Distributed Distributed by:by: Novartis Novartis Pharma Pharma Stein Stein AGAG Novartis Novartis Pharmaceuticals Pharmaceuticals Corporation Corporation Stein, Stein, Switzerland Switzerland East East Hanover, Hanover, New New Jersey Jersey 07936 07936 ©© Novartis Novartis T2012-153 T2012-153 August August 2012 2012

The ASCO Post | DECEMBER 15, 2013

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Chemotherapy Foundation Symposium Gastrointestinal Oncology

Genetic Profiling in Colorectal Cancer continued from page 1

Prevalence of KRAS Mutations KRAS codons 12 and 13 mutations are present in 40% of patients with colorectal cancer. However, KRAS exon 3 and 4 and NRAS exon 1, 2, 3, and 4 mutations are present in about 16% of KRAS wild-type tumors and are of clinical significance. The phase III PRIME trial evaluated treatment with FOLFOX4 (leucovorin, fluorouracil [5-FU], and oxaliplatin) with or without panitumumab (Vectibix) in patients with colorectal cancer. Extended RAS testing found that additional mutations beyond codons 12 and 13 were predictive of therapeutic outcome. Panitumumab was beneficial in patients with wildtype RAS and potentially harmful in those with extended KRAS and NRAS mutations.2 “This one study provided compelling data that when we take patients we would have considered KRAS wild-type and

treat them with our current drugs, we may be harming them,” he told listeners. “As this finding has recently been replicated, we now feel confident that these data should change clinical practice.” Data from the phase III FIRE-3 study presented at the 2013 European Cancer Congress showed that most patients with wild-type KRAS treated with FOLFIRI (leucovorin, 5-FU, and irinotecan) plus cetuximab (Erbitux) or bevacizumab (Avastin) had an overall survival benefit of 3.7 months. A retrospective analysis found that in patients with no mutations in KRAS codons 12 and 13, expanded KRAS and NRAS testing revealed other mutations associated with a trend toward a decrement in benefit. In patients found to have RAS wild-type tumors on extended profiling, the median survival difference in favor of the cetuximabcontaining regimen was 7.5 months.3 “This supports the concept that if we can better profile our patients, we can improve outcomes,” Dr. Kopetz said. Expanded KRAS and NRAS test-

EXPERT POINT OF VIEW

ddressing a presentation by Scott Kopetz, MD, PhD, at the 2013 Chemotherapy Foundation, Howard Hochster, MD, Yale University Cancer Center, New Haven, Connecticut, said he agrees with Dr. Kopetz about the need for expanded RAS testing. “Now we have two studies suggesting that tumors with all the RAS mutations, including KRAS exons 2, 3, and 4, and NRAS exons 2, 3, and 4, do not benefit from anti–epidermal growth factor receptor (EGFR) antibodies. We need to incorporate these mutations into testing as soon as possible,” Dr. Hochster said in an interview with The ASCO Post. “The PRIME study suggests that treatment with Howard Hochster, MD oxaliplatin-based regimens could be detrimental to patients with those mutations. This makes expanded RAS testing for these mutations all the more compelling,” he stated. Most physicians who treat colorectal cancer order KRAS testing if they are considering anti-EGFR therapy, he said, which only tests for the common exon 2, codon 12, 13 mutations. This is the FDA-approved test. “They need to request extended RAS testing from their pathologists.” At Yale and some other academic centers, patients with colorectal cancer are profiled for a “snapshot” of more than 120 common mutations. Additionally, a 409-gene profile is available based on next-generation sequencing technology. “About 40% of colorectal cancer patients harbor KRAS codon 12 and 13, and another 20% will harbor these additional mutations that make them ineligible for anti-EGFR therapy. That is 60% of patients,” Dr. Hochster noted. n Disclosure: Dr. Hochster reported no potential conflicts of interest.

ing was found to have significance in three studies, including the PRIME trial, the FIRE-3 trial, and a study of single-agent panitumumab vs best supportive care.4 Results are awaited from the Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG) 80405 study.

PIK3CA as Biomarker New data suggest that PIK3CA is a potential biomarker for the benefit of aspirin in stage II/III colorectal cancer. PIK3CA mutations are present in about 15% to 20% of colorectal cancer patients, Dr. Kopetz continued. In a cohort of 964 patients with colorectal cancer from the Nurses’ Health Study and the Health Professionals FollowUp Study, patients with mutated PIK3CA tumors who were regular aspirin users had a striking decrease in the probability of death. This effect was not seen in patients with wild-type PIK3CA tumors.5 A separate study called VICTOR confirmed that the PIK3CA mutation was associated with a reduced rate of colorectal cancer recurrence in patients taking regular aspirin after diagnosis, whereas recurrence was not reduced in those with PIK3CA wild-type who used aspirin.6 “These are intriguing data, but there are a number of questions, including how much aspirin is optimal, the required duration of treatment, and what is the mechanism,” Dr. Kopetz said.

Molecular Testing The standard of care is to test for KRAS codons 12 and 13, BRAF, and microsatellite instability. “In my opinion, it is time to extend KRAS testing, perform NRAS testing, and start testing for PIK3CA and aspirin therapy,” he stated. “For those who want to adopt this now, testing is available. For those who are more conservative, it is reasonable to wait for a prospective randomized controlled trial of aspirin intervention, which

is being considered currently,” he added. Breast cancer has taken the lead in developing a taxonomy based on luminal and basal cell origin, as an example. The taxonomy of colorectal cancer has lagged behind, but increasing evidence suggests that serrated adenoma, BRAFmutated, microsatellite instability, and epithelial-mesenchymal transition are emerging subtypes. “There may be multiple other subtypes. We struggle with this in colorectal cancer. There is no consensus yet,” he said. n

Disclosure: Dr. Kopetz is on advisory boards for Roche/Genentech, Amgen, and Bristol-Myers Squibb.

References 1. Kopetz S: Molecular profiling in CRC. 2013 Chemotherapy Foundation Symposium. Presented November 6, 2013. 2. Douillard JY, Oliner KS, Siena S, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023-1034, 2013. 3. Stintzing S, Jung A, Rossius L, et al: Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wildtype (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. 2013 European Cancer Congress. Abstract 17. Presented September 28, 2013. 4. Oliner KS, Douillard J-Y, Siena S, et al: Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). 2013 ASCO Annual Meeting. Abstract 3511. Presented June 4, 2013. 5. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-1606, 2012. 6. Domingo E, Church DN, Sieber O, et al: Evaluation of PIK3CA Mutation As a Predictor of Benefit From Nonsteroidal Anti-Inflammatory Drug Therapy in Colorectal Cancer. J Clin Oncol. September 23, 2013 (early release online).

Molecular Profiling in Colorectal Cancer ■■ Standard testing for KRAS codons 12 and 13 may not be sufficient to identify patients with colorectal cancer who can benefit from current therapies. ■■ Expanded genetic profiling to include other KRAS and NRAS mutations may enable better patient selection for therapy.

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Chemotherapy Foundation Symposium Hematology

Treating Earlier to Avoid Progression to Multiple Myeloma By Alice Goodman

ith an expanded list of drugs to treat multiple myeloma, experts are interested in whether treating precursor diseases to multiple myeloma can prevent progression to full-blown myeloma. In addition, new drugs are entering the armamentarium for treating multiple

Ruben Niesvizky, MD

myeloma, noted Ruben Niesvizky, MD, Associate Professor of Medicine at Weill Medical College of Cornell University and at NewYork Presbyterian Hospital/Weill Cornell Medical Center in New York,1 at the Chemotherapy Foundation Symposium XXXI, held recently in New York.

Precursors and Sequelae “Most multiple myeloma has a precursor disorder, either smoldering myeloma or monoclonal gammopathy of undetermined significance. Someone should cap-

italize on those stages to see if the natural history of the disease can be altered,” said Dr. Niesvizky. Patients with multiple myeloma can develop renal failure, myelosuppression, bone disease, and hypercalcemia, he continued. “It is disappointing that after all these years and advances we are now first trying to address disease in early stages. If we could intervene earlier we might be able to impact disease progression. We need drugs with low toxicity and high efficacy,” he said. “Now that good drugs are available, and we can characterize higher-risk patients with smoldering myeloma, we need to address this question,” he added.

Smoldering Myeloma Study Although the definition of high risk is a moving target, patients with one of the following abnormalities are considered high-risk: bone marrow plasma cells ≥ 10%, ≥ 95% aberrant antigenic features by immunophenotyping, or abnormal free light chain ratio. A recent study looked at whether treatment of high-risk patients with smoldering myeloma would slow the progression to multiple myeloma, and increase survival, response rate, duration of response, and

Treatment of Smoldering Myeloma ■■ Recent evidence suggests that treating high-risk patients with smoldering myeloma may avoid progression to multiple myeloma. ■■ Further studies of agents used to treat multiple myeloma, including newer drugs, will determine whether treating the disease at a precursor stage will change the natural history of the disease.

safety.2 The study randomly assigned 119 patients—60 to treatment with lenalidomide (Revlimid) and dexamethasone followed by lenalidomide maintenance for 2 years, and 59 to no treatment. In an intent-to-treat analysis with a median follow-up of 40 months, the time to progression to multiple myeloma was superior in the treatment arm: Median time to progression was not reached in the treatment arm vs 21 months in the control group (P < .001). Treatment was also associated with an overall survival advantage; 3-year overall survival was 94% in the treated arm vs 80% in the no-treatment arm (P = .03). “This study opens a new window of opportunity to initiate research in precursor disorders and perhaps prevent the evolution of the disease,” Dr. Niesvizky told the audience. He said that two trials of treatment

are currently accruing patients with smoldering myeloma. One is evaluating a combined regimen of carfilzomib (Kyprolis), lenalidomide, and dexamethasone in smoldering myeloma, and the other is a biomarker study of the investigational monoclonal antibody elotuzumab in high-risk smoldering myeloma. He encouraged audience members to enroll patients in these trials.

New Drugs for Multiple Myeloma Turning to treatment advances in multiple myeloma, he noted that the disease is heterogeneous, and genomic profiling makes it clear that there is no one single treatment target. Multiple myeloma is characterized by multiple genetic abnormalities, and no single drug can address these. Further complicating continued on page 22

EXPERT POINT OF VIEW

ommenting on the evidence for treating precursor myeloma in the study by Mateos et al,1 Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Har-

monoclonal antibodies, and others to delay progression of smoldering to active myeloma. Importantly, this study highlights the need to redefine active myeloma and the category of patients who can benefit from therapy in myeloma.”

Three Important Questions

Kenneth C. Anderson, MD

vard Medical School and Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at DanaFarber Cancer Institute in Boston, said, “This study is paradigm-changing but not practice-changing. It opens up the opportunity for clinical evaluation of novel agents, vaccines,

Asked how she would interpret the data from the Mateos et al trial, Martha Q. Lacy, MD, Professor of Medicine at the Mayo Clinic in Rochester, Minnesota, said that the study needed to be confirmed before concluding that lenalidomide (Revlimid) plus dexamethasone should be the standard for all patients with high-risk smoldering myeloma. She added that the study raises three important questions: What should be the standard for considering smoldering myeloma to be high risk? “The study used aberrant plasma

cell phenotype and suppressors of uninvolved immunoglobulins to define a high-risk group rather than molecular markers that are commonly accepted as high-risk markers in overt myeloma. Recent reports have shown that smoldering myeloma patients with serum immunoglobulin free light chain ratio > 100 or bone marrow plasma cells > 60% are at high risk of progression,” said Dr. Lacy. Why did the high-risk observation patients do so poorly? “The 3-year survival rate of highrisk smoldering myeloma patients in this study was 94% in the treatment arm vs 80% in the observation arm. The 3-year 80% survival for the observation group is surprising. This group did not start treatment until CRAB criteria [hypercalcemia, renal failure, anemia, and lytic bone lesions attributable to clonal expansion of plasma cells] were met; yet their survival is no better than that

seen in many trials of overt myeloma,” she noted. How were the observation patients treated at the time of progression? “The supplementary appendix [to the Mateos et al study publication] includes a table that gives details regarding the 13 patients in the observation arm who died. None received lenalidomide as their first therapy, and it is not stated whether they ever received lenalidomide. If many observation patients died without ever getting lenalidomide, then this is an important flaw in the study,” Dr. Lacy commented. n Disclosure: Dr. Lacey reported no potential conflicts of interest.

Reference 1. Mateos MV, Hernandez M-T, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.

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Chemotherapy Foundation Symposium Multiple Myeloma continued from page 21

treatment, the genetic heterogeneity is present at all stages of the disease, and different genetic abnormalities are evident at different stages. The majority of patients with multiple myeloma relapse after an initial response to therapy, and by that time, the disease has evolved into a more aggressive cancer. Pomalidomide (Pomalyst), carfilzomib, and clarithromycin are being studied in various combinations with other myeloma drugs to see if outcomes can be improved. Pomalidomide has achieved an objective response rate of about 30% in relapsed/refractory multiple myeloma and about 60% in early relapse in phase II trials.3 The combination of clarithromycin, lenalidomide, and dexamethasone is undergoing phase II study in multiple myeloma patients (80% refractory). With this triplet, objective response rate was 57% and clinical benefit rate (ie, complete response, partial response, and stable disease) was 66%. Progression-free survival was a median of 8.67 months, whereas it is typically about 4 months in refractory patients, Dr. Niesvizky said.4 Carfilzomib is undergoing phase II testing in combination with lenalidomide and low-dose dexamethasone. Median duration of response is about 2 years, and median progression-free survival is 15.4 months.5 Front-line therapy with carfilzomib plus lenalidomide achieved an objective response rate of 97%, and at 24 months, 94% of patients were alive.6 A study in Europe showed that combined carfilzomib, melphalan, and prednisone achieved an objective response rate of 91% as frontline therapy in multiple myeloma patients, including those at high risk.7 The phase III CLARION study will compare carfilzomib, melphalan, and prednisone vs bortezomib (Velcade), melphalan, and prednisone in transplant-ineligible patients with newly diagnosed multiple myeloma.8 n

Pomalidomide: New immunomodulatory agent with potent antiproliferative effects. Crit Rev Oncol Hematol 88(suppl 1):S36-S44, 2013. 4. Mark TM, Rodriguez M, Shah M, et al: (Clarithromycin/[Biaxin®], pomalidomide, dexamethasone) therapy in relapsed or refractory multiple myeloma. Blood 118(ASH Annual Meeting Abstracts):Abstract 635, 2011. 5. Wang M, Martin T, Bensinger W, et al: Phase 2 dose-expansion study (PX-171-006)

of carfilzomib, lenalidomide and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood 122:3122-3128, 2013. 6. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012. 7. Moreau P: CMP—carfilzomib (CFZ) plus melphalan-prednisone (CMP)—in el-

derly patients with newly diagnosed multiple myeloma (NDMM): Results of a phase 1/2 trial. 2013 Congress of the European Hematology Association. Abstract P224. Presented June 14, 2013. 8. Phase 3 study of carfilzomib, melphalan, prednisone vs bortezomib, melphalan, prednisone in newly diagnosed multiple myeloma (CLARION). Available at www.clinicaltrials. gov. Accessed November 21, 2013.

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

References 1. Niesvizky R: Trials of new agents in multiple myeloma. 2013 Chemotherapy Foundation Symposium. Presented November 6, 2013. 2. Mateos MV, Hernandez M-T, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013. 3. Richardson PG, Mark TM, Lacy MC:

References: 1. Hanna JA, Bordeaux J, Rimm DL, Agarwal S. The function, proteolytic processing, and histopathology of Met in cancer. Adv Cancer Res. 2009;103:1-23. 2. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26. 3. Quint LE, Tummala S, Brisson LJ, et al. Distribution of distant metastases from newly diagnosed non-small cell lung cancer. Ann Thorac Surg. 1996;62:246-250. 4. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003;22:309-325. 5. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915-925. 6. Lai AZ, Abella JV, Park M. Crosstalk in Met receptor oncogenesis. Trends Cell Biol. 2009;19:542-551.

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Announcements

Centers in Massachusetts Collaborate in Joint Center for Cancer Precision Medicine

he Joint Center for Cancer Precision Medicine, a collaborative initiative among Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston Children’s Hospital, and the Broad

Institute of MIT and Harvard, has been established to create “precision medicine treatment pathways” for patients with advanced cancers and to speed the development of personalized therapies.

The Joint Center brings together expertise and resources in state-of-the-art capabilities including DNA sequencing and other tumor molecular profiling technologies, pathology, radiology, surgery, com-

putational interpretation, and new tumor model systems; and reinforces the joint commitment to pursue advances in cancer genetics to improve patient care. It will be headquartered at Dana-Farber.

Big Questions to Answer “This center will allow us to be optimally positioned to answer the big questions in cancer genetics, especially as they affect clinical decision-making,” sadi Levi Garraway, MD, PhD, Associate Professor of Medicine at Dana-Farber and Director of the new Center. “Our mission is to accelerate the development of personalized therapies that achieve long-term disease control and, eventually, the cure of many patients with advanced cancer,” Dr. Garraway said. “The Center is creating a new capability to use these huge resources in sequencing and pathology and making sure the data gets to caregivers to help customize treatment,” said Edward Benz, Jr, MD, President of Dana-Farber.

From Bench to Bedside

WHERE WILL MET+ NSCLC GO NEXT? MET protein overexpression helps stimulate cancer cell proliferation, survival, and metastasis1-6 • Half of NSCLC tumors overexpress the MET protein2 • Genentech is conducting research into the role of the MET pathway in multiple tumor types

Learn more at ResearchMET.com

NSCLC=non–small cell lung cancer.

“This exciting collaboration will allow the life-giving breakthrough of advanced genetic analysis of cancer to be translated into clinical care,” said Betsy Nabel, MD, President of Brigham and Women’s Hospital. “Patients will benefit from having the latest genetic discoveries applied to an individual treatment plan that will make a difference in their care,” she added. “This is an extraordinary moment in biomedicine,” said Eric Lander, PhD, President and Director of the Broad Institute. “By learning from genomic information obtained in the course of clinical care of patients, this remarkable new center will be poised to make critical discoveries, and to ensure that those discoveries get translated back to the clinic.” Because genome sequencing produces a massive amount of data, the new center will create a computational biology group working in spaces at Dana-Farber, the Broad, and Brigham and Women’s Hospital. These institutions will also support a translational innovation laboratory for a variety of studies on “actionable” cancer mutations, drug resistance, and preclinical studies of targeted drug combinations. “Ultimately, all of this is for patients,” Dr. Garraway said. “We need to figure out how to leverage this very exciting time to forge what may be a new way of practicing cancer medicine.” n

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Quality Care Symposium Shared Decisions: What Should We Expect? By Ronald Piana

here is growing interest by patients, policymakers, and clinicians in shared decision-making as a means to include patients in health decisions and translate patient evidence into clinical practice. Conceptually, sharing of information seems like a natural interplay between doctors and their patients. However, while studies indicate that most patients want more dialogue, many clinicians don’t feel adequately trained to implement shared decision-making in their oncology practice. At the recent ASCO Quality Care Symposium in San Diego, Steven J. Katz, MD, MPH, examined this important issue.

Show Me the Data “There’s compelling evidence that’s been summarized in several editions of a Cochrane Review that addresses the impact of patient decision aids suggesting that sharing makes decisions more

Shared Treatment Decision-Making continued from page 1

said. “While greater patient engagement, in itself, has value—the enhancement of knowledge and improvement in patient satisfaction—whether this results in more evidence-based treatment decision-making is the question mark.”

Does Shared Decision-Making Aim Too High? The aim of shared decision-making, according to Dr. Katz, is to incorporate patient values and preferences into treatment decisions. He noted that shared decisionmaking—which strives for greater engagement of patients with their physicians—is being strongly promoted as an ethical responsibility, a way to facilitate understanding about treatment risks and benefits, and a means toward greater patient satisfaction. But shared decision-making is also being touted as a strategy to reduce overtreatment and costs. The rationale is that better-informed patients will be more likely to choose more conservative treatments and avoid unnecessary ones. “The increasing expectations about the role of [shared decision-making] in clinical and health policy warrant closer scrutiny of the evidence,” Dr. Katz wrote in the JAMA article. “Despite some well-documented benefits of [shared decision-making], the litera-

effective,” said Dr. Katz. “Patients are more informed and more deliberative. And although the evidence also suggests that patients are more satisfied, there is little evidence that shared decision-making changes behavior.” Dr. Katz noted that over the past 3 years we’ve seen an additional rationale emerge in the literature for increasing shared decision-making. “Some have argued that incorporating patient preferences into treatment decision-making could reduce overtreatment and overall costs,” he said, pointing to recent commentaries and studies that suggest that informed patient choice via the use of decision aids may decrease the demand for invasive surgical procedures and reduce costs. He enumerated three main limitations to the argument that more shared decision-making between patients and clinicians could reduce overtreatment ture does not support its potential to reduce overtreatment and costs.” Dr. Katz made several observations in support of his argument: • Studies of shared decision-making do not clearly differentiate (“disentangle”) whether the effects of an intervention can be attributed to patient- or physician-level factors. • There is inadequate appreciation of the complexity of how patients construct and express their preferences for treatment. • It is assumed, with little evidence, that patient preferences would inherently favor less extensive treatment; to the contrary, some studies suggest patients have unrealistically high expectations about what treatments can offer them. • There is an oversimplistic view of the clinical encounter, with blanket assumptions about which conditions or treatments are more or less sensitive to patient preferences.

Patient Engagement Will Not Reduce Costs “In the age of cost-containment and concerns about overtreatment, we can’t assume that involving patients more in treatment decision-making will help solve these problems,” Dr. Katz said. The concept of “cost-effectiveness” is generally applied at the system or patient population level, but patients

and medical costs: The literature fails to distinguish clinician vs patient influences on treatment decisions, there is insufficient consideration of the complexity of how patients construct and express treatment preferences, and the studies project an oversimplistic view of the doctor/patient clinical encounter.

What Do Patients Value? “Ultimately, the question is, what do patients value? There are really only three things. The first two are quantity of life and quality of life, as far as their physical, social, and emotional well-being. But the third value is something we as doctors under-recognize, and that is the treatment decision-making process itself, “ said Dr. Katz. “When we’re in the exam room, there is an interplay between the three basics of making a decision: rational deliberation, intuition, and of course the in the exam room are not focused on cost-effectiveness; individual patients are not interested in the population, but themselves, he maintained. “Patients are not looking to cut corners and minimize cost, unless they are held accountable. Patients participate in overtreatment. The key issue is that patients are not good arbiters about the cost-effectiveness of their treatment,” he insisted. He suggested that the growing use of contralateral prophylactic mastectomy is an example of the influence of patient preferences on potential overtreatment in cancer. Dr. Katz and Monica Morrow, MD, a breast surgeon at Memorial Sloan-Kettering Cancer Center, New York, recently coauthored a “viewpoint” in JAMA that examined this issue.2 They maintained that the substantial increase in contralateral prophylactic mastectomy (from 39 to 207 per 1,000 between 1989 and 2008) stems from a number of factors, including a sense of urgency in treatment planning, the belief that “bigger is better,” the overestimation of recurrence risk and benefit of prophylactic treatment, the influence of word of mouth and high-profile patients, and the use of more sensitive imaging techniques that reveal suspicious lesions. But a strong determinant of the use of contralateral prophylactic mastectomy, he pointed out, is “the desire of patients to reduce the fear of recurrence, if not the actual likelihood.”

clinical rules that guide physicians. For the patient, it is all new and pretty scary. There are a number of interdependent treatment options, and the evaluative information is very complex. This creates a challenging environment for shared decision-making, which is often done at a pressured pace,” he continued. Dr. Katz concluded, “Shared decision-making improves the patients experience with the clinical encounter and makes decisions more effective— patients are more informed and more engaged. However, there is no compelling evidence that more shared decision-making with patients will reduce overtreatment and medical cost inflation. So this is a strong call for more research about the consequences of shared treatment decision-making between patients and their clinicians.” n Disclosure: Dr. Katz reported no potential conflicts of interest.

In fact, thanks to highly effective systemic therapies, the likelihood of a second primary breast cancer is exceedingly small, except in patients with BRCA mutations. It is only for this subset that contralateral prophylactic mastectomy is recommended. Surgeons also contribute to this overtreatment for breast cancer, he said. They may be convinced that aggressive surgery will improve long-term quality of life (which cannot be proven), or they may acquiesce to patients’ desires. The availability of insurance coverage for contralateral prophylactic mastectomy regardless of risk reinforces the notion that the procedure is medically indicated in any patient, he added. “The use of contralateral prophylactic mastectomy has been growing over 7 years, and many surgeons are becoming increasingly uncomfortable with removing the unaffected breast when this will have no effect on distant disease or death but may contribute to morbidity. In an atmosphere of patient-centered care, refusing a patient request for contralateral prophylactic mastectomy is difficult,” Dr. Katz emphasized.

Call for Validation “Ultimately, we ought to share decision-making, but the responsibility for cost-containment is in the hands of the doctors,” he said. Thus, he addcontinued on page 26

The ASCO Post | DECEMBER 15, 2013

PAGE 26

Journal Spotlight Continued from page 6

S9704 Trial: Autologous Transplantation as Consolidation in Aggressive Lymphoma By Richard I. Fisher, MD

utologous bone marrow or stem cell transplantation has had an important role in the treatment of aggressive lymphoma for several decades. The important results of the PARMA study1 demonstrated that patients in first relapse who remained chemosensitive had improved progression-free and overall survival compared to patients who continued to receive standard-dose salvage therapy. Based on that trial, salvage autologous bone marrow transplantation became the standard of care for these patients and resulted in a long-term progression-free survival rate of approximately 50%.

duction of chemoimmunotherapy with R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Therefore, S9704 was amended to use R-CHOP as the standard induction therapy. As we recently reported in the The New England Journal of Medicine,2 and as reviewed in this issue of The ASCO Post, the trial showed that progression-free

Although autologous bone marrow transplantation might be the current recommended therapy for high-risk diffuse large B-cell lymphoma patients, we will likely see the development of novel targeted treatments that will also be studied in these patients.

Consolidation Strategy If salvage bone marrow transplantation is effective, would consolidation bone marrow transplantation immediately after initial chemotherapy further improve the survival of advanced-stage, aggressive lymphomas? Over the past 2 decades, numerous randomized studies demonstrated no improvement in overall survival when all patients received consolidative autologous bone marrow transplantation or stem cell transplantation (which has largely replaced bone marrow transplant). However, multiple subset analyses of these trials did suggest there might be a benefit in the subgroup of patients with high-intermediate– or high-risk characteristics, as defined by the International Prognostic Index (IPI). The S9704 trial was designed to answer that question. In the midst of accrual to the S9704 trial, the results of the initial treatment of patients with aggressive lymphoma improved approximately 15% as a result of the introDr. Fisher is President and CEO, Fox Chase Cancer Center-Temple Health, and Chair, SWOG Lymphoma Committee.

Shared Treatment Decision-Making continued from page 24

ed, ASCO is “spot on” in its Choosing Wisely campaign. The focus should be on educating providers, addressing the system-level factors that drive overtreatment, and breaking down the system barriers that lead to undertreatment, according to Dr. Katz. The breast cancer treatment context is

highly unlikely that a randomized trial restricted to the high IPI subset of patients will ever be conducted. The prognosis of this subset remains poor even in the era of R-CHOP. Thus, for younger, otherwise healthy patients with high-risk lymphoma, initial treatment with R-CHOP followed immediately by autologous stem cell transplantation seems a reasonable alternative.

—Richard I. Fisher, MD

survival was improved, but there was no overall survival improvement for the entire study population. However, a secondary subset analysis suggested a major overall survival benefit for a small subset of patients with high-risk characteristics. The question remains: How should the results of S9704 affect clinical practice? It is very clear that the group of patients who might benefit from upfront consolidative autologous stem cell transplantation has decreased with every large randomized trial. The patients with high-risk characteristics are a small fraction of the overall population with aggressive lymphoma. The numbers are such that it is

However, even as we now evaluate this randomized trial, the world of lymphoma treatment has changed and is poised to change even more dramatically. Our understanding of the biology of aggressive lymphomas has been altered in the past few years as a result of molecular profiling. We now divide diffuse large B-cell lymphoma into the germinal center B-cell (GCB) and the activated Bcell (ABC) subtypes. Each not only has distinctive biology but also potentially different targetable pathways. The details of the S9704 high-risk cases are still being analyzed—recall that the trial was designed in 1997— but the poorer prognosis of the ABC subtype would suggest that this group might be enhanced for that biology.

an excellent model for evaluating the value of shared decision-making, since treatment planning and management are already highly interdisciplinary, and interdisciplinary care links well with shared decisionmaking. “Breast cancer can be a model for proof of concept and implementation of shared decision-making,” he suggested. “Shared decision-making is not yet a quality measure, but we are headed in that direction as patient-reported

outcomes—the patient’s appraisal of care—is of growing importance,” he concluded. “But we are in the infancy of standards about what shared decisionmaking is or should be, and a lot can go wrong while we figure this out.” n For more on shared decision-making based on Dr. Katz’s recent presentation at the 2013 Quality Care Symposium, see “Shared Decisions: What Should We Expect?” on page 24.

Clinical Impact

Likewise, the recent recognition of the poor prognosis of the “double-hit” and “triple-hit” lymphomas (translocations involving c-myc, bcl-2, and bcl-6) suggests that those subtypes may also be overexpressed in the high-risk group.

Further Considerations In addition, recent studies have demonstrated that the results of salvage stem cell transplantation have changed since the PARMA trial. In the postchemoimmunotherapy era, it appears that fewer than 50% of patients who were initially treated with R-CHOP, relapsed, and then had salvage therapy followed by stem cell transplantation have long-term survival. This suggests that the subset of diffuse large B-cell lymphoma patients who experienced increased survival with R-CHOP were part of the group of patients who could be salvaged by autologous bone marrow transplantation in the CHOP era. Thus, although autologous bone marrow transplantation might be the current recommended therapy for high-risk diffuse large B-cell lymphoma patients, we will likely see the development of novel targeted treatments that will also be studied in these patients. n

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

References 1. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540-1545, 1995. 2. Stiff PJ, Unger JM, Cook JR, et al: Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369:1681-1690, 2013.

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

References 1. Katz SJ: The value of sharing treatment decision making with patients: Expecting too much? JAMA 310:1559-1560, 2013. 2. Katz SJ, Morrow M: Contralateral prophylactic mastectomy for breast cancer: Addressing peace of mind. JAMA 310:793794, 2013.

ASCOPost.com | DECEMBER 15, 2013

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Journal Spotlight

Transplant Now or Later for High-Risk Aggressive Non-Hodgkin Lymphoma? By Julie M. Vose, MD, MBA

he use of high-dose chemotherapy and autologous hematopoietic blood or marrow transplantation for high-risk aggressive non-Hodgkin lymphoma has been extensively evaluated over the past few decades. This treatment was originally used only for patients with relapsed aggressive lymphoma. However, as the patients who were at higher risk for relapse could more easily be identified by clinical features and the technique became safer, it was used in some trials earlier in the course of the disease for higherrisk patients according to the International Prognostic Index (IPI).1 Prior to the addition of rituximab (Rituxan) to standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), several trials demonstrated an improvement when early transplantation was performed in first remission.2,3 However, there were also conflicting trials that did not demonstrate a benefit for early transplantation in this patient population.4,5 A meta-analysis of these earlier randomized trials demonstrated similar overall survival among patients undergoing upfront autologous stem cell transplantation.6

Evolving Trial Design In a study reported by Stiff et al,7 reviewed in this issue of The ASCO Post, 370 patients with aggressive non-Hodgkin lymphoma were entered into a trial starting in 1999 and ending accrual in 2007. During this time period, the classification of the non-Hodgkin lymphomas was modified from the Working Formulation to the World Health Organization classification. In addition, over the time frame of the study, rituximab plus CHOP (R-CHOP) was found to be superior to CHOP alone for the treatment of CD20-positive aggressive lymphomas.8 Therefore, after about Dr. Vose is the Neumann M. and Mildred E. Harris Professor and Chief of the Division of Hematology/Oncology at the University of Nebraska Medical Center, Omaha.

one-third of the patients were entered, the induction therapy was changed to R-CHOP for this study. Patients entered on the trial were those with high or high-intermediate IPI risk. The patients who obtained a complete or partial response to the RCHOP or CHOP induction therapy were randomly assigned to a consolidation autologous stem cell transplant in first remission or to complete the induction therapy, after which they could receive a stem cell transplant at the time of relapse.

Study Considerations The first lesson from this study is that a third of the patients entering the

nificant with a 2-year progression-free survival in the transplant group of 75% compared to only 41% in the standard therapy group (P = .001). The overall survival rate was also significantly higher for the high IPI patients who underwent transplant—82% vs 64% for the standard therapy patients (P = .01).

Next Steps This study is an important step forward in defining the use of high-dose chemotherapy and stem cell transplantation for patients who will benefit the most from transplant in the R-CHOP induction era. Although other recent trials have given us an expected base-

This study is an important step forward in defining the use of highdose chemotherapy and stem cell transplantation for patients who will benefit the most from transplant in the R-CHOP induction era. —Julie M. Vose, MD, MBA

study did not go on to the randomization due to early progression of their aggressive lymphoma or other issues. Despite the improved outcome with R-CHOP, there are still a number of high-intermediate or high IPI risk patients who don’t get a remission with the induction regimen or relapse soon after R-CHOP. Overall, the 2-year progressionfree survival was higher in the early transplant group compared to the RCHOP group (69% vs 55%, P = .005). However, the estimated 2-year overall survival was not different between the groups—74% in the transplant group and 71% in the standard group (P = .30). In the subset of high-intermediate IPI patients, there was no difference in progression-free or overall survival (P = .32). However in the subset of high IPI patients, the effect was sig-

line for transplantation in relapsed aggressive lymphoma, contemporary trials in the R-CHOP era that define the role of early transplantation in highrisk patients have been missing. The next step will be further identification of high-risk populations with specific genetic abnormalities, such as the “double-hit” or “triple-hit” lymphomas, and the role of early transplantation or alternative therapies in these genetic subsets. As our understanding of the cell of origin and activated pathways in the different types of lymphomas improves, the use of more targeted therapies may evolve. Based upon the study by Stiff et al,7 and pending further information on which specific genetic subtypes of aggressive lymphomas can benefit from early transplantation, this treatment should be considered for transplanteligible patients with aggressive lym-

phoma who present with a high-risk IPI. n

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

References 1. International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin lymphoma. N Engl J Med 329:987-994, 1993. 2. Haioun C, Lepage E, Gisselbrecht C, et al: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: Final analysis of the prospective LNH87-2 protocol—a Groupe d’Etude des Lymphomes de l’Adulte study. J Clin Oncol 18:3025-3030, 2000. 3. Freedman AS, Takvorian T, Neuberg D, et al: Autologous bone marrow transplantation in poor-prognosis intermediate-grade and high-grade B-cell nonHodgkin’s lymphoma in first remission: A pilot study. J Clin Oncol 11:931-936, 1993. 4. Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:2472-2479, 2002. 5. Martelli M, Gherlinzoni R, De Renzo A, et al: Earl autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in highrisk, aggressive non-Hodgkin’s lymphoma: An Italian multicenter randomized trial. J Clin Oncol 21:1255-1262, 2003. 6. Greb A, Bohlius J, Trelle S, et al: High-dose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma—results of a comprehensive meta-analysis. Cancer Treat Rev 33:338346, 2007. 7. Stiff PJ, Unger JM, Cook JR, et al: Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369:1681-1690, 2013. 8. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002.

The ASCO Post | DECEMBER 15, 2013

PAGE 28

AACR Conference on Cancer Prevention Breast Cancer

Breast Cancer Vaccines for Primary Prevention Move Toward Clinical Use By Caroline McNeil

he first candidate vaccine to prevent recurrence of breast cancer entered clinical trials about 8 years ago, and since then, the idea of a vaccine for secondary prevention has gained traction; more such vaccines are now in development. But this fall, it was vaccines for primary prevention that had the spotlight. In a study featured at the 12th Annual American Association for Cancer Research (AACR) International Conference on Frontiers in Cancer Prevention Research, held recently in National Harbor, Maryland, investigators tested a triple-antigen vaccine combined with bexarotene (Targretin) in a murine model. The treatment prevented mammary tumor development in 90% of the mice, many of which had preinvasive lesions, reported Nora Disis, MD, who leads the University of Washington’s Tumor Vaccine Group where the vaccine was developed. The researchers are now ready to file their investigational new drug (IND) application with the U.S. Food and Drug Administration (FDA). Also recently, the Cleveland Clinic announced that it had created a company to move ahead with clinical testing of a preventive vaccine that targets a single protein, alpha-lactalbumin. Vincent Tuohy, PhD, an immunologist at the Clinic’s Lerner Institute and Chief Scientific Officer of the new company, said that his group was preparing for a preliminary IND meeting with the FDA in early 2014. The two recent developments underline how far cancer vaccines have come in just the past few years. The first treatment vaccine, sipuleucel-T (Provenge) for prostate cancer, won FDA approval 2 years ago. One breast cancer vaccine for secondary prevention, NeuVax, is now in a phase III trial and another, called AE37, is in phase II. Both target peptides of HER2/neu.

Triple-Antigen Approach The two new primary prevention candidates take different approaches. At the University of Washington, Dr. Disis’s group had already developed vaccines based on three antigens separately—HER2/neu, insulinlike growth factor binding protein-2 (IGFBP-2), and insulin-like growth factor receptor-1 (IGF1R). They

found that each could partially inhibit tumor development in mice, but the three antigens combined in one vaccine were significantly more effective, blocking development of palpable lesions in 65% of mice. The researchers then tried pairing the triple-antigen vaccine with two therapeutic agents that had been shown to prevent tumor development in mice, lapatinib (Tykerb) and bexarotene. Adding lapatinib proved no more effective than vaccination alone, but in the mice given bexarotene plus the vaccine, 90% had no pathologic evidence of carcinomas at 1 year. The mice used in the studies were older and many had preinvasive lesions, like the women who might someday be

tations, to test its efficacy in preventing invasive disease. This group has also been working on a prophylactic vaccine targeted at cancer stem cells, called StemVac. They expect to submit the IND in January or February and to begin trials later in the year, Dr. Disis said.

Targeting Alpha-Lactalbumin The Cleveland Clinic’s prevention vaccine made news this fall, when Cleveland Clinic Innovations announced that a spin-off company, Shield Biotech, would take the vaccine to trials. Popular media like The Huffington Post and MORE magazine ran articles, raising awareness of cancer prevention vaccines in general and bringing numer-

Combination immunechemoprophylaxis may significantly improve the protective efficacy of vaccines designed to prevent breast cancer in high-risk populations and postmenopausal women. —Nora Disis, MD, and colleagues

candidates for a preventive vaccine, Dr. Disis said. In the triple-antigen study, published in Cancer Prevention Research in October,1 she and her colleagues concluded that “combination immunechemoprophylaxis may significantly improve the protective efficacy of vaccines designed to prevent breast cancer in high-risk populations and postmenopausal women.” The phase I trial of the triple-antigen vaccine—named WokVac in honor of a patient advocacy group called Wings of Karen that raised money to cover its manufacturing costs—could begin by March or April, Dr. Disis said in an interview. Because one of the antigens, IGF1R, has not yet been tried in humans, the vaccine will be tested first in women who already have invasive breast cancer; the phase I trial will determine the safety of that vaccine component, as well as the optimal dose for all three. Once past phase I, trials will enroll women with abnormal lesions, such as ductal carcinoma in situ, and women at high risk, such as those with BRCA mu-

ous inquiries and pledges of support. “There’s an eagerness in the patient community,” Dr. Tuohy said. Two Cleveland auto repair companies organized a nationwide effort of 68 auto repair shops in over 23 states that donated 10% of their brake sales during October to the vaccine project. This vaccine’s target antigen, alphalactalbumin, is overexpressed in many breast cancers, but particularly in triplenegative tumors. It is a breast-specific protein normally expressed only in late pregnancy and during lactation. In a 2010 Nature Medicine article,2 Dr. Tuohy and colleagues reported they had vaccinated young mice at high risk for mammary tumors and found, after 8 months, that none had developed tumors. In contrast, all of the control vaccinated mice developed tumors. Currently, Shield Biotech is working on FDA-required protocols for preparation and manufacture of the vaccine and toxicology studies. The major safety concern with this and other vaccine strategies that use the immune system to target self-proteins is the risk of a

systemic, inflammatory autoimmune response. The researchers are proposing two trials: A phase Ia trial, primarily to determine dosage, frequency, and safety, would enroll women with triple-negative breast cancer who have been treated with standard therapy and are in remission. The phase Ib trial would enroll women at very high risk of breast cancer who have elected to undergo a bilateral prophylactic mastectomy and who receive the vaccine several months before surgery. The removed tissue would be examined for any potential safety issues. As with the University of Washington vaccine, the ultimate goal is to vaccinate healthy women who are at high risk for breast cancer.

Artemis Project While many researchers see self-proteins as the key to a prophylactic breast cancer vaccine, some are focusing on infectious agents. The National Breast Cancer Coalition’s (NBCC’s) Artemis Project for a breast cancer prevention vaccine has awarded seed grants to several researchers to search through breast cancer genomes for evidence of infectious agents not found in normal breast tissue. Half of the funding for the grants comes from the National Philanthropic Trust, but like the Cleveland Clinic and University of Washington projects, the NBCC welcomes donations. A recent YouTube video urges viewers to contribute through RocketHub, the crowdfunding website. “Advocates and scientists are working side by side,” the text of the video reads. “Support NBCC’s Artemis Project... Be a part of history!” n

Disclosure: Dr. Tuohy is Chief Science Officer of Shield Biotech, Inc, and as such may have a financial interest in this company that has several patent applications related to the vaccine technology he invented. Dr. Disis reported no potential conflicts of interest.

References 1. Disis ML, Gad E, Herendeen DR, et al: A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease. Cancer Prev Res. November 19, 2013 (early release online). 2. Jaini R, Kesaraju P, Johnson JM, et al: An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat Med 16:799-803, 2010.

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The ASCO Post | DECEMBER 15, 2013

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Journal Spotlight Breast Cancer

Long-Term Follow-up of the HERA Trial Shows No Benefit of 2 Years vs 1 Year of Trastuzumab in Early Breast Cancer But enduring survival benefits seen for 1 year of trastuzumab vs observation, despite large crossover By Matthew Stenger

s reported in The Lancet by Aron Goldhirsch, MD, of the European Institute of Oncology in Milan, Italy, and colleagues from the Breast International Group (BIG), the comparison of 1 vs 2 years of trastuzumab (Herceptin) in patients with HER2-positive early breast cancer in the phase III HERA trial has shown no advantage of 2 years over 1 year of treatment.1 However, an update of the HERA trial comparison of 1 year of trastuzumab vs observation showed continued significant disease-free survival benefit and a significant overall survival benefit of trastuzumab after a median follow-up of 8 years, despite substantial crossover to trastuzumab.

Study Details In this international open-label trial, 5,102 patients with HER2-positive

early breast cancer were randomly assigned to 1 year (n = 1,703) or 2 years (n = 1,701) of trastuzumab or observation (n = 1,698) after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both. The comparison of 2 years vs 1 year of trastuzumab treatment involved a landmark analysis of 3,105 patients who were disease-free at 12 months after randomization and was planned to occur after observation of ≥ 725 disease-free survival events. The primary endpoint was disease-free survival. The 1-year group (n = 1,552) and 2-year group (n = 1,553) were well balanced for age (< 35 years in 7% in both, 35–49 years in 45% in both, 50–59 years in 32% and 33%, and ≥ 60 years in 16% in both), receipt of adjuvant chemotherapy (89% in both), receipt of neoadjuvant chemotherapy (11% in both), and previous neoadjuvant/adjuvant therapy (anthracycline but no taxane in 68.5% and 69%, an-

Two years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2positive early breast cancer. [One] year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care. —Aron Goldhirsch, MD, and colleagues

thracycline and taxane in 25.5% and 26%, no anthracycline in 6% in both). The two groups were also well matched for menopause status (premenopausal in 15% and 13%, postmenopausal in 44.5% and 46%), pathologic tumor size (not assessed– neoadjuvant therapy in 11% in both, 0–2 cm in 40% and 39%, > 2–5 cm

in 45% and 44%, > 5 in 4% and 6%), nodal status (negative in 33% in both, 1–3 positive nodes in 29% and 30%, ≥ 4 positive in 27% in both), hormone receptor status (estrogen and progesterone receptor–positive in 51% in both, estrogen and progesterone receptor–negative in 49% in both), and continued on page 32

Adjuvant Trastuzumab Duration: When Is Enough, Enough? By Andrew D. Seidman, MD

he duration of adjuvant systemic chemotherapy for breast cancer has been a subject of investigation, scrutiny, and meta-analysis.1,2 With the appreciation that prolonged regimens of cytotoxic chemotherapy of, for example, 1 to 2 years in duration were not superior in reducing breast cancer recurrence or death over those of 4 to 6 months in duration,3,4 such extended treatment programs have largely become a historical footnote. This important observation spares patients undue toxicity, and the healthcare system is spared unnecessary costs. With respect to adjuvant antiestrogen therapy, the opposite relationship has been revealed, with longer

Dr. Seidman is Attending Physician, Breast Cancer Medicine Service, Memorial SloanKettering Cancer Center, Professor of Medicine, Weill Cornell Medical College, New York.

Apart from the analysis of trastuzumab duration, this report is most gratifying for its demonstration of the durable and robust impact of adjuvant trastuzumab on long-term diseasefree and overall survival. —Andrew D. Seidman, MD

duration of therapy demonstrating improved outcomes.5-7 Such results, coupled with an appreciation of the indolent nature of some estrogen receptor–positive (eg, luminal A) breast cancers, lead to reasonable speculation that extended adjuvant endocrine therapy for durations even beyond a decade may one day be

proven to be advantageous for some patients.

Trastuzumab Gold Standard A recent report from Goldhirsch and colleagues,8 summarized in this issue of The ASCO Post, shows a lack of benefit for 2 years of trastuzumab (Herceptin) over 1 year, suggesting

that for this agent—unlike the adjuvant chemotherapy and hormonal therapy duration story—perhaps we have hit the nail on the head from the outset. Indeed, the somewhat arbitrarily chosen 1 year duration of adjuvant trastuzumab may in fact be optimal. In this quite large open-label randomized trial, with over 1,500 patients per arm randomly assigned to 1 vs 2 years of trastuzumab (vs none), no advantage in relapse-free survival or overall survival was noted for doubling the adjuvant trastuzumab exposure from 1 to 2 years, while an increase in some nonfatal adverse events occurred with longer treatment duration. Thus, for the moment, taken together with the PHARE trial result demonstrating that 6 months of trastuzumab was not noninferior to 12 months, 1 year of trastuzumab should remain the gold standard. The continued on page 33

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The ASCO Post | DECEMBER 15, 2013

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Journal Spotlight

HERA Trial Long-Term Follow-up continued from page 30

proportion of hormone receptor– positive patients receiving adjuvant endocrine therapy (92% and 93%).

2- vs 1-Year Outcomes After a median follow-up of 8 years, there was no significant difference between the 2-year group and the 1-year group in disease-free survival (hazard ratio [HR] = 0.99, P = .86). At 8 years, disease-free survival rates were 75.8% in the 2-year group and 76.0% in the 1-year group. Disease-free survival events consisted of local recurrence in 4.1% vs 3.7% of patients, regional recurrence in 0.9% vs 1.4%, distant recurrence in 14.4% vs 13.4%, contralateral breast cancer in 1.9% vs 2.0%, second primary malignancy in 2.1% vs 2.5%, and death with no evidence of disease in 0.3% vs 0.6%. There were no significant differences between groups in disease-free survival according to hormone receptor–positive status (HR = 1.05, P = .67) or hormone receptor–negative status (HR = 0.93, P = .51). Similarly, overall survival did not differ between the two groups (HR = 1.05, P = .63). Separate assessment of the contributions of breast cancer–related events and competing risks to disease-free survival using standard cumulative in-

cidence methods indicated that results were similar for the 2-year and 1-year groups, with the exception that breast cancer–related events seemed to be nonsignificantly more common in patients with hormone receptor–negative disease in the 1-year group. No difference was observed among patients with hormone receptor–positive disease, al-

before occurrence of a disease-free survival event. Despite this crossover, the updated analysis showed persistence of benefits in the 1-year group. Disease-free survival was significantly prolonged in the 1-year group (HR = 0.76, P < .001), and overall survival, which was nonsignificantly prolonged in the 1-year group

Updated Analysis of HERA Trial ■■ Two years of trastuzumab did not improve disease-free survival or overall survival compared with 1 year. ■■ Updated analysis of the 1 year of trastuzumab vs observation comparison indicates significant disease-free and overall survival benefit with trastuzumab despite crossover of half the observation group to trastuzumab treatment. ■■ Two years of trastuzumab was associated with an unfavorable benefit-risk ratio, supporting continuation of the 1-year regimen as the standard of treatment.

most all of whom were receiving adjuvant endocrine therapy.

Updated 1-Year vs Observation Analysis The updated intention-to-treat comparison of 1 year of trastuzumab (n = 1,702) vs observation (n = 1,697) included 3,399 patients at a median follow-up of 8 years (range, 0–10 years). After publication of the initial trial results, 52.1% of the observation group crossed over to receive trastuzumab

at median follow-up of 4 years (HR = 0.85, P = .1087), was significantly prolonged at 8-year follow-up (HR = 0.76, P = .0005).

Adverse Events Grade 3 or 4 adverse events (20.4% vs 16.3%, and 8.2% in observation group) and decreases in left-ventricular ejection fraction during treatment (7.2% vs 4.1%, and 0.9% in observation group) were reported more frequently in the 2-year vs 1-year group. Fatal ad-

verse events occurred in 1.2% of the 2-year group, 1.1% of the 1-year group, and 0.4% of the observation group. Primary cardiac endpoints occurred in 1.0%, 0.8%, and 0.1%, respectively. The body systems with the highest frequency of grade 3 or 4 adverse events were neoplasms (4.6% of 2-year group, 3.6% of 1-year group, and 1.8% of observation group), infections and infestations (3.3%, 2.2%, and 0.7%), nervous system disorders (2.0%, 0.8%, and 0.7%), vascular disorders (2.0%, 1.8%, and 1.0%), and cardiac disorders (1.9%, 1.9%, and 0.5%). The investigators concluded, “Two years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. [One] year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care.” n Disclosure: The study was funded by F Hoffmann-La Roche (Roche). For full disclosures of the study authors, visit www. thelancet.com.

Reference 1. Goldhirsch A, Gelber RD, PiccartGebhart MJ, et al: 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial. Lancet 382:10211028, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Sibylle Loibl, MD, on the NeoALTTO Trial in Breast Cancer see page 9

Richard I. Fisher, MD, and Julie M. Vose, MD, on Non-Hodgkin Lymphoma see pages 26 and 27

Howard Hochster, MD, on Genetic Profiling in Colorectal Cancer see page 20

Kenneth C. Anderson, MD, on Smoldering Myeloma see page 21

Andrew D. Seidman, MD, on Adjuvant Trastuzumab Duration see page 30

Howard I. Scher, MD, on etastatic Prostate Cancer M see page 41

William T. Curry, MD, on Valganciclovir in Glioblastoma see page 44

Reshma Jagsi, MD, DPhil, on Patient-Reported Outcomes see page 63

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | DECEMBER 15, 2013

PAGE 33

Journal Spotlight

Andrew D. Seidman, MD on Adjuvant Trastuzumab continued from page 30

results of other trials of shorter duration vs 1 year of exposure are awaited.

Higher-Risk Patients A provocative predefined subgroup analysis by hormone receptor status showed that a short-term reduction in breast cancer–related events occurred among patients with estrogen receptor–negative disease receiving trastuzumab for 2 years as compared to 1. This was not observed for patients with estrogen receptor–positive disease, most of whom received adjuvant antiestrogen therapy. While intriguing, this observation should not be practicechanging, as the authors note. Could a higher-risk patient, for example one with ≥ 10 positive axillary lymph nodes and hormone receptor– negative, HER2-positive breast cancer possibly benefit from a more extended exposure to adjuvant trastuzumab? These results cannot adequately answer that question. Notably, about a quarter of patients enrolled in HERA had four or more involved axillary nodes. It is quite possible that in the future, dual or multiple inhibition of HER2 will be demonstrated to prolong overall survival for HER2-pos-

itive early-stage breast cancer over trastuzumab alone, as has been demonstrated in the metastatic setting.9 While it is reasonable to speculate that the optimal duration of combined anti-HER2 agents in the adjuvant setting could be different (eg, possibly shorter) than the 1-year duration of trastuzumab anti-HER2 monotherapy that currently is the benchmark, such hypotheses will require prospective evaluation.

Closing Thoughts Apart from the analysis of trastuzumab duration, this report is most gratifying for its demonstration of the durable and robust impact of ad-

results with newer anti-HER2 agents in more advanced-stage disease,9,10 there is much reason for optimism that further progress will be made for patients with HER2-positive early breast cancer in coming years. n

Disclosure: Dr. Seidman has received consultant and speaker honoraria from Genentech/Roche.

References 1. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005. 2. Early Breast Cancer Trialists’ Collaborative Group: Comparisons between

There is much reason for optimism that further progress will be made for patients with HER2-positive early breast cancer in coming years. —Andrew D. Seidman, MD

juvant trastuzumab on long-term disease-free and overall survival. With a median follow-up of 8 years, overall survival is significantly prolonged (hazard ratio = 0.76, P = .0005), a result consistent with updated results of the National Surgical Adjuvant Breast and Bowel Project and Intergroup trials. Given the exciting

different polychemotherapy regimens for early breast cancer: Meta-analyses of longterm outcome among 100,000 women in 123 randomised trials. Lancet 379:432-444, 2012. 3. Early Breast Cancer Trialists’ Collaborative Group: Multi-agent chemotherapy for early breast cancer. Cochrane Database Syst Rev 4:CD000487, 2008.

4. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998. 5. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG AM.17. J Natl Cancer Inst 97:1262-1271, 2005. 6. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor positive breast cancer: ATLAS, a randomized trial. Lancet 381:805-816, 2013. 7. Strasser-Weippl K, Badovinac-Crnjevic T, Fan L, et al: Extended adjuvant endocrine therapy in hormone-receptor positive breast cancer. Breast 22:S171-S175, 2013. 8. Goldhirsch A, Gelber R, Piccart-Gebhart MJ, et al: 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomized controlled trial. Lancet 382:1021-1028, 2013. 9. Baselga J, Cortes J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012. 10. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012. Erratum in N Engl J Med 368:2442, 2013.

Jame Abraham, MD, Moves to Taussig Cancer Institute

ame Abraham, MD, has been appointed to the positions of Director, Taussig Cancer Institute Breast Oncology Program, and Co-Director of the Cleveland Clinic Multidisciplinary Breast Cancer Program. Dr. Abraham is the former Medical Director of the West Virginia University Mary Babb Randolph Cancer Center and Chief of the West Vir-

Jame Abraham, MD

ginia University Section of Hematology/Oncology in the Department of Medicine. Over the past 10 years, Dr. Abraham has served as the principal investigator for more than 50 clinical trials, and his research is widely published in the cancer literature. He also has edited the Bethesda Handbook of Clinical Oncology. In 2009, Dr. Abraham

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was named the Bonnie Wells Wilson Distinguished Professor and Eminent Scholar in Breast Cancer Research. Before joining the West Virginia University Mary Babb Randolph Cancer Center in 2001, Dr. Abraham was a senior clinical fellow specializing in developmental therapeutics at the National Cancer Institute. n

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The ASCO Post | DECEMBER 15, 2013

PAGE 34

Journal Spotlight Breast Cancer

Similar High Complete Response Rate With Neoadjuvant Trastuzumab, Lapatinib, and Combined Therapy in HER2-Positive Breast Cancer By Matthew Stenger

n a phase III trial (NSABP B-41) performed to assess the potential benefit of neoadjuvant dual HER2 blockade in HER2-positive breast cancer, André Robidoux, MD, of Centre Hospitalier de l’Université de Montréal, and colleagues in the National Surgical Adjuvant Breast and Bowel Project (NSABP) evaluated tumor response in patients receiving neoadjuvant lapatinib (Tykerb) or trastuzumab

cm in 56%, 47%, and 51%), nodal status (positive in 51%, 52%, and 49%), hormone receptor status (positive in 67%, 58%, and 62%), ethnic origin (eg, white in 85%, 84%, and 88%), histologic grade (eg, high in 48%, 56%, and 48%), and type of surgery (eg, lumpectomy in 55%, 46%, and 50%). A total of 12 patients withdrew consent before response evaluation or did not have

Rates of pathologic complete response were similar with lapatinib and trastuzumab, with the combination producing a numerically but not statistically greater response rate. —André Robidoux, MD, and colleagues

(Herceptin) alone and in combination after doxorubicin/cyclophosphamide treatment.1 The study, reported in The Lancet Oncology, showed that rates of pathologic complete response were similar with lapatinib and trastuzumab, with the combination producing a numerically but not statistically greater response rate.

Study Details In this open-label trial, 529 women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 with operable HER2-positive breast cancer received four cycles of doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² IV on day 1 every 3 weeks followed by four cycles of weekly paclitaxel (80 mg/m²) IV on days 1, 8, and 15 every 4 weeks. Patients were randomly assigned to receive weekly paclitaxel concurrently with either trastuzumab (4 mg/ kg load, then 2 mg/kg IV) weekly until surgery (n = 181), lapatinib (1,250 mg orally) daily until surgery (n = 174), or weekly trastuzumab plus lapatinib (750 mg orally) daily until surgery (n = 174). After surgery, all patients received trastuzumab to complete 52 weeks of HER2targeted therapy. Patients were stratified by clinical tumor size, clinical nodal status, hormone receptor status, and age. The primary endpoint was pathologic complete response in the breast. The trastuzumab, lapatinib, and combination groups were generally well balanced for age (eg, ≤ 49 years in 56%, 53%, and 48%), clinical tumor size (eg, 2.1-4.0

surgery; thus, a total of 519 patients, including 177 in the trastuzumab group, 171 in the lapatinib group, and 171 in the combination group had pathologic responses determined. In total, neoadjuvant therapies were completed per protocol in 77% of trastuzumab patients, 65% of lapatinib patients, and 63% of combination group patients with complete neoadjuvant treatment information available. Targeted therapy was completed per protocol in 82%, 66%, and 66%, respectively. After discontinuing study therapy, 4% of the lapatinib group crossed over to trastuzumab.

Response Rates Compared with the trastuzumab group, in the combination group the proportions of patients with pathologic complete response in breast (62.0% vs 52.5%, P = .095) and pathologic complete response in breast and nodes (60.2% vs 49.4%, P = .056) were numerically but not significantly greater. There was no dif-

ference between the trastuzumab group and the lapatinib group in pathologic complete response in breast (53.2%, P = .99 vs trastuzumab) or in breast and nodes (47.4%, P = .78 vs trastuzumab). Odds ratios for complete pathologic response for the combination vs trastuzumab were 1.47 (95% confidence interval [CI] = 0.96–2.26) in breast and 1.55 (95% CI = 1.01–2.37) in breast and nodes, and those for lapatinib vs trastuzumab were 1.03 (95% CI = 0.67–1.57) in breast and 0.92 (95% CI = 0.60–1.40) in breast and nodes.

Outcome by Hormone Receptor Status and Subgroups In hormone receptor–positive patients, pathologic complete response in the breast was observed in 55.6% of combination patients (P = .23 vs trastuzumab), 48.0% of lapatinib patients (P = .96 vs trastuzumab), and 46.7% of trastuzumab patients, with complete response in breast and nodes observed in 54.6% (P = .21), 42.0% (P = .70), and 45.5%, respectively. In hormone receptor–negative patients, complete response in breast was observed in 73.0% (P = .49), 60.6% (P = .71), and 65.5% of patients, respectively, with complete response in breast and nodes in 69.8% (P = .29), 54.9% (P = .85), and 58.2%, respectively. For all groups, compete response rates were greater among hormone receptor–negative patients than hormone receptor–positive patients. Analyses by stratification subgroups indicated that the improvement in pathologic complete response rates with the addition of lapatinib occurred predominantly in clinically node-positive patients. Odds ratios for response in breast were 2.32 (95% CI = 1.25–4.31) in node-positive patients and 0.95 (95% CI = 0.53–1.74) in node-negative patients (P = .043 across nodal status). Odds ratios for response in breast and nodes were 2.58 (95% CI =

Neoadjuvant Lapatinib and Trastuzumab in HER2-Positive Breast Cancer ■■ Pathologic complete response rates in breast and in breast and nodes were similar with the trastuzumab and lapatinib groups and nonsignificantly greater with the trastuzumab/lapatinib combination. ■■ The improvement with the combination appeared to be predominantly due to improvement among clinically node-positive patients. ■■ Grade 3 or 4 adverse events were more common with lapatinib and the combination than with trastuzumab.

1.39–4.81) in node-positive patients and 0.96 (95% CI = 0.53–1.73) in node-negative patients (P = .023 across nodal status). Improvements were similar across subgroups according to tumor size, hormone receptor status, and age at study entry.

Toxicities Patients in the two groups receiving lapatinib had more grade 3 or 4 adverse events (62% of lapatinib patients and 60% of combination patients) than did trastuzumab patients (50%). The most common grade 3 or 4 toxic effects were neutropenia, which occurred in 16% of trastuzumab patients (grade 4 in 3%), 16% of lapatinib patients (grade 4 in 5%), and 17% of combination patients (grade 4 in 5%), and grade 3 diarrhea, which occurred in 2% of trastuzumab patients, 20% of lapatinib patients, and 27% of combination patients (P < .0001 for both lapatinib-containing groups vs trastuzumab). Symptomatic congestive heart failure defined as New York Heart Association class III or IV events occurred in 4% of patients in the trastuzumab group, 4% in the lapatinib group, and < 1% of the combination group (P = .185). Neoadjuvant treatment was discontinued due to adverse events in 15% of the trastuzumab group, 24% of the lapatinib group, and 26% of the combination group, including discontinuation of targeted therapy in 7%, 19%, and 24%. The investigators concluded: “Substitution of lapatinib for trastuzumab in combination with chemotherapy resulted in similar high percentages of pathological complete response. Combined HER2targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than singleagent HER2-directed therapy; these findings are consistent with results from other studies. Trials are being undertaken to further assess these findings in the adjuvant setting.” n

Disclosure: The study was funded by GlaxoSmithKline. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Robidoux A, Tang G, Rastogi P, et al: Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): An openlabel, randomised phase 3 trial. Lancet Oncol 14:1183-1192, 2013.

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The ASCO Post | DECEMBER 15, 2013

PAGE 40

Journal Spotlight Prostate Cancer

Adding Abiraterone to Prednisone Significantly Prolongs Time to Pain Progression in Chemotherapy-Naive Men With Metastatic Castration-Resistant Prostate Cancer By Matthew Stenger

n interim analysis of the COUAA-302 phase III trial in asymptomatic or mildly symptomatic chemotherapy-naive men with metastatic castration-resistant prostate cancer showed that the addition of abiraterone (Zytiga) to prednisone significantly delayed radiographic progression and improved overall survival although the prespecified significance level of P ≤ .0008 was not reached.1 On this interim analysis, the addition of abiraterone also significantly delayed time to opiate use for cancerrelated pain, patient-reported pain intensity progression, and health-related quality-of-life deterioration. In a recently reported analysis in The Lancet Oncology, Ethan Basch, MD, of The University of North Carolina at Chapel Hill, and colleagues described patient-reported outcomes in the second preplanned interim analysis of the trial. The analysis showed that the addition of abiraterone delayed patientreported pain progression and healthrelated quality-of-life deterioration compared with prednisone alone.

Study Details In the multinational, double-blind trial, 1,088 patients with progressive, metastatic castration-resistant prostate cancer were randomly assigned to receive abiraterone at 1 g/d plus prednisone (5 mg twice daily; n = 546) or prednisone plus placebo (n = 542) in continuous 4-week cycles. Eligible patients were asymptomatic (score of 0 or 1 on item three of the Brief Pain Inventory Short Form [BPI-SF] questionnaire) or mildly symptomatic

(score of 2 or 3) and had not previously received chemotherapy. Pain was assessed with the BPISF questionnaire, and health-related quality of life was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Predefined thresholds for pain progression and deterioration in func-

ments for multiple comparisons were made because of the exploratory nature of these analyses. At baseline the abiraterone/prednisone and prednisone groups had similar FACT-P and subscale scores, 69% vs 65% were asymptomatic and 24% vs 28% were mildly symptomatic, and 65% vs 69% were using no

Abiraterone plus prednisone delays patient-reported pain progression and [health-related quality-of-life] deterioration in chemotherapy-naive patients with metastatic castrationresistant prostate cancer. These results provide further support for the efficacy of abiraterone in this population. —Ethan Basch, MD, and colleagues

tional status were: increases of ≥ 30% from baseline for the progression of mean pain intensity and progression of worst pain intensity items and an increase of ≥ 50% of baseline standard deviation for the progression of interference of pain with activities of daily living item on the BPI-SF; and decreases of 10, 9, 9, 3, and 3 points from baseline for the total score, general function score (physical wellbeing, social and family well-being, emotional well-being, and functional well-being subscales), trial outcome index, prostate cancer–specific subscale, and general function subscales, respectively, on FACT-P. No adjust-

Impact of Abiraterone Plus Prednisone on Patient-Reported Outcomes ■■ The addition of abiraterone to prednisone resulted in significantly prolonged time to progression of mean pain intensity and time to progression of pain interference with daily activities. ■■ The addition of abiraterone to prednisone resulted in significantly prolonged time to health-related quality-of-life deterioration as reflected in prolonged times to deterioration on the FACT-P total score, prostate cancer–specific subscale, trial outcome index, general function score, emotional well-being subscale, and functional well-being subscale.

analgesics and 32% vs 26% were using nonopiate analgesics. In both groups, cumulative compliance for completion of both the BPI-SF and FACT-P was ≥ 95% for all treatment cycles.

Pain Progression At the time of the second prespecified interim analysis, median followup was 22.2 months (interquartile range, 20.2–24.8 months). The abiraterone/prednisone group had significantly prolonged median time to progression of mean pain intensity (26.7 vs 18.4 months, hazard ratio [HR] = 0.82, P = .0490) and median time to progression of pain interference with daily activities (10.3 vs 7.4 months, HR = 0.79, P = .005). The abiraterone/prednisone group had a nonsignificantly increased median time to progression of worst pain intensity (26.7 vs 19.4 months, HR = 0.85, P = .109. In a post hoc sensitivity analysis in which progression was defined as change in BPI-SF worst pain intensity by two points from baseline, median time to progression was not reached in either group; median time to pro-

gression at the 25th percentile was significantly longer with abiraterone/ prednisone (14.8 vs 12.0 months, HR = 0.78, P = .045).

Health-Related Quality-of-Life Deterioration On FACT-P assessment, abiraterone/prednisone was associated with significantly prolonged median time to health-related quality-of-life deterioration on FACT-P total score (12.7 vs 8.3 months, HR = 0.78, P = .0028), prostate cancer–specific subscale (11.1 vs 5.8 months, HR = 0.70, P < .0001), trial outcome index (13.9 vs 9.3 months, HR = 0.75, P = .0006), general function score (16.6 vs 11.1 months, HR = 0.76, P = .0023), emotional well-being subscale (22.1 vs 14.2 months, HR = 0.71, P = .0008), and functional well-being subscale (13.3 vs 8.4 months, HR = 0.76, P = .0012), with no difference between groups being observed only for the social and family well-being subscale (18.4 vs 16.6 months, HR = 0.94, P = .5283). The investigators concluded: “Abiraterone plus prednisone delays patient-reported pain progression and [health-related quality-of-life] deterioration in chemotherapy-naive patients with metastatic castrationresistant prostate cancer. These results provide further support for the efficacy of abiraterone in this population.” n

Disclosure: The study was funded by Janssen Research & Development. For full disclosures of the study authors, visit www. thelancet.com.

References 1. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013. 2. Basch E, Autio K, Ryan CJ, et al: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapynaive men with metastatic castration-resistant prostate cancer: Patient-reported outcome results of a randomised phase 3 trial. Lancet Oncol 14:1193-1199, 2013. 2013.

ASCOPost.com | DECEMBER 15, 2013

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Journal Spotlight

Correctly Assessing Pain Progression and Quality-of-Life Deterioration in Metastatic Castration-Resistant Prostate Cancer By Howard I. Scher, MD

he therapeutic landscape for the treatment of castration-resistant prostate cancer has changed dramatically in the past 4 years, as five new agents affecting different aspects of the malignant process were proven to prolong life. The results are a great benefit to patients, but at the same time make it more difficult to prove a survival benefit for future drugs because effective treatment given after enrollment on a trial can blunt a survival outcome. Urgently need are validated biomarkers of clinical benefit that can be used as intermediate endpoints or that can serve as endpoints that are approvable in their own right. Bone metastases are the most frequent form of prostate cancer spread and are responsible for some of the most feared complications of the disease, including pain, spinal cord compression, and deterioration in functional status and overall quality of life. Pain in itself is an adverse prognostic factor for survival. Problems in assessing disease in bone have long been recognized due to the lack of standards for interpreting the imaging modalities used to detect and monitor the illness. Similarly, problems arise from the lack of validated and reliable biomarkers that reflect the adverse impact of the disease on the individual patient or a cohort of patients at baseline or following treatment.

Paradigm for Drug Development In 2008, the Prostate Cancer Working Group (PCWG2) described a paradigm for drug development in castration-resistant prostate cancer focused on short-term “response” measures (reflecting the control, relief, or elimination of disease manifestations present at the time treatment is initiated) and “progression” measures (repDr. Scher is Chief, Genitourinary Oncology Service at the Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan-Kettering Cancer Center, New York.

resented by the delay or prevention of future manifestations).1 To apply the approach in a clinical setting requires analytically valid “biomarkers” of the disease that, in turn, are validated clinically in prospective trials focused specifically on the context in which they will be used. Qualification of a biomarker to be used in a filing for regulatory approval requires evidence generated from multiple phase III trials, each addressing the same context of use (ie, the clinical setting for which the results of the test will be used to inform a medical decision) in accordance with PCWG2 recommendations and U.S. Food and Drug Administration (FDA) guidelines.

validated measures to compare the effects of abiraterone (Zytiga) plus prednisone vs placebo plus prednisone on maintaining (controlling) quality of life and on preventing (delaying) deterioration of pain status and overall health of patients enrolled in the phase III COU-AA-302 trial.2,3 The coprimary endpoints of this registration trial were radiographic progression-free survival and overall survival. The analyses reported here were prespecified secondary outcomes.2 Pain was assessed using an instrument validated according to standards defined by the FDA in its guidance for patient-reported outcomes, the Brief Pain Inventory

Validated intermediate endpoint biomarkers that can serve as surrogates for benefit, or that represent a benefit in their own right, would significantly shorten drug development time lines, enable the evaluation of more treatments, and make needed drugs available to patients more rapidly. —Howard I. Scher, MD

The process requires close collaboration among investigators, study sponsors, and regulatory agencies. “Prevent or delay” biomarkers such as pain progression must also undergo rigorous statistical analysis to assess their adequacy as surrogates. Several candidate biomarkers seek to fulfill the unmet need for validated indicators of treatment efficacy, of which changes in circulating tumor cell enumeration as a surrogate for survival is most mature.

COU-AA-302 Trial In a study reported in The Lancet Oncology and reviewed in this issue of The ASCO Post, Basch and coworkers applied the PCWG2 principle of using

Short Form coupled with World Health Organization analgesic use criteria. The measures were recorded at baseline, repeatedly at 4-week intervals during treatment, and at treatment discontinuation, and the definition of pain progression included a confirmatory measurement. Overall patient compliance was outstanding. The results showed that the combination of abiraterone plus prednisone was superior to placebo plus prednisone for all of the quality-of-life measures reported and demonstrated the feasibility of measuring pain progression and deterioration in quality of life in a

patient with minimal or no symptoms. The association of the benefit shown for abiraterone plus prednisone relative to placebo plus prednisone with the delay in time to radiographic progression-free survival events provided additional evidence in support of the clinical utility of the health-related qualityof-life endpoint used.

Importance of Biomarker Questions The trial also illustrates the importance and value of investing time and resources to embed biomarker questions using validated instruments in large scale randomized trials so that the outcomes assessed with the biomarker can be associated with the clinical benefit outcome that the trial was designed to demonstrate. Validated intermediate endpoint biomarkers short of survival that can serve as surrogates for benefit, or that represent a benefit in their own right, would significantly shorten drug development time lines, enable the evaluation of more treatments, and make needed drugs available to patients more rapidly. n

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

References 1. Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26:1148-1159, 2008. 2. Basch E, Autio K, Ryan CJ, et al: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: Patient-reported outcome results of a randomised phase 3 trial. Lancet Oncology 14:1193-1199, 2013. 3. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013.

The ASCO Post | DECEMBER 15, 2013

PAGE 42

JCO Spotlight Thoracic Oncology

No Apparent Benefit of Adjuvant Gefitinib in Resected NSCLC in Prematurely Closed Trial By Matthew Stenger

s reported in Journal of Clinical Oncology by Glenwood D. Goss, MD, of the Ottawa Hospital Cancer Center, and colleagues, the prematurely closed NCIC CTG BR19 study showed no apparent survival benefit of adjuvant gefitinib (Iressa, withdrawn from U.S. market) vs placebo in patients with completely resected non– small cell lung cancer (NSCLC).1

Study Details In this phase III trial, activated in 2002, patients with completely resected stage IB, II, or IIIA NSCLC stratified by stage, histology, sex, postoperative radiotherapy, and chemotherapy were randomly assigned to receive gefitinib at 250 mg/d or placebo for 2 years. The target population was 1,242 patients and study endpoints were overall survival, disease-free survival, and toxicity. In December 2004, a phase III study in advanced NSCLC (ISEL study) showed no survival benefit of gefitinib vs placebo.2 An unplanned interim analysis of another trial (SWOG S0023 study) showed that maintenance gefitinib after chemoradiation in patients with stage III NSCLC did not improve overall survival and was potentially detrimental.3 In April 2005, based on these results, the BR19 Data and Safety Monitoring Committee recommended closure of the study and discontinuation of study medication. The trial committee elected to conduct a final analysis once all patients were followed for at least 4 years. Due to early closure, only 503 of the planned patients were randomly assigned to gefitinib (n = 251) or placebo (n = 252). Patients in the gefitinib group and placebo group had median ages of 66 and 67 years, and 54% of both groups were male. The groups were well balanced for race, histology, smoking history, stage, Eastern Coop-

erative Oncology Group performance status, type of surgery, prior adjuvant chemotherapy, and prior radiotherapy. Overall, only 17% of patients had received adjuvant chemotherapy and 5% had received adjuvant radiotherapy. Approximately 52%, 35%, and 13% of patients had stage IB, II, and IIIA disease, respectively, and 60% and 28% had adenocarcinoma and squamous cell carcinoma, respectively.

Survival Data After a median follow-up of 4.7 years, median disease-free survival was 4.2 years in the gefitinib group and not reached in the placebo group (hazard ratio [HR] = 1.22, P = .15). Multivariate analysis showed that only tumor size ≥ 4 cm was significantly associated

or overall survival benefit (HR = 1.24, P = .18) from gefitinib among 344 patients with EGFR wild-type tumors, and no disease-free survival (HR = 1.84, P = .40) or overall survival benefit (HR = 3.16, P = .15) from gefitinib among 15 patients with EGFR mutant tumors. No benefit of gefitinib was seen according to presence or absence of KRAS mutations. The study results did not appear to be related to nonprotocol treatment received after disease progression, which was balanced between treatment groups.

Safety and Tolerability Median durations of treatment were 4.8 months in the gefitinib group and 8.9 months in the placebo group. Dose adjustment occurred in 39% of

Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, theseresults indicate that it is unlikely to be of benefit. —Glenwood D. Goss, MD, and colleagues

with poorer disease-free survival, with gefitinib treatment remaining nonsignificant and potentially harmful (HR = 1.27, P = .096). Median overall survival was 5.1 years in the gefitinib group and had not been reached in the placebo group (HR = 1.24, P = .14). Multivariate analysis showed that age ≥ 65 years and tumor size ≥ 4 cm were significantly associated with poorer overall survival, with gefitinib treatment remaining nonsignificant and potentially harmful (HR = 1.27, P = .097). Exploratory analyses showed no disease-free survival (HR = 1.28, P = .14)

Adjuvant Gefitinib in Resected Lung Cancer ■■ In this prematurely closed trial, there was no evidence of disease-free or overall survival benefit of adjuvant gefitinib in patients with fully resected NSCLC. ■■ Adverse events were those expected with EGFR inhibitor therapy.

gefitinib patients and 20% of placebo patients, drug was held temporarily for 23% and 11%, and treatment was discontinued due to toxicity in 15% and 3%. The patient refusal or withdrawal rate after beginning therapy was 24% in the gefitinib group and 7% in the placebo group. Gefitinib recipients had a higher incidence of any-grade rash, dry skin, diarrhea, anorexia, and nausea but less chest pain, muscle pain, and dyspnea. Grade 3 to 4 diarrhea, skin effects, and chest pain were reported in 5% to 8% of both groups. The most common serious adverse event in both cohorts was dyspnea, occurring in 13% and 7% of patients on gefitinib and placebo, respectively. One patient in each group had fatal pneumonitis. Five gefitinib and four placebo patients died from an adverse event; three of the five deaths in the gefitinib patients were considered drug-related.

Conclusions The investigators concluded, “Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.” Based on a full intent-to-treat analysis, the conditional power observing a beneficial effect of gefitinib, had the study reached its target accrual, was only 17.5% supporting their conclusions. They noted that potential contributions to the findings include the underpowering of the study overall and with regard to EGFR mutationpositive patients, short duration of treatment, and the possibility that the EGFR pathway plays a less important role in early disease. In addition, the authors stated, “BR19 has left us with unanswered questions, and we look forward to the results of the erlotinib [Tarceva] adjuvant trial RADIANT (NCT 00373425) and two adjuvant studies in EGFR mutation-positive patients, the Chinese study (NCT01405079) and the ongoing Japanese study of adjuvant gefitinib versus chemotherapy.” n

Disclosure: The study was supported by the Canadian Cancer Society Research Institute, the U.S. National Cancer Institute, Ontario Cancer Research Network, and AstraZeneca. For full disclosures of the study authors, visit jco.ascopubs.org.

References 1. Goss GD, O’Callaghan C, Lorimer I, et al: Gefitinib versus placebo in completely resected non–small-cell lung cancer: Results of the NCIC CTG BR19 Study. J Clin Oncol. August 26, 2013. 2. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:15271537, 2005. 3. Kelly K, Chansky K, Gaspar LE, et al: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26:2450-2456, 2008.

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The ASCO Post | DECEMBER 15, 2013

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Journal Spotlight Neuro-Oncology

Investigators Report Valganciclovir May Increase Survival in Glioblastoma By Matthew Stenger

n a letter to The New England Journal of Medicine, Cecilia Söderberg- Nauclér, MD, PhD, and colleagues from the Karolinska Institutet, Stock-

Cecilia Söderberg-Nauclér, MD, PhD

holm, described experience with the anti-cytomegalovirus (CMV) agent valganciclovir (Valcyte) in the treatment of glioblastoma, citing dramatically improved overall survival that increased with increasing duration of treatment.1

CMV in Glioblastoma In studying more than 250 cases of glioma, these investigators have found only 1 patient who was CMV-negative. Among 75 patients followed, median overall survival was 33 months in those with low-grade CMV infection and 13 months in those with high-grade

CMV infection (P = .04), and 2-year overall survival was 63.6% vs 17.2% (P = .003), suggesting that CMV affects tumor progression.2 In the randomized VIGAS trial in 42 patients with glioblastoma performed by the investigators, valganciclovir treatment did not significantly reduce tumor growth, the primary endpoint of the study, at 3 and 6 months after surgery.3 However, an exploratory analysis showed that among 22 patients receiving at least 6 months of therapy, 2-year overall survival (50% vs 20.6%, P < .001) and median overall survival (24.1 vs 13.7 months, P = .003) were significantly increased compared with contemporary controls. Given these findings, 28 additional patients have been treated with compassionate-use valganciclovir in addition to standard therapy at Karolinska University Hospital.

Increased Overall Survival Among the total of 50 patients treated with valganciclovir, 2-year overall survival was 62% compared with 18% among 137 contemporary controls with similar disease stage, surgical resection grade, and baseline treatment (P < .001), and median overall survival was 25.0 months vs 13.5 months (hazard ratio [HR] = 2.59, P < .001). Among 40 patients who received at least 6 months of valganciclovir, 2-year overall survival was 70% and median overall survival was 30.1 months (HR = 3.20 vs controls, P < .001). Among 25 patients who received continuous valganciclovir treatment after the first 6 months, the 2-year overall survival rate was 90% and median overall survival was 56.4 months (HR = 5.52 vs controls, P < .001).

Glioblastoma, Cytomegalovirus, and Valganciclovir ■■ In experience with valganciclovir therapy in glioblastoma patients, median overall survival was 25.0 months vs 13.5 months in contemporary controls. ■■ Median overall survival was 30.1 months in patients receiving at least 6 months of valganciclovir and 56.4 months in those receiving continuous valganciclovir after 6 months.

The authors stated, “It is unlikely that any bias in patient selection could have resulted in these high rates of survival. Our results highlight the need for a randomized trial targeting CMV in patients with glioblastomas.” n Disclosure: The study was supported by an independent investigational grant from Hoffmann–La Roche. For full disclosures of the study authors, visit www.nejm.org.

References 1. Söderberg-Nauclér C, Rahbar A, Stragliotto G: Survival in patients with glioblastoma receiving valganciclovir (correspondence). N Engl J Med 369:985986, 2013. 2. Rahbar A, Orrego A, Peredo I, et al: Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival. J Clin Virol 57:36-42, 2013. 3. Stragliotto G, Rahbar A, Solberg NW, et al: Effects of valganciclovir as an add-on therapy in patients with cytomegaloviruspositive glioblastoma: A randomized, double-blind, proof-of-concept study. Int J Cancer 133:1204-1213, 2013.

Valganciclovir in Glioblastoma, Selection Bias, and Flawed Conclusions By William T. Curry, MD

s reviewed in this issue of The ASCO Post, Söderberg-Nauclér et al from the Karolinska Institute have written a provocative letter to The New England Journal of Medicine suggesting that long-term administration of valganciclovir (Valcyte), a drug that targets cytomegalovirus (CMV), improves overall survival in patients with glioblastoma.1

Prospective Study This is a highly accomplished group in the field of virology. Their letter serves as a companion piece to a randomized study of valganciclovir combined with standard surgery, radiation, and chemotherapy for patients with newly diagnosed glioblastoma, published recently in the International Journal of Cancer.2 Dr. Curry is Associate Professor and Attending Neurosurgeon in the Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston.

In this prospective trial, 42 patients with CMV-positive glioblastoma were randomly assigned in double-blind fashion to receive either valganciclovir or placebo in addition to standard therapy. The primary endpoints were tumor

nificant differences in tumor volume at either timepoint. Also, progression-free survival (5.6 vs 5.5 months) and overall survival (17.9 vs 17.4 months) were similar between these intent-to-treat groups. After the initial 6-month study peri-

Although there is some evidence suggesting that CMV infection of glioblastoma cells drives an oncogenic phenotype, it is premature and perhaps wrong to infer that valganciclovir treatment improves outcomes for these patients. —William T. Curry, MD

volume at 3 and 6 months; secondary endpoints, for which the study was not powered, were progression-free survival and overall survival. There were no sig-

od, patients could either continue taking valganciclovir or, if in the placebo group, to cross over and initiate valganciclovir treatment. Patients taking valganciclo-

vir for longer than 6 months, regardless of the point of initiation, lived longer than patients receiving either short-term (< 6 months) or no valganciclovir.

Selection Bias This is an extremely flawed conclusion, for the simple fact that good performance score patients and surviving patients, for that matter, are more likely to take any drug for a longer period of time, so the selection bias is heavy. The futility of this sort of analysis is detailed by Anderson, Cain, and Gelber in a methodology review in the Journal of Clinical Oncology.3 However, based on this “generated” hypothesis, the group from the Karolinska Institute treated 28 more patients (in addition to the ones on the protocol) with valganciclovir. These 50 patients form the substrate for the letter to The New England Journal of Medicine. This report seems to corroborate the initial finding in the randomized trials.

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Journal Spotlight

Compared to historical controls, patients receiving valganciclovir for at least 6 months had longer median overall survival. Among these patients, those who took valganciclovir continuously after the initial 6 months had the longest median survival—56 months. Continued selection bias compels us to interpret the authors’ conclusions with circumspection. Most importantly, patients were only eligible for valganciclovir if they were in good neurologic condition and had stable disease after the completion of surgery and initial chemoradiation—no such selection criteria were applied to the “controls.” Immediately, “valganciclovir treatment” selects for a prognostically favorable population. Hints of this reality can be seen in the patient details, which are provided in the supplementary data. For instance, the control patients have lower Karnofsky performance scores, and they represent the only cohort for which the well-validated recursive partitioning analysis class data are not provided. The fact that patients within the treatment cohort must achieve certain exclusive criteria prior to enrollment unavoidably drives “immortal time bias”4 and shifts the Kaplan-Meier curves from the outset. Furthermore, 30 of the 50 valganciclovir-treated patients are taken from the randomized trial; the 20 treated under compassionate use “had good neurological function and either approached their doctor and requested valganciclovir or learned about this option from their treating physician while discussing possible treatment options, including other clinical trials open for recruitment.” Both clinical trial participation and socioeconomic and educational status have been associated with improved survival in cancer, and the treatment cohort here is likely enriched for both.

Premature Inference Although there is some evidence suggesting that CMV-infection of glioblastoma cells drives an oncogenic phenotype,5 it is premature and perhaps wrong to infer that valganciclovir treatment improves outcomes for these patients. It is not clear that a properly designed and powered randomized trial is justified at this point. However, if the

authors are so motivated, they should be able to answer the question of whether long-term valganciclovir treatment impacts survival in glioblastoma patients in a relatively straightforward—though resource-intense—manner, with the help of a biostatistician. n

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

References 1. Söderberg-Nauclér C, et al: N Engl J Med 369:985-986, 2013. 2. Stragliotto G, et al: Int J Cancer

133:1204-1213, 2013. 3. Anderson JR, et al: J Clin Oncol 26:3913-3915, 2008. 4. Suissa S: Am J Epidemiol 167:492499, 2008. 5. Dziurzynski K, et al: Clin Cancer Res 17:4642-4649, 2011.

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The ASCO Post | DECEMBER 15, 2013

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Issues in Oncology Clinical Trials

NCI-Led Scientists Develop Criteria for ‘Omics’ Tests Used in Clinical Investigations By Caroline Helwick

igh-throughput “omics” technologies that generate molecular profiles on tumor specimens are increasingly being incorporated into clinical trials, but some of these assays have not been well validated, leading many in the research community to question their fitness for use in patient-care decisions. Recently, the scientific community united in an effort to produce guidelines that would promote quality. Tumor biomarker tests are key to accomplishing the goal of personalized medicine. However, much of the translational research regarding tumor biomarker tests has “ignored many of the principles of the scientific method,” according to Lisa M. McShane, PhD, of the Biometric Research Branch, Division of Cancer Treatment and Diagnosis, at the National Cancer Institute (NCI). The recognition of this suboptimal situation led Dr. McShane and a group of other scientists to develop a “criteria

checklist” for clinical trial use of these tests. The checklist should be applied when incorporating a tumor biomarker test into any clinical trial that prospec-

opment.… The ultimate goal is to develop a more efficient, reliable and transparent process to move omics assays from promising research results to clinically

The ultimate goal is to develop a more efficient, reliable and transparent process to move omics assays from promising research results to clinically useful tests that improve patient care and outcome. —Lisa M. McShane, PhD, and colleagues

tively evaluates its clinical utility, the group suggested. The criteria were recently published simultaneously in the journal Nature1 and, elaborated on in greater detail, in BMC Medicine.2 “It is hoped that this 30-point checklist will guide investigators toward the use of best practices in omics test devel-

useful tests that improve patient care and outcome,” the authors wrote.1

What Are ‘Omics’? The papers focus on molecular tests derived from high-throughput omics assays, generally used for predicting patient outcomes in clinical trials. The

EXPERT POINT OF VIEW

aniel F. Hayes, MD, FASCO, the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan, Ann Arbor, wrote an accompanying editorial on

Daniel F. Hayes, MD, FASCO

the value of these newly developed omics-related criteria.1 Dr. Hayes pointed out that since the cloning of the human genome, there has been great interest in the development of multiparameter signatures that correlate with biologic or clinical phenotypes and outcomes. Few diagnostics, however, have been successfully integrated into clinical care, largely because of challenges that must be addressed.

These include the need for analytical validity (accuracy, reproducibility, and reliability) and clinical utility (based on high levels of evidence). The publications offer a “comprehensive yet concise set of criteria about which any investigator considering a clinical trial to generate high levels of evidence for clinical utility of a tumor biomarker test must be aware.… Taken together with several other initiatives to increase the rigor of tumor biomarker research, these criteria will increase the perception of value for tumor biomarker test research and application in the clinic,” Dr. Hayes maintained.

Checklist Rationale The checklist is needed, he emphasized, because “a bad tumor marker is as bad as a bad drug,” and because “tumor biomarker investigations have, too often, been studies of convenience, in which the investigators have applied an assay (which may or may not have analytical va-

lidity) to some available patient specimens, observed separation in some outcome of the population at hand with a P value < .05, and declared victory,” he wrote in his editorial. Such studies, he pointed out, may suggest clinical utility but do not prove it. Few biomarker tests have gained a high enough level of evidence to warrant use in direct patient care, he said. Without addressing these problems—and the checklist is a good roadmap, he said—the promise of personalized oncology will never materialize. n

Disclosure: Dr. Hayes has three patents pending regarding clinical use of circulating tumor cells. He serves on the advisory boards of Oncimmune LLC and Inbiomotion, LLC, and has stock options in both of these companies.

Reference 1. Hayes DF: Omics-based personalized oncology: If it is worth doing, it is worth doing well! BMC Medicine 11:221, 2013.

chief omics disciplines are genomics, transcriptomics, proteomics, metabolomics, and epigenomics. A distinguishing characteristic of the omics tests, which are the focus of the checklist, is that computational methods are applied to the data to build mathematical predictor models. This is in contrast to molecular tests based on such variables as genetic mutations, which can be used to screen patients for eligibility for a trial and to select patients for targeted treatments. To date, relatively few omics tests have entered clinical use but they are increasingly incorporated into clinical trials, even though their performance, reproducibility, and robustness are often not proven, and they may be based on statistical and mathematical approaches that are flawed. “It is essential to consider all these issues before launching into a clinical study using an omics test in a way that might influence the clinical management of patients,” Dr. McShane argued.

Group Concerns Checklist coauthor William L. Bigbee, PhD, outgoing Chair of the National Institutes of Health Cancer Biomarkers Study Section and past Leader of the Cancer Biomarkers Shared Facility at the University of Pittsburgh Cancer Institute, provided some background in an interview with The ASCO Post. “Omics-based tests are very powerful, emerging tools that are revolutionizing medicine, particularly in predicting and treating cancer. However, there are many variables and opportunities for error, including issues pertaining to study design, patient selection, biologic sample integrity, and data analysis and management. The NCI checklist is intended to provide clear expectations and guidelines for the development and implementation of omics-based tests and will hopefully eliminate unintentional errors,” he explained. He said the scientific community has been witnessing the development and initial implementation of omicsbased technologies, anticipating their impact on “personalized medicine. Their mutual concern has been a lack of rigorous clinical validation, and therefore premature use, of some of these

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Issues in Oncology

tests. These thought leaders, who have broad expertise in the omics field, were brought together for a 2011 NCI Workshop to examine the issues. The Workshop was followed by an Institute of Medicine (IOM) report that also called for an examination of the omics evaluation process.3 The level of interest in the issue led to further dialogue and the subsequent development of the published checklist to operationalize the principles set forth in the IOM report and the NCI workshop discussions. “The criteria encompass all the interests, disciplines and technologies that need to weigh in on the development of omics-based predictors in a way that will have clinical relevance and application,” Dr. Bigbee said. The authors scrutinized published literature pertaining to their specific areas of expertise and asked, “To what degree can we take these predictors from the research environment and have confidence that they could be used in different settings, specifically, clinical trials? Given their complexity, how can we assure that these predictors can go forward in ways that will have a clinical impact for patient selection?” he said. The authors believe this document will be useful in three contexts: the basic or translational research setting, the clinical trial setting, and within the NCI itself. “The NCI was very interested in having a reference document like this, together with the IOM report, as part of a more formal framework for the review process in evaluating applications for omics-based research and NCI-sponsored trials,” he said. “We also think it will be useful to journal reviewers and editors as a reference document as they think critically about the evaluation of manuscripts reporting omics-based studies. ”

What’s on the Checklist? The checklist applies to any clinical trial that involves the investigational use of an omics test that will influence the clinical management of patients in the study. The criteria generally also apply to retrospective analysis of specimens in older studies. The researchers recommend that investigators consult the checklist during the research planning and early development phases of their trials. The checklist contains specific recommendations in the following areas: • Specimen collection, processing, storage, and so forth • Technical issues related to omicsbased assays (eg, reagents, specimens, instrumentation, scoring methods)

• Model development, specification, and preliminary performance evaluation • Clinical trial design and conduct (eg, rigorous statistical design, informatics plan for the data, complete specification of the omics test) • Ethical, legal, and regulatory issues (safety and privacy of patients, intel-

lectual property issues) n

Disclosure: Dr. McShane and Bigbee reported no potential conflicts of interest.

References 1. McShane LM, Cavenagh MM, Lively TG, et al: Criteria for the use of omicsbased predictors in clinical trials. Nature 502:317-320, 2013.

2. McShane LM, Cavenagh MM, Lively TG, et al: Criteria for the use of omics-based predictors in clinical trials: Explanation and elaboration. BMC Medicine 11:220, 2013. 3. Micheel CM, Nass SJ, Omenn GS (eds): Evolution of translational omics: Lessons learned and the path forward. Washington, DC, National Academies Press, 2012.

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Clinical Cancer Advances 2013: ASCO’s Annual Report on Progress Against Cancer

he Society has recently published Clinical Cancer Advances 2013: ASCO’s Annual Report on Progress Against Cancer, a comprehensive review of progress in clinical cancer research that has come to fruition in 2013. The report highlights advances across the entire continuum of cancer care, from prevention to treatment and survivorship, and covers a broad range of cancer subspecialties. It also documents FDA approvals of new anticancer agents, clinical practice guidelines, and policy priorities that are likely to influence cancer care delivery in the near term.

About the CCA Now in its ninth year, the Clinical Cancer Advances (CCA) report offers the public a window into the achievements, trends, and challenges in oncology. It serves as an educational resource for oncology residents and fellows, and seasoned oncologists and primary care physicians may look to the document to catch up on the most promising developments in cancer research and care. CCA 2013 was developed under the direction of an editorial board chosen by ASCO, comprised of experts in their respective fields of oncology. The editors reviewed research published in peer-reviewed scientific journals and presented at major scientific meetings over a 1-year period (October 2012 to September 2013), which covers prevention, screening, treatment, patient and survivor care, biomarkers, tumor biology, and cancer disparities.

Major Advances in Cancer Care Among the 76 studies featured in CCA 2013, many capitalize on our growing understanding of tumor biology and genomics. Marked progress has also been achieved in treatment of rare and therapy-

resistant cancers through new precision medicine and immunotherapy approaches. The most significant advances in those fields include: • Identification of new prognostic markers and potential therapeutic targets in brain, kidney, and head and neck cancers, and new molecular subtypes of endometrial cancer and glioblastoma. • Molecularly targeted drugs that stall disease progression in patients with treatment-resistant forms of cervical and thyroid cancer. • New strategies to enhance the ability of patients’ own immune systems to fight cancer. In addition, two landmark studies this year showcase cancer screening paradigms poised to reduce socioeconomic and racial disparities in cancer survival: • Low-cost cervical cancer screening involving simple vinegar delivered by primary health workers reduced cervical cancer deaths by one-third in India; this approach could save more than 70,000 women’s lives per year worldwide. • A statewide colorectal cancer screening and treatment program that has nearly eliminated disparities in colorectal cancer outcomes for African Americans in Delaware.

Cancer Policy Priorities In the United States, cancer research is critically dependent on federal funding, which underpins the National Clinical Trial Network (NCTN) and supports research that the private sector typically doesn’t pursue. But the future of progress against cancer is being threatened by a pattern of flat federal funding over the last decade and the 2013 sequester, which triggered across-the-board cuts to ongoing research. In the CCA this year, ASCO is calling on Congress to provide a fiscal year

Newly Updated: Managing the Cost of Cancer Care

anaging 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. 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/managingcostofcare. n © 2013. American Society of Clinical Oncology. All rights reserved.

2014 appropriation of $5.2 billion to the National Cancer Institute, increase funding for the NCTN, avoid future sequestration budget cuts to the National Institutes of Health, and issue clear guidance on the clinical trial provision of the Patient Protection and Affordable Care Act. Clinical Cancer Advances 2013 is funded in part through the Conquer Cancer Foundation Mission Endowment.

Clinical Cancer Advances 2013: ASCO’s Annual Report on Progress Against Cancer was published online in the Journal of Clinical Oncology (www.jco.org) on December 10, and is also available with additional resources at www.cancerprogress. net/cca. n © 2013. American Society of Clinical Oncology. All rights reserved.

Save the Date 2014 Genitourinary Cancers Symposium January 30-February 1, 2014 San Francisco Marriott Marquis San Francisco, California

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Conquer Cancer Foundation–Funded Research Identified Among Top Cancer Advances of 2013

he recently released Clinical Cancer Advances 2013: ASCO’s Annual Report on Progress Against Cancer, highlights the most impactful advances in clinical cancer research of the year, and this year’s report identifies two studies that were funded by the Conquer Cancer Foundation.

many benefits of receiving a [Conquer Cancer Foundation] grant, but perhaps the greatest is the recognition by peers that one is trying to solve an important question in cancer.”

Richard J. Lee, MD, PhD, of Massachusetts General Hospital received a 2009 Conquer Cancer Foundation of ASCO Career Development Award (CDA) for his work investigating tu-

mor cells that circulate in the blood of patients with prostate cancer. He led a phase II clinical trial, funded in part by the CDA and published continued on page 50

Advances in Targeted Therapy One of the Foundation-funded studies identified as an important advance was led by Ingo Mellinghoff, MD, of Memorial Sloan-Kettering Cancer Center, recipient of a 2009 Conquer Cancer Foundation of ASCO Advanced Clini-

Ingo Mellinghoff, MD

Advertisement not displayed in digital edition at advertiser’s request Richard J. Lee, MD, PhD

cal Research Award (ACRA) in Glioma. His study, published this year in Science, was supported in part by the ACRA and shows that a new experimental drug that targets the protein product of the gene IDH1 is a potential important new therapeutic in the fight against cancer. Importantly, the drug blocks mutant IDH1, found in many cancers including glioma and acute myeloid leukemia, and does not affect the normal, nonmutated protein. The preclinical data in Dr. Mellinghoff ’s study paves the way for the drug to enter clinical trials for patients whose tumors have this gene mutation. Dr. Mellinghoff also received a 2003 Young Investigator Award (YIA) from the Conquer Cancer Foundation early in his career. “Receiving the ACRA in Glioma and the YIA provided financial support and motivation during critical parts of my career,” said Dr. Mellinghoff in an interview with the Foundation. “There are

The ASCO Post | DECEMBER 15, 2013

PAGE 50

Direct From ASCO Conquer Cancer Foundation– Funded Research

Investing in the Future of Oncology

continued from page 49

The Conquer Cancer Foundation provides critical funding through its Grants and Awards Program to support young investigators like those featured in the 2013 Clinical Cancer Advances report. Career development grants like the YIA, CDA, and ACRA help researchers launch successful careers, become established in the oncology community, and make discoveries that benefit patients with cancer. Clearly, the Foundation’s initial investment in these young researchers is paying dividends, as they are succeeding in their careers, making an impact on patients, and advancing the field of oncology. By donating to the Conquer Cancer Foundation, you can help fund aspiring scientists in making the next big

earlier this year in Clinical Cancer Research, in which a lower dose of a new targeted therapy still led to shrinkage of prostate cancer metastases in 82% of patients when evaluated on bone scans and 58% of patients on this dose had a reduction in the number of tumor cells circulating in their blood. In addition to these two studies, many advances highlighted in the 2013 report were led by researchers, such as Marcia Brose, MD, who have received Foundation support early in their careers. To view and download the full 2013 report, visit www.cancerprogress.net/cca or www.jco.org.

Volume 29, Issue 15

May 20, 2011

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

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

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

What’s Hot in

JCO JCO.org

Marriage Is As Protective As Chemotherapy in Cancer Care by David W. Kissane

Marital Status and Survival in Patients With Cancer by Ayal A. Aizer, et al

TLAS: Randomized, Double-Blind, Placebo-Controlled, Phase A IIIB Trial Comparing Bevacizumab Therapy With or Without Erlotinib, After Completion of Chemotherapy, With Bevacizumab for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer by Bruce E. Johnson, et al

breakthroughs in cancer research. Visit www.conquercancerfoundation.org/ donate to make a gift today. All gifts made before December 31, 2013, will be matched dollar for dollar by Raj

Volume 7, Issue 3

May 2011

Journal of oncology Practice 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

www.jop.ascopubs.org

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

What’s Hot in

JOP

JOP.ascopubs.org Improving Pediatric Hematology/Oncology Care in the Emergency Department by Jill C. Beck

The National Cancer Institute–American Society of Clinical Oncology Cancer Trial Accrual Symposium: Summary and Recommendations by Andrea M. Denicoff, et al

Effect of Medical Oncologists’ Attitudes on Accrual to Clinical Trials in a Community Setting by Carol P. Somkin, et al

Insight or Confusion: Survival After Response-Guided Neoadjuvant Chemotherapy in Breast Cancer by Melinda L. Telli

Is Physician Employment by Health Systems an Answer? by Alice G. Gosfield

Everolimus for Previously Treated Advanced Gastric Cancer: Results of the Randomized, Double-Blind, Phase III GRANITE-1 Study by Atsushi Ohtsu, et al

Using Quality Oncology Practice Initiative Metrics for Physician Incentive Compensation by Grace Makari-Judson, et al.

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A New Gift to Add to Your List—One to Conquer Cancer

onquering cancer requires the commitment, talent, and resources of all members of our community. It requires the innovation of researchers and the insight of clinicians, the courage of our worldwide community of patients and survivors, and it requires the generosity of ev-

eryone who believes in a world free from the fear of cancer. This year, as you plan your yearend giving, consider a tax-deductible gift to the Conquer Cancer Foundation. Your gift will be matched dollar for dollar by Raj Mantena, RPh, of Jupiter, Florida, doubling the differ-

Want to learn more about the researchers your gift supports?

Visit www.conquercancerfoundation.org/researcherspotlights to see videos of featured researchers discussing their work and the impact of their Conquer Cancer Foundation grant.

ence your support will make in the lives of people living with cancer and those who care for and about them. Together, we can: • Fund breakthrough research and advance new discoveries in cancer care and treatment • Put up-to-the minute, accurate cancer information directly into the hands of patients and caregivers, so that they can be empowered in their care and survivorship • Support cutting-edge training and professional development for oncology practitioners • Improve the standard of care worldwide—particularly in developing nations—by promoting international communication, collaboration, and education among cancer practitioners The Conquer Cancer Foundation funds research focused on finding new therapeutics to conquer cancer and is also committed to supporting research in areas that are typically underfunded, such as palliative care,

rare cancers, pediatric cancers, and high-risk areas. With government support of research becoming increasingly tenuous, support from donors like you are needed more than ever before to help young oncology researchers get their start and to continue to advance the practice of oncology worldwide. As the end of the year approaches, we hope that you will join us in building a world free from the fear of cancer by making a gift to conquer cancer at www .c o n q u e r c a n c e r f o u n d a t i o n .o r g /donate. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO’s Innovative Quality Improvement Programs Highlighted at Symposium

everal presentations at the 2013 Quality Care Symposium demonstrated the current and potential impact of ASCO’s initiatives to achieve higher-quality cancer care with better outcomes for patients. Key presentations at the conference centered on the development of ASCO’s ground-breaking “big data” initiative, CancerLinQ™; the Virtual Learning Collaborative pilot project on palliative care; and on the impact of the Society’s Quality Oncology Practice Initiative (QOPI®), all major efforts to improve the quality of cancer care.

CancerLinQ Quality improvement has always been at the core of ASCO’s mission. The Society issued its first clinical practice guideline in 1994. QOPI, launched in 2006, is the first national

program to help practices measure and improve the quality of care they deliver. With CancerLinQ, ASCO is developing a knowledge-generating computer network that will collect and analyze cancer care data from millions of patient visits, together with expert guidelines and other evidence, to generate real-time, clinical guidance and quality feedback for physicians. CancerLinQ is ASCO’s effort to build a health information technology–based learning health system to achieve higher quality, higher value cancer care with better outcomes for patients. A functional CancerLinQ prototype was completed in just 8 months and includes more than 170,000 de-identified medical records of breast cancer patients. The prototype demonstrated the feasibility of all major components of a learning

Save the Date

health system, including the conversion of clinical practice guidelines into a machine-readable format that can be queried to deliver real-time guidance to physicians at the point of care.

Virtual Learning Collaborative ASCO’s Virtual Learning Collaborative (VLC), developed in partnership with the American Academy of Hospice and Palliative Medicine (AAHPM), will support quality improvement initiatives targeting palliative care delivered by medical oncologists. The VLC is based on the

quality collaborative model, which has achieved wide success with both the Institute for Healthcare Improvement’s Breakthrough Series and the Department of Veterans’ Affairs EBQI program. The VLC will test a digital approach, moving the collaboration to an online platform environment, allowing participation no matter where a practice is located. To learn more about ASCO’s efforts in quality improvement, please visit www.asco.org/quality-guidelines. n © 2013. American Society of Clinical Oncology. All rights reserved.

2014 Gastrointestinal Cancers Symposium January 16-18, 2014 Moscone West Building San Francisco, California

IN A L K+ N SC LC

reCognize progression

iDentify symptoms

• Prior to 2011, there were no targeted therapies available to treat patients with ALK+ NSCLC1-3

• Symptoms, including cough, dyspnea, fatigue, pain, hemoptysis, and anorexia, can serve as signals of progression7,8

• Inevitably, patients develop resistance to currently available ALK inhibitor therapy and typically progress after 10 months4-6 • Common sites of disease progression include the CNS, lung, and liver6

• Up to half of patients with NSCLC may develop CNS metastases, and symptoms include headaches, seizures, cognitive impairment, and neurological deficits9,10

ALK, anaplastic lymphoma kinase; CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer. References: 1. XALKORI® (crizotinib) Prescribing Information. New York, NY: Pfizer Labs; October 2013. 2. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773-1780. 3. US Food and Drug Administration. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm. Released August 26, 2011. Accessed November 5, 2013. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.2.2014. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed November 4, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 5. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):1-12. doi:10.1126/scitranslmed.3003316. 6. Camidge DR, Bang Y-J, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011-1019. 7. Hollen PJ, Gralla RJ, Kris MG, et al. Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Cancer. 1994;73(8):2087-2098. 8. de Marinis F, Pereira JR, Fossella F, et al. Lung cancer symptom scale outcomes in relation to standard efficacy measures. J Thorac Oncol. 2008;3(1):30-36. 9. Hu C, Chang EL, Hassenbusch SJ III, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer. 2006;106(9):1998-2004. 10. Fokas E, Steinbach JP, Rödel C. Biology of brain metastases and novel targeted therapies: time to translate the research. Biochim Biophys Acta. 2013;1835(1):61-75. 11. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 12. Sánchez de Cos J, Sojo González MA, Montero MV, et al. Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 2009;63(1):140-145.

A LOT CAN HAPPEN IN A MONTH Can CheCking monthly for symptoms help yoU DeteCt progression earlier? intervene noW • By assessing patient symptoms monthly during routine physical exams, progression may be detected earlier8 • According to guidelines, a CT scan is the best method for monitoring response to therapy11 • Early detection of CNS metastases by cranial CT or MRI—even before symptoms develop—may improve prognosis12

visit www.progressioninALK.com to register for updates.

novartis oncology is committed to advancing research into the alk pathway to help find new options for patients with lung cancer.

Novartis Pharmaceuticals Corporation east hanover, new Jersey 07936-1080

11/13

lCD-1074669

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Issues in Oncology

Oncology Drug Dosing: Can an Optimal Dose Be Fine-Tuned for Each Patient? By Margot J. Fromer

SCO Chief Medical Officer Richard L. Schilsky, MD, and other oncology drug experts presented a panel on drug dosing at a recent meeting, cosponsored by the Friends

erated dose is the optimal dose,” he said. “We simply don’t have the license to cause patients so much toxicity—even in the face of the threat to life. We have got to find a better balance between doing good and doing harm,” Dr. Pazdur added.

Easier Said Than Done

Richard L. Schilsky, MD

of Cancer Research and the Brookings Institution, in Washington, DC.1 The presentations made it clear that issues surrounding drug dosing are among the thorniest problems in oncology.

Major Problems “We want patients to live longer and enjoy a better quality of life,” said Dr. Schilsky, “but we need to do a better job of balancing the benefits and risks of therapy, that is, identifying the drug dose at which efficacy is maximized and toxicity minimized. A dose that is too high can render an otherwise effective drug intolerable, and one that is too low can negate the expected benefit.” Because cancer is life-threatening, a high degree of toxicity is accepted, as is the need to develop new drugs quickly. These two factors often take precedence over finding an optimal dose. “We have accepted too high a degree of toxicity in cancer drugs, and it has become a serious problem,” said Richard Pazdur, MD, Director of the U.S. Food and Drug Administration

Richard Pazdur, MD

(FDA) Office of Hematology and Oncology Products. “We do a terrible job of exploring dosing prior to a phase III trial. The emphasis in clinical trials is primarily on efficacy, and drug companies don’t want to do phase II dosing studies to determine whether the maximum tol-

The “right” dose is often elusive, said Dr. Schilsky, and even if it could be pinpointed, it may be only an estimate. “For any drug dose, a range of beneficial and toxic effects will vary based on the unique characteristics of each patient.” Dr. Schilsky noted that many recently approved oncology drugs are labeled for use at doses that are either too high or too low for at least some patients. “We need to devise a strategy for drug development that includes dose optimization but doesn’t delay market entry.” Phase I trials determine the highest tolerable dose; small numbers of patients are given increasing doses until dose-limiting toxicity is reached. The amount of drug immediately below that is the maximum tolerated dose, which is then used for phase II and III trials, which rarely evaluate doses other than maximum tolerated dose. “The [maximum tolerated dose] may not be appropriate for targeted therapy,” said Atiqur Rahman, PhD, Director, FDA Division of Clinical Pharmacology V. “Moreover, dose selection based on [maximum tolerated dose] does not mean there will not be serious toxicity.” This process has other limitations as well: For example, it does not evaluate patient variability in treatment response and toxicity. “Doses used in phase II and III often achieve concentrations that may substantially surpass those needed to inhibit or stimulate the intended target(s),” said Dr. Rahman. This can lead to a high rate of dose reductions in clinical trials, as well as failure to identify patients who might benefit from a higher dose. Moreover, pharmacodynamic endpoints that assess target inhibition might be more relevant for agents such as hormonal and targeted therapies. In addition, oncology drug development does not evaluate long-term cumulative toxicity or changes in tolerability over time. This is significant because patients tend to stay on therapy longer now than in the past. Finally, decisions about dosing and tolerability are different among the heavily pretreated, usually sicker,

patients in phase I trials as compared to those in phase II and III trials.

Approach to Dose Determination The way to approach dose determination is to understand the relationship between drug exposure and clinical outcomes. “Defining ranges of toxic and therapeutic concentrations may let us monitor patient drug levels, which could be used to guide decisions, particularly for chronic treatment,” said Dr. Schilsky.

Lori Minasian, MD

A key component is randomized dose-comparison studies, which are not typically done in oncology. Phase I trials should include sufficient pharmacokinetic sampling to clearly determine the pharmacokinetic properties of the drug. Phase II should go beyond assessment of drug activity to include adaptive designs and/or randomized exploration of doses. Phase III should incorporate population pharmacokinetic sampling to further evaluate the relationship between drug exposure and clinical outcomes. Regarding toxicity, when possible, patient-reported outcomes should be assessed and measured in all phases of clinical trials as one guide to optimal dosing. Moreover, pharmacokinetic and patientreported outcomes data could be used in the postmarketing setting with an eye toward individual dose adjustment. But to do all this, exposure data are required. The label of an approved drug represents the average response of trial patients, but many factors affect the amount of drug that patients are exposed to. Some oral drugs are affected by taking them with food, and drug metabolism is affected by genetic polymorphisms. Then there are concomitant medications, age, body weight, hepatic and renal function, and comorbidities. Pharmacokinetic data can reveal drug concentrations and lead to estimation of a therapeutic index for individual patients or a defined patient population. The FDA can use these data to assess the need for postmarketing studies.

The panel agreed that randomized dosecomparison studies should be included in phase II, and exposure-response analyses should be part of phase III.

Patient-Reported Outcomes “Physicians are trained to recognize serious side effects and usually capture accurate adverse events, but they tend to underreport effects that they consider merely ‘bothersome,’” said Lori Minasian, MD, Deputy Director, National Cancer Institute (NCI) Division of Cancer Prevention. Nevertheless, “bothersome,” if it lasts long enough, can make a patient stop taking a drug. Toxicities are currently reported using the NCI Common Terminology Criteria for Adverse Events (CTCAE). This is a valuable tool, but clinicians often underreport patient symptoms. In come cases, early patient reports of mildto-moderate events have presaged poor long-term treatment tolerability or an increased risk of severe toxicity. Dr. Minasian noted the often-significant discrepancies between clinician and patient reports of adverse events. She pointed out that in a study looking at reporting of symptoms by patients and their physicians, about a third of the time there is discrepancy, with physicians underreporting the symptom. “Patients’ report of side effects correlates with function and overall health status and may better reflect tolerability over time,” she said. A new tool potentially could be used to capture both physician-observed adverse events and patient-reported outcomes. Dr. Minasian described the PRO-CTCAE instrument as follows: In phase I, it can gauge side effects relative to dose escalation, as well as refine measurement of adverse events. In phase II, it can define toxicity in depth by assessing the tolerability of the recommended dose, and it can identify chronic toxicity. In phase III, it can assess overall risk and benefit for a particular regimen and more deeply evaluate efficacy and tolerability. In phase IV (postmarketing), it can optimize tolerability and tailor regimens for vulnerable populations (older patients and those with comorbidities).

Improving Clinical Outcomes Dose-comparison studies in phase II could improve the design of phase III trials. They also could identify drugs ame-

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Issues in Oncology

nable to dose escalation or reduction. For instance, a comparison trial might indicate that while antitumor responses can be achieved at multiple doses, some patients do not respond at lower doses and some do not tolerate higher ones. If the trial design had adaptations built in, individual dosing could lead to a better, more realistic response rate. For most oncology drugs, the label provides only a starting dose that may need to be modified, but if exposure and tolerability data existed for a range of doses, it would be easier to define a threshold dose as well as peak exposure that correlates with excess toxicity. This also would make it easier to monitor and adjust doses in clinical practice. Targeted therapies are usually taken for a longer time than classical cytotoxics, and their toxicities are different—ie, later onset and more cumula-

tive. For example, a patient has been on a targeted drug for several months with low-grade toxicity. Eventually he or she may reach a point where treatment is no longer tolerable, but if the dose can be lowered, unnecessary discontinuation might be forestalled.

Dose-Comparison Studies Randomized dose-comparison studies prior to registration trials could improve the chance of approval by minimizing the likelihood of excessive toxicity. Moreover, collection of drug exposure and clinical outcomes data in the postmarketing setting could improve understanding of real-world patient experience, as well as identify vulnerable populations. Nevertheless, there are downsides to this design. If approval is in doubt or the drug is on a fast track, dose comparison could be burdensome and take

too long. In the postmarketing arena, patients may be reluctant to be in a trial with an approved drug, so sponsors would have to look for participants outside the United States, where the FDA has limited enforcement powers once a drug has been approved. One solution is for companies to conduct such trials after registration studies are complete but before approval is granted. This window of opportunity may appeal to patients who want access once it becomes known that the drug has met the goals of the registration trials, especially if there is no current standard of care. Drug companies can benefit as well. If they are confident of approval, it would be to their advantage to determine whether a lower dose would decrease efficacy at an early endpoint such as response rate. But if a lower dose

works as well as a higher one, patients could stay on the drug longer, and it’s possible that the drug would increase the company’s competitiveness. In short, said Dr. Schilsky, knowing more about tolerable dosing regimens would benefit everyone: The FDA would have more information to guide the approval process, clinicians would know more about optimal dosing and have more choices, and patients would be more likely to tolerate their treatment. n

Disclosure: Dr. Schilsky is Chief Medical Officer, ASCO. Dr. Pazdur is FDA’s Director of the Office of Hematology and Oncology Products. Drs. Rahman and Minasian reported no potential conflicts of interest.

Reference 1. 2013 Friends-Brookings Conference on Clinical Cancer Research. Session Three: Optimizing Dosing of Oncology Drugs. Presented November 7, 2013.

American Association for Advancement of Science Elects New Fellows

he American Association for the Advancement of Science (AAAS) has identified 388 individuals who have been named AAAS Fellows. These individuals have been recognized by their peers for their efforts to advance science or its applications. The new AAAS Fellows, whose names were published in the November 29, 2013 issue of Science, will be honored at the AAAS Fellows Forum on February 15, 2014, during the AAAS Annual Meeting in Chicago. AAAS members who have made scientifically or socially distinguished efforts to advance science or its applications and who have been continuous members for the 4 years preceding their nomination are eligible for election as AAAS Fellows. Three current AAAS members who were previously elected AAAS Fellows may nominate new AAAS Fellows, though only one of the three sponsors may share the nominee’s affiliated institution and each AAAS Fellow may sponsor no more than two nominees each year. Fellows may also be nominated by the steering group of one of the 24 sections of AAAS or the chief executive officer. The Fellows are elected by the AAAS Council from a list of approved nominees submitted by the section steering committees. Among the individuals named to one of 24 sections of AAAS are 42 who were named AAAS Fellows in the Sec-

tion on Medical Sciences. These individuals are listed below.

2013 AAAS Fellows to the Section on Medical Sciences • Michael Andreeff, The University University of Texas MD Anderson Cancer Center • Carlos L. Arteaga, Vanderbilt University School of Medicine • Robert Daniel Beauchamp, Vanderbilt University School of Medicine • Donald M. Bers, University of California, Davis • James B. Bliska, Stony Brook University, SUNY • Marc G. Caron, Duke University Medical Center • John M. Coffin, Tufts University School of Medicine • Timothy L. Cover, Vanderbilt University School of Medicine • Robin L. Davisson, Cornell University College of Veterinary Medicine/Weill Cornell Medical College • George S. Deepe Jr., University of Cincinnati College of Medicine • Ethan Dmitrovsky, The University of Texas MD Anderson Cancer Center • Robert W. Doms, University of Pennsylvania Perelman School of Medicine • Ferric C. Fang, University of Wash-

• • • •

• • • • • • • • • •

ington School of Medicine Toren Finkel, NIH/National Heart, Lung and Blood Institute Walter R. Frontera Roura, Vanderbilt University School of Medicine Frank Davis Gilliland, Keck School of Medicine of the University of Southern California James Richard Goldenring, Vanderbilt University School of Medicine/Nashville VA Medical Center Sandra Lee Hofmann, The University of Texas Southwestern Medical Center Michael J. Holtzman, Washington University School of Medicine in St. Louis Michael B. Kastan, Duke University Karl D. Kieburtz, University of Rochester School of Medicine & Dentistry Robert J. Lefkowitz, Duke University Medical Center MacRae Fort Linton, Vanderbilt University School of Medicine Fu-Tong Liu, Academia Sinica (Taiwan)/University of California, Davis Kevin C. Kent Lloyd, University of California, Davis SchoolofMedicine Mark Alan Magnuson, Vanderbilt University School of Medicine Rob McConnell, Keck School of Medicine of the University of Southern California

• Paul B. McCray Jr., University of Iowa Carver College of Medicine • Frederick J. Meyers, University of California, Davis School of Medicine • Charles Emerson Murry, University of Washington • M. Bishr Omary, University of Michigan Medical School • Heloise Anne Pereira, University of Oklahoma Health Sciences Center • Edward F. Plow, Cleveland Clinic • David Robertson, Vanderbilt University School of Medicine • Diane M. Robins, University of Michigan Medical School • Marc Elliot Rothenberg, University of Cincinnati College of Medicine/Cincinnati Children’s Hospital • Samuel A. Santoro, Vanderbilt University School of Medicine • Timothy Alan Springer, Boston Children’s Hospital/Harvard Medical School • John L. Sullivan, University of Massachusetts Medical School • Luke I. Szweda, Oklahoma Medical Research Foundation • Joel E. Tepper, University of North Carolina at Chapel Hill • David M. Virshup, Duke-NUS Graduate Medical School (Singapore) For a comprehensive list of all 2013 AAAS Fellows, visit www.AAAS.org. n

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR)

100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20% 0%

ORR 7.4% (n=8) POMALYST (N=108)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST + low-dose dex (N=113)

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

Study design: A Phase II, multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception POMALYST is available only through a restricted program called the POMALYST REMS program. VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and 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 a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious

adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported

Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age

were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

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FDA Approves Sorafenib to Treat Late-Stage Differentiated Thyroid Cancer

he U.S. Food and Drug Administration recently expanded the approved uses of sorafenib (Nexavar) to treat late-stage differentiated thyroid cancer. The new indication is for patients with locally recurrent or metastatic, progressive differentiated thyroid

cancer that no longer responds to radioactive iodine treatment. “Differentiated thyroid cancer can be challenging to treat, especially when unresponsive to conventional therapies,” said Richard Pazdur, MD, Director of the Office of Hematology

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “[The recent] approval demonstrates the FDA’s commitment to expediting the availability of treatment options for patients with difficult-totreat diseases.”

Toxicity

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

Clinical Trial Results The safety and effectiveness of sorafenib were established in a clinical study involving 417 participants with locally recurrent or metastatic, progressive differentiated thyroid cancer that does not respond to radioactive iodine

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-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 POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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treatment. Treatment with sorafenib resulted 41% reduction in the risk of disease progression or death. The median progression-free survival was 10.8 months in patients treated with sorafenib, compared to 5.8 months in patients receiving placebo. The most common side effects in patients treated with sorafenib were

• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains,

(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

and hypertension. Thyroid-stimulating hormone, a potential promoter of thyroid cancer, is more likely to become elevated while on treatment with sorafenib, requiring adjustment of thyroid hormone replacement therapy. The FDA completed its review of sorafenib’s new indication under its

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

priority review program. Sorafenib also received orphan-product designation by the FDA because it is intended to treat a rare disease or condition. The FDA approved sorafenib to treat advanced kidney cancer in 2005. In 2007, the agency expanded the drug’s label to treat liver cancer that cannot be surgically removed. n

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FDA Update

FDA Grants Regular Approval to Crizotinib for ALK-Positive NSCLC

he U.S. Food and Drug Administration (FDA) has granted regular approval for crizotinib (Xalkori) for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive

8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. 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 POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

as detected by an FDA-approved test. The approval was based on demonstration of superior progressionfree survival and overall response rate for crizotinib-treated patients compared to chemotherapy in patients with ALK-positive NSCLC

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

with disease progression after platinum-based doublet chemotherapy. Crizotinib was previously granted accelerated approval in August 2011 based on durable objective response rates of 50% and 61% in two singlearm, open-label studies.

Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

Prolonged Progression-Free Survival An open-label, active-controlled, multinational, randomized trial enrolled 347 patients with ALK-positive, metastatic NSCLC. Patients were required to have progressed following platinumbased chemotherapy and to have ALK expression in tumor specimens detected by fluorescence in situhybridization on central laboratory testing. Patients were randomly assigned to receive either crizotinib at 250 mg orally twice daily (n = 173) or chemotherapy (n = 174). Patients randomly assigned to chemotherapy received pemetrexed (Alimta) (58%) or docetaxel (42%) if

they had received prior pemetrexed. Approximately 64% of patients on the chemotherapy arm subsequently received crizotinib. The trial demonstrated significantly prolonged progression-free survival for crizotinib treatment compared to chemotherapy (hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.37– 0.64, P < .0001). Median progressionfree survival was 7.7 and 3.0 months on the crizotinib and chemotherapy arms, respectively. The overall response rate was significantly higher for the crizotinib arm (65% vs 20%) with median response durations of 7.4 and 5.6 months in the crizotinib and chemotherapy arms, respectively. No difference in overall survival was noted between the two arms (HR= 1.02, 95% CI = 0.68–1.54) in a planned interim analysis.

Adverse Reactions Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 25% or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. Safety data from this trial were evaluated in 172 crizotinib-treated patients. Serious adverse events were reported in 37% of crizotinib-treated patients. The most common serious adverse reactions to crizotinib were pneumonia, pulmonary embolism, dyspnea, and interstitial lung disease. Fatal adverse reactions occurred in nine crizotinibtreated patients. n

ASCOPost.com | DECEMBER 15, 2013

PAGE 63

JOP Spotlight Health-Care Policy

Patient-Reported Outcomes, a Central Component to Value and Rapid-Learning Systems By Ronald Piana

ith the passage of the Patient Protection and Affordable Care Act in 2010, value became the operative word in assessing the success of health care, from outcomes to cost. To drive more value, the Affordable Care Act seeks to implement initiatives such as comparative effectiveness research that will inform system-wide health-care decisions by providing evidence on the effectiveness, benefits, and harms of different treatment options. While comparative effectiveness research might be a relatively new concept on the macro health-care landscape, the oncology community has long been engaged in introspective methods of deriving more value out of care.

Capturing Quality Data The concept of a rapid-learning system, which provides a continuous cycle of learning by capturing evidence-based guidelines and creating insights through analysis of data from every patient experience is gaining traction in oncology organizations. ASCO, for one, is committed to making a health information– driven rapid-learning system a reality. One of the keys to establishing a rapidlearning system is capturing the bidirectional information exchanges among patients and providers. Naturally, the ultimate aim is to encourage patients to provide information that can be used to inform shared decision-making, which leads to timely interventions and improved patient outcomes. To that end, there is growing interest in the systematic collection of patient-reported outcomes, which can directly contribute to the larger scheme of developing a rapid-learning healthcare model. Research has shown that collecting and using patient-reported outcomes in oncology can identify issues of concern to patients and improve communication and outcomes. Although there is growing interest in incorporating routine patient-reported outcomes into clinical practice, there are few data that capture how oncologists view the use of patientreported outcomes in daily clinical practice. A recent study published in the Journal of Oncology Practice ( JOP) shed light on this important issue.1

In the JOP study, Reshma Jagsi, MD, DPhil, Associate Professor in the Department of Radiation Oncology at the University of Michigan Health System, Ann Arbor, and colleagues used the Quality Oncology Practice Initiative (QOPI) and a minority-based Community Clinical Oncology Program (MBCCOP) to identify potential interview candidates. The researchers conducted 45-minute semistructured interviews of practicing oncologists to identify the critical features that ensure ease of collection of patient-reported outcomes in a busy oncology practice.

tured fairly accurately by the following response: “Something like this would clearly improve … the quality of care of our patients because I think a lot of times in our hectic and busy day, a lot of these things slip through the cracks.”

Common Concerns Although most of the participants saw benefits in adopting patient-reported outcomes, many of the respondents shared concerns about the effects of receiving an excessive amount of information. Another major concern, not surprisingly, was cost of im-

The time is right to begin pilot testing such measures with community oncologists so they can lend their expertise to national discussions on which measures to use and how best to use them. —Reshma Jagsi, MD, DPhil, and colleagues

For the study, the investigators identified a diverse group of physicians identified through their affiliation with MB-CCOPs or QOPI. They ultimately conducted and thematically coded transcripts of interviews with 17 of these physicians for their qualitative analysis. The interview participants came from both academic and community practices around the country.

Value of Patient-Reported Outcomes At the onset of the study, there was varied ability to define a patientreported outcome among the participants. To ensure consistent interpretations, the authors gave clear definitions prior to continuing the interviews. Many of the participants said that implementing patient-reported outcomes improved the quality and thoroughness of their patient interactions. Several benefits perceived by the participants included increased efficiency and better accuracy in identifying patient concerns prior to the office visit. The authors concluded that the consensus among doctors could be cap-

plementation and the impact on clinic flow and efficiency. The following statements captured these concerns about information overload and costs: • “If somebody came in and filled out an entire review of systems, it would … be a little bit overwhelming in terms of trying to deal with all the symptoms they may check off.” • “The number-one thing is that the burden to the practice in terms of implementing—whether that’s financial, technical, or personnel—is not too onerous that it becomes problematic.” Another concern was about how the information would be used, given the potential to penalize providers by divulging measures of patient satisfaction that were negative. “If this is a tool that we will eventually make public in any fashion, you will have a lot of resistance … if you are sincere about improving care, you don’t put it out in the public domain,” said one participant.

Results and Conclusions The authors concluded that their study complemented other work in

this area, which have all suggested that, in general, physicians and patients have a positive view on the feasibility and worth of patient-reported outcomes. Most participants saw an improvement in efficiency and quality of patient encounters when using patient-reported outcomes. In particular, community oncologists noted the value of patient-reported outcomes in adding more ability to identify, track, and document their patients’ most important symptoms, which has the added value of helping providers prevent underreported symptoms that lead to unnecessary procedures. The main concerns expressed by participants were the costs and feasibility of implementation and the potential information overload that could hamper the efficiencies of a busy community practice. However, the participant responses indicated that most community oncologists felt that the potential benefits of implementing patient-reported outcomes greatly outweighed the concerns over cost and workflow issues. The authors also observed that quality assessment measures like patient-reported outcomes are part of oncology’s future, so it behooves them to keep ahead of the curve. Given the general acceptance and enthusiasm among physicians and patients, the authors concluded, “The time is right to begin pilot testing such measures with community oncologists so they can lend their expertise to national discussions on which measures to use and how best to use them.” This added knowledge on how to harvest patient-related data will serve the greater goal of making the dream of a rapid-learning system a reality in the clinical oncology care model. n

Disclosure: Dr. Jagsi reported no potential conflicts of interest. For full disclosures of the study authors, visit jop.ascopubs.org.

Reference 1. Jagsi R, Chiang A, Polite BN, et al: Qualitative analysis of practicing oncologists’ attitudes and experiences regarding collection of patient-reported outcomes. J Oncol Pract. August 6, 2013 (early release online).

The ASCO Post | DECEMBER 15, 2013

PAGE 64

Health-Care Policy Issues in Oncology

National Cancer Policy Summit: Setting Priorities for the Next 3 Years By Margot J. Fromer

“W

elcome to the meeting we hold every 3 years to choose our next projects,” said John Mendelsohn, MD, Chair of the National Cancer Policy Forum and Director of the Khalifa Institute for Personalized Cancer Therapy at The University of Texas M.D. Anderson Cancer Center, Houston.

John Mendelsohn, MD

“We have here a roomful of thought leaders in cancer research and care— the best audience to identify our most pressing policy issues, and I look forward to hearing what you think are those with the highest priority—that have opportunities for action,” he said at the Institute of Medicine’s 2013 National Cancer Policy Summit, held recently in Washington, DC.

Basic and Translational Research “Today’s cancer scientists must train replicas of themselves for the future,” said William G. Kaelin, Jr, MD, Professor of Medicine, Dana-Farber Cancer Institute, Boston. To that end, he suggested three critical needs: basic discovery in the public sector that complements private applied research, a

Andrea Califano, PhD

sustainable model for scientific training and research funding, and exchange of information and reagents in the public and private sectors. In other words, he summarized, continue current efforts and make sure there’s money to keep it going. Andrea Califano, PhD, Clyde and Helen Wu Professor of Chemical and

Today’s cancer scientists must train replicas of themselves for the future. —William G. Kaelin, Jr, MD

I worry that investigational drug safety is rarely discussed and that there is a dearth of safety data from single-arm trials. We have to be more concerned about the harms these drugs can potentially do to patients.

• Proof-of-mechanism trials, based on preclinical models that incorporate specific individualized data at treatment initiation as well as at disease progression • Collaboration that applies new models to drug development Richard Pazdur, MD, Director of the U.S. Food and Drug Administration (FDA) Office of Hematology and Oncology Products, noted that because cancer drugs are more effective than ever, we need to rethink clinical

—Richard Pazdur, MD James H. Doroshow, MD

Systems Biology, Columbia University, New York, talked about what he sees as the difference between traditional approaches to precision medicine and a systems biology approach. In the former, he said, predictions are based on statistical associations, whereas in the latter, predictions are based on a physical regulatory model. “Switching from one to the other requires significant change.” He noted that there are now 500 phase III clinical trials underway in the United States. “This provides an untapped opportunity for precision medicine because it makes patient data broadly available to the research community; it allows blind, prospective prediction of responders vs nonresponders; and it is an evaluative tool when the study closes.” He also believes that trials should be started earlier. “Patients may be too sick by the time they have access to experimental therapy.” Spyro Mousses, PhD, Director of Pharmaceutical Genomics at TGen, Phoenix, noted that open biomedical knowledge and private patient data can be combined to form a systems oncology clearinghouse to form an evolving network of knowledge with links to drugs and patients’ genomic data, thus creating matches via evolving multiscalar models. He posed three provocative questions. First, should personalized medicine and clinical drug development be

regulated differently, or are they “flip sides of the same coin”? Second, how do we refine policies that limit how genomic data are interpreted to inform clinical decisions? Third, how do we reconcile evidence-based medicine when there

Spyro Mousses, PhD

is only one patient in a clinical trial (N=1)? Specifically, how do we incorporate mechanistic knowledge from genomic medicine to justify individual treatment decisions?

Diagnostics and Therapeutic Development James H. Doroshow, MD, NCI Deputy Director for Clinical and Translational Research, Bethesda, Maryland, said that in order to optimize patient-centric models of cancer research, we need to change the preclinical paradigm to: • One with individual predictive therapeutic models using systems derived from molecularly characterized tumor biopsies or circulating DNA

trials. For example, instead of assuming that a randomized controlled trial is the best—or the only—way to demonstrate safety and efficacy, we need to rethink the way we do things and ask whether or not a randomized trial is needed or even ethical to conduct. “Is a randomized trial appropriate at all when the control group is at a clear disadvantage at the outset and will likely cross over to the investigational arm to obtain the drug they believe is more effective from the start? Equipose may be lost from the onset,” he stated. To expedite drug development when similar drugs are being developed for an indication, he suggested a study design in which several investigational drugs are compared at the same time to an alreadyapproved common control. The investigational drugs would not necessarily be in competition with one another, and more than one could “win.” “I also worry that investigational drug safety is rarely discussed and that there is a dearth of safety data we obtain from single-arm trials. We do not have comparative safety data when we rely on a single arm trial to determine safety and efficacy. We have to be more concerned about the harms these drugs are doing to patients, regardless of how effective they are and how life-threatening the disease,” said Dr. Pazdur. continued on page 66

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The ASCO Post | DECEMBER 15, 2013

PAGE 66

Health-Care Policy

National Cancer Policy Summit continued from page 64

New Paradigms

Razelle Kurzrock, MD, Murray Professor of Medicine, UC San Diego Moores Cancer Center, asked one of the most disconcerting questions of the day: What if every patient with metastatic disease is genomically

acquired or repurposed, and there are greater regulatory burdens. “Despite this, we need new paradigms: N=1 strategies, drug trials that take place earlier in the course of a disease, and more customized drug combinations.”

Drug Development Strategies Mace Rothenberg, MD, Senior Vice President for Clinical Development and

We need to find an ethical way to combine systems biology and social data with clinical care and outcomes from providers. —Warren A. Kibbe, PhD

In the model we use now, patients are not selected by molecular characteristics, and this results in a poor likelihood of efficacy because many of them do not have the molecular defect in question. —Razelle Kurzrock, MD

unique? If this were true, trial design would have to be turned on its head. “In the model we use now, patients are not selected by molecular characteristics, and this results in a poor likelihood of efficacy because many of them do not have the molecular defect in question.” If most (or all) patients require a specially tailored treatment regimen, the current clinical trial endeavor is almost impossible. Given an estimate of at least 300 current oncology drugs (that are either approved or in advanced testing), said Dr. Kurzrock, there are 45,000 two-drug combinations and 4,455,100 three-drug combinations. This means 1,000 years of trial and error to figure out what would work for a particular patient. A new model uses smaller trials where all patients have the relevant mutation or genetic defect, leading to a greater chance of success. “In phase II, for instance, we could use multiplex markers to diagnose and classify cancers, validate a specific strategy, and understand convergence pathways.” There are problems with this model, though. Drugs may not be easily

Medical Affairs, Pfizer Oncology, New York, addressed four provocative questions. First, how can we integrate genomics and other platform diagnostics into drug development strategies that will meet regulatory requirements for companion diagnostics? His response was that the era of “one-off ” diagnostics is over for certain diseases where multiple driver or actionable mutations are identified. Moreover, there is a limited amount of tissue for stand-alone diagnostics. But even if genomics and similar platforms provide sufficient accuracy, consistency, reliability, and reproducibility, regulatory agencies may not accept single-analyte results. Second, can the results of minimally invasive diagnostic tests be used to expedite drug development and inform

Mace Rothenberg, MD

therapeutic decisions? Dr. Rothenberg said that technology is improving rapidly for detection and analysis of circulating tumor cells, and we know that enumeration of and change in circulating tumor cells are useful prognostic and predictive tools. But can we take the next step and evaluate the relationship between molecular characteristics of circulating tumor cells and development of clinical resistance? Third, how can we make the greatest use of N=1 studies? This question led to others: What threshold of evidence should qualify a biomarker for patient selection? When are single genetic abnormalities sufficient? What threshold of activity should we expect in biomarker-selected cohorts? And how can we learn from failed N=1 studies? Dr. Rothenberg urged the group to consider these questions as it settled on priorities. Fourth, is it possible to define a preferred sequence or hierarchy of therapies for a specific disease? For instance, a drug with a longer progression-free survival in first-line therapy but which confers cross-resistance to other drugs may not be preferable over a drug with a shorter progression-free survival, which can then be followed by second- and third-line drugs that, taken together, result in a longer progression-free survival, overall.

Keynote Speech In his keynote presentation, Warren A. Kibbe, PhD, Director, NCI Center for Biomedical Informatics and Information Technology, Rockville, Maryland, offered three policy issues: • Does informed consent enable research? Is there a role for standardized consent, and can translational research be undertaken without it? • Identification of specimens and data— any tissue will be rapidly identifiable, and sequence is like a fingerprint. What is privacy? If patients would like to see their specimens and data available for research and discovery, how do we enable that? • Open access to data—how can we promote the desire of patients to enable the open access to specimens and data to make truly transformative inferences and observations? Consent is a process, and how can we give patients better control over their consent decision on an ongoing basis? What does that mean for data and specimens that have already been released. How do we incorporate this into standardized consent and open science discussions? He noted that social media could mea-

sure and explain attitudes and behavior in a population, perhaps enabling better risk estimates. “Social media are a big data opportunity, but what are the ethics of using them for research? People say they want more data sharing, but using data in a way that translates into health statistics and personal information changes the paradigm. To put that in cancer terms, we need to find an ethical way to combine systems biology and social data with clinical care and outcomes from providers.” The future, said Dr. Kibbe, may reside in elastic computing clouds, that is, social networks and big data analytics to produce semantic and synoptic data that can result in precision medicine, accurate health measurement, and protective medicine—intervention before health is compromised.

Evidence Generation and Delivery of Care Mark B. McClellan, MD, PhD, Senior Fellow and Director of the Initiative on Value and Innovation in Health Care, Brookings Institution, Washington, DC, made the future seem somewhat uncertain. There will be more federal budget legislation, as well as changes in Medicare physician payments and possible continued sequestration. Despite current glitches in the Affordable Care Act, there will be new coverage in 2014, including insurance market reforms and Medicaid expansion. “The traditional approach to paying for health care,” said Dr. McClellan, “is to squeeze payment rates, reduce cost per service, shift costs, and increase volume and intensity. An alternative is to identify

Mark B. McClellan, MD, PhD

ways to reduce overall costs while improving outcomes and to reform financing to support reform—with accountability for better results and lower costs.” In oncology, treatment pathways must be based on guidelines that use clinical evidence and expert opinion, he noted. Off-pathway care, including some costly chemotherapy, may not be reimbursed. Future oncology reforms include patient-centered medical homes, bundled payments, and accountable care organizations.

ASCOPost.com | DECEMBER 15, 2013

PAGE 67

Health-Care Policy

We need a new model of survivorship care. We must create well survivors, and that entails working closely with them to prevent or control comorbidities as well as the chronic effects of treatment. But most especially, we need to promote healthy behaviors. —Catherine M. Alfano, PhD

We desperately need to recommit our focus on prevention of disease. Thirty percent or more of cancers are due to tobacco, and a substantial proportion are now related to obesity, high caloric intake, and lack of physical activity. —Otis W. Brawley, MD

Cancer Control and Prevention “By 2016, there will be 16 million cancer survivors in the United States, most of them over age 65,” said Catherine M. Alfano, PhD, Deputy Director, NCI Office of Cancer Survivorship, Bethesda, Maryland. Adult survivors are at risk for a host of chronic and late effects of cancer, primarily recurrence and/or new cancers, obesity, diabetes, osteoporosis, cerebrovascular disease, and various functional limitations. Among 10,397 survivors of childhood cancer, 73% had at least one chronic health condition, 42% of which were severe or life-threatening, and 39% had two or more chronic conditions. Overall, survivors of childhood cancer are 8.2 times more likely than their siblings to have a severe or life-threatening condition. “We need a new model of survivorship care,” said Dr. Alfano. “We must create well survivors, and that entails working closely with them to prevent or control comorbidities as well as the chronic effects of treatment. But most especially, we need to promote healthy behaviors.” Otis W. Brawley, MD, Chief Medical Officer, American Cancer Society, Atlanta, said, “We desperately need to recommit our focus on prevention of disease. Thirty percent or more of cancers are due to tobacco, and a substantial proportion are now related to obesity, high caloric intake, and lack of physical activity. These problems are formidable and best overcome by education.” He added that a substantial number

of people—the uninsured, underinsured, and those who don’t know how to work the system—have poor access to care. There is also a fear of—and misunderstanding about—rationing. “At the American Cancer Society, we see a lot of irrational use of health care. This overand underutilization of appropriate care must be addressed in order to make the system more efficient,” he said. Jeffrey Levi, PhD, Executive Director, Trust for America’s Health, Washington, DC, agreed and urged financial incentives that hold health systems accountable for outcomes. “Few doubt the effect of lifestyle on cancer prevention

Jeffrey Levi, PhD

and recurrence, and there is growing evidence that lifestyle changes require a partnership between clinical efforts and the community,” he said. “Many cancer survivors die of competing causes, not cancer itself,” he added, using obesity as an example. By 2030, there will be more than 6 million new cases of type 2 diabetes, 5 million cases of coronary heart disease, and 400,000 obesity-related cancers. But, in Wisconsin alone for instance, if [body mass index] is reduced by only 5%, about

75,000 cases of diabetes can be averted (with a cost savings of a billion and a half dollars), 60,000 cases of coronary heart disease can be prevented ($2 billion saved), and 90,000 cases of obesity-related cancer can be avoided ($75 million). “Although intervention is critical to change lifestyle, so are systems, policy, and community changes,” said Dr. Levi. He listed three important opportunities: prevention and public health funding support for community grants, financial incentives that hold systems accountable for outcomes, and public health programs that promote lifestyle change.

Affordability and Models of Payment “Out of control” now describes the cost of cancer care, said Lowell E. Schnipper, MD, Clinical Director, Beth Israel Deaconess Cancer Center, Boston. “People with cancer go bankrupt more than 2.65 times as often as others,” he continued. (Lee N. Newcomer, MD, MHA, Senior Vice President, UnitedHealthcare, Minneapolis, added that by 2016, 50% of all household income will be used to pay

Lowell E. Schnipper, MD

for health insurance premiums and outof-pocket medical expenses.) Once a patient goes bankrupt, it is often impossible to get back on one’s feet, in which case purchasing cancer care is out of the question. Cancer is the most expensive disease, Dr. Schnipper commented. A price tag of $100,000 or more is now commonplace for one course of treatment—surely out of the reach of the uninsured and underinsured. Even the well insured may soon be priced out of care, he said. Blame for this situation is often placed on pharmaceutical companies, but they are not the only culprits, Dr. Schnipper pointed out. Generic cancer drugs are not readily available, off-label use of targeted drugs is rarely reimbursed, much oncology care is not reimbursed, multidisciplinary care is highly touted but not yet the norm, there is little incentive to avoid redundancy, and accountable care organizations, although beneficial in principle, are neither commonplace nor efficient.

Moreover, said Dr. Schnipper, “Physicians have not exerted sufficient leadership in bending the cost curve. They could do much more to reduce the cost of cancer care by providing equally effective cheaper alternatives; they could

Lee N. Newcomer, MD, MHA

eschew care that has no benefit, or unclear or marginal benefit; they could not use treatments that patients don’t want; and they could avoid duplicated tests and services.” He added that there are ways to exert cost controls, but in order to achieve them, we must establish a system that defines and rewards high-quality care by: • Establishing better ways to reimburse providers for time spent with patients • Allowing the Centers for Medicare & Medicaid Services to negotiate prices for antineoplastic and other agents, as well as payment for off-label use of targeted therapies • Pricing drugs to reward innovation, uniqueness, and clinical impact • Using cancer therapy that carries only a high level of evidence • Avoiding surveillance that carries little or no benefit, such as PSA screening in men with low mortality risk and tumor marker testing after curative breast cancer treatment n Disclosures: William G. Kaelin, Jr, MD, owns equity in, and consults for, Agios, Fibrogen, Lilly, Nextech, Peloton, and Tracon. John Mendelsohn, MD, has received royalty income from the University of California, San Diego, which owns the patent on Erbitux. Mark B. McClellan, MD, PhD, has received for remuneration for emploment with Brookings Institution, Washington Speakers Bureau. Mace Rothenberg, MD, is Senior Vice President of Clinical Development and Medical Affairs for the Oncology Business Unit at Pfizer. Otis W. Brawley, MD, is Chief Medical Officer, of the American Cancer Society. Lee N. Newcomer, MD, MHA, is Senior Vice President, Oncology, Genetics and Women’s Health, UnitedHealthcare, and owns stock in UnitedHealthcare. Lowell E. Schnipper, MD, has served in a leadership or employment role for Up to Date and as a consultant for evite. No potential conflicts of interest were reported by Drs. Pazdur, Alfano, Califano, Mousses, Levi, Doroshow, Kibbe, and Kurzrock.

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Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1282b 09/13

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

Patients (%)

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus kinase.

• Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

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Dermatologic Events in Oncology How to Measure the Impact of Dermatologic and Mucosal Adverse Events on Symptom Burden and Quality of Life By Christine B. Boers-Doets, RN, MSc

argeted anticancer therapies like epidermal growth factor receptor (EGFR) inhibitors, multitargeted

tyrosine kinase inhibitors (mTKIs), and mammalian target of rapamycin (mTOR) inhibitors frequently result in

dermatologic adverse events and mucosal adverse events, or, taken together, mucocutaneous adverse events.

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pretreatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting therapy with Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions]. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discontinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse All All a Grade 3 Grade 4 Grades Grade 3 Grade 4 Reactions Grades (%) (%) (%) (%) (%) (%) Bruisingb 23.2 0.6 0 14.6 0 0 Dizzinessc 18.1 0.6 0 7.3 0 0 Headache 14.8 0 0 5.3 0 0 Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 Weight Gaine 7.1 0.6 0 1.3 0.7 0 Flatulence 5.2 0 0 0.7 0 0 Herpes Zosterf 1.9 0 0 0.7 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Grade 4 (%) 0 3.3 1.3

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

Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Jakafi is a registered trademark of Incyte Corporation. All rights reserved. U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved. Issued: June 2013 RUX-1216

Christine B. Boers-Doets, RN, MSc

Mucocutaneous adverse events, including acneiform rash, xerosis, pruritus, paronychia, hand-foot skin reaction, stomatitis, and hair changes, occur in the majority of patients. Distinct mucocutaneous adverse events can be present with a variable symptom burden and affect patients’ quality of life, leading to undesirable dose modifications (Figs. 1 and 2).

Accurate Assessment An accurate assessment of the morbidity of the toxicity may allow for informed decisions on dose modifications and discontinuation, which may affect clinical outcome. Currently, decisions about dose modifications due to dermatologic adverse events are based on clinician assessment utilizing the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) grading system. Despite its widespread use and its utility, the CTCAE has not been validated. Existing evidence suggests that clinicians and patients may differ in their assessments of the severity of toxicities. Ideally, a grading system that captures both patient and clinician assessments would be more appropriate. Various dermatologic adverse event–specific assessment tools are currently under development. At present, several questionnaires are available for use in the cancer population, including instruments for evaluating symptom burden, quality of life, general skin and hair diseases, hand-foot Ms. Boers-Doets is a researcher and a PhD candidate in the Department of Clinical Oncology at Leiden University Medical Center, Leiden, The Netherlands. She is a registered nurse and Master of Science in Nursing with a special interest in mucocutaneous conditions that result from targeted anticancer treatments. She is a member of the Board of Directors of the International Society of Oral Oncology.

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Dermatologic Events in Oncology skin reaction, and stomatitis. Notably, the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) system provides a Web-based platform to collect patient reports of symptoms they are experiencing while undergoing treatment, for the purpose of enhancing adverse event reporting.1

DERETT Mucocutaneous adverse events can be assessed using the patient-completed mucocutaneous adverse events–specific symptom experience diary for targeted therapies (DERETT, for DErmatologic REaction Targeted Therapy–Patient Symptom Experience Diary). DERETT was created to effectively assess dermatologic adverse events and effectiveness of supportive care interventions. This tool gathers information such as area involved, severity and duration of symptoms, products used to address symptoms, effectiveness of medical interventions, treatment adherence, and symptom-related distress. DERETT provides more relevant and precise information on the patient’s experience than would be provided by CTCAE grading alone.2

mains: symptoms, functioning, and emotions on a 0-to-5 numerical analog scale.5

GUEST EDITOR

HFS-14 The Hand-Foot Syndrome 14 (HFS14) is a quality-of-life scale for patients experiencing chemotherapy-associated hand-foot syndrome and targeted therapy–associated hand-foot skin reaction. This instrument measures its severity and its impact on patients. It addresses the body parts affected (hand, foot, or both), symptoms, and social impact. The 14 items on the questionnaire are organized into two modules, differentiated by the involvement of foot-specific or hand-specific events. Validation of the HFS-14 confirmed its internal consistency and very high reproducibility.6

mIAS Scale mTOR inhibitor–associated stomatitis (mIAS) is a dose-limiting toxicity of mTOR inhibitors. The mIAS scale has a subjective component measuring pain and an objective component measuring duration of lesions. The subjective grading criteria can be assessed on a 0-to-3

Mario E. Lacouture, MD

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, an Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan-Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments.

numerical analog scale. The objective grading criteria range from 0 for no visible lesion to 3 for lesion(s) persisting for more than 7 days. It is suggested that dose-modification be considered only when both subjective and objective scales are assessed as grade 3, representing persistent lesions with significant pain, despite antitoxicity interventions.2

Conclusion In summary, patient-reported tools to measure the impact of dermatologic and mucosal adverse events on quality of

FACT-EGFRI-18 The impact of EGFR inhibitor–associated mucocutaneous adverse events on quality of life can be evaluated with the Functional Assessment of Cancer Therapy Epidermal Growth Factor Receptor Inhibitor 18 (FACT-EGFRI-18) scale.3 The FACT-EGFRI-18 is a dermatology-specific patient-reported outcomes questionnaire, consisting of 18 items encompassing well-being in three qualityof-life domains: symptoms, functioning, and emotions. The questionnaire is based on items from dermatologic quality-oflife instruments such as the Skindex (see below).4

Fig. 1: Patient developed a grade 1 lapatinib-associated acneiform rash. He reported a very low quality of life and requested discontinuation of the therapy because of this rash.

Skindex-16 and Hair Specific Skindex-29 Skindex-16 is a validated patient-completed disease-specific outcome measure with a 0-to-6 numerical analog scale. The measure is reliable and valid for general skin diseases. It assesses how bothered patients were by skin problems (eg, itching, burning, hurting) in the previous week. It consists of 16 items encompassing wellbeing in three quality-of-life domains: symptoms, functioning, and emotions. The Hair Specific Skindex-29 scale is used to assess the quality of life of patients with androgenetic alopecia. This questionnaire consists of three scale do-

Fig. 2: Patient developed a grade 2 everolimus-associated stomatitis (according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0) and experienced a low quality of life.

life, along with clinician grading, can provide optimal assessments in order to ensure appropriate antitoxicity interventions, consistent dosing of antineoplastic therapy, and maintenance of quality of life. To view each of the tools discussed in this report, visit http://bit.ly/1eWEvHk or see the URLs provided with each reference. You may also access these using the QR code on this page. n Disclosure: Ms. Boers-Doets is a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, and Roche.

References 1. National Cancer Institute: PatientReported Outcomes version of the CTCAE. NCI Wiki. Available at https:// w i k i . n c i . n i h . g o v / p a g e s / v i e w p a g e. action?pageId=10857328. Accessed October 23, 2013. 2. Foundation TARGET-RCI: Research. Available at www.targetrci.com/research. Accessed October 24, 2013. 3. Boers-Doets CB, Gelderblom H, Lacouture ME, et al: Experiences with the FACT-EGFRI-18 instrument in EGFRI-associated mucocutaneous adverse events. Support Care Cancer 21:1919-1926, 2013. 4. MAPI Research Trust: SKINDEX questionnaire: 16- and 29-item versions. Available at http://www.mapi-trust.org/ services/questionnairelicensing/catalogquestionnaires/299-skindex. Accessed October 23, 2013. 5. Han S-H, Byun J-W, Lee W-S, et al: Quality of life assessment in male patients with androgenetic alopecia: Result of a prospective, multicenter study. Ann Dermatol 24:311-318, 2012. 6. Sibaud V, Dalenc F, Chevreau C, et al: HFS-14, a specific quality of life scale developed for patients suffering from hand– foot syndrome. Oncologist 16:1469-1478, 2011.

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10th International SIO Conference Highlights From the 10th International Conference of the Society for Integrative Oncology By Jo Cavallo

he 10th International Conference of the Society for Integrative Oncology (SIO) was held recently in Vancouver, British Columbia, Canada, and attracted over 300 oncologists and internal medicine physicians, researchers, nurses, integrative medicine practitioners, cancer survivors, and patient advocates from 16 countries. The theme of this year’s conference was Translational Science in Integrative Oncology: From Bedside to Bench to Best Practices and featured presentations on cancer prevention and survivorship, mind-body interventions for stress reduction, the use of cannabis in the management of treatment side effects, chemoprevention through natural health products, and advances in nutrition therapy. Over 130 abstracts were presented at the conference.

Growing Interest “We had a record number of abstracts submitted this year, and I think that represents a growing interest in the field of integrative oncology,” said Susan BauerWu, PhD, RN, FAAN, Immediate PastPresident of SIO and Kluge Professor in Contemplative End-of-Life Care at the University of Virginia School of Nursing in Charlottesville. “And it shows SIOs’ commitment to evidence-based research in integrative care of patients with cancer.” The number of attendees at this year’s conference and the increase in the amount of scientific research is a good indicator, added Dr. Bauer-Wu, that the field of integrative oncology is creating a cultural change in clinical oncology care. “Many oncologists are realizing that they are falling short on all they could be doing for their patients. Yes, they may be

The Best of SIO

he following four abstracts, which describe findings in three clinical studies and one basic science study, were singled out as the top abstracts at this year’s International Conference of the Society for Integrative Oncology.

Self-Administered Acupressure Zick S, Wyatt G, Murphy S; et al: The effect of two types of self-administered acupressure compared to standard of care on depression and anxiety in fatigued breast cancer survivors. 10th International Conference of the SIO. Abstract 107. Presented October 22, 2013. This study compared outcomes after 6 weeks of self-administered stimulating acupressure or relaxing acupressure vs standard of care in 89 breast cancer survivors with depression or anxiety. The investigators concluded that selfadministered relaxing acupressure produces a greater antidepressive response compared to stimulating acupressure or standard care in this population, and recommended more rigorous studies of these modalities.

Electro-Acupuncture Mao JJ, Xie SX, Farrar JT, et al: Electro-acupuncture for aromatase inhibitor related arthralgia and co-morbid symp-

toms in breast cancer survivors: A randomized placebo-controlled trial. 10th International Conference of the SIO. Abstract 67. Presented October 22, 2013. In this randomized, placebo-controlled trial, 67 postmenopausal women with breast cancer who attributed their arthralgia to taking aromatase inhibitors were assigned to 10 treatments of tailored acupuncture with 2 Hz electrostimulation via a TENS unit, a wait-list control group, or sham acupuncture with nonpenetrating needles at nontraditional acupuncture points, without electrostimulation. The investigators concluded that electro-acupuncture significantly improved aromatase inhibitor–related arthralgia as well as comorbid fatigue and sleep problems over usual care “with clinically important and durable changes.”

Physical Activity Garland SN, Speck RM, Palmer C, et al: Association of physical activity and telomere length in breast cancer survivors. 10th International Conference of the SIO. Abstract 53. Presented October 22, 2013. This study sought to clarify the link between physical activity and telomere length in 392 postmenopausal women with stage 0 to III breast cancer. A ques-

able to rid patients of their cancer or reduce tumor burden, but often patients are left feeling unwell and have troubling side effects from their treatment,” said Dr. BauerWu. “There is much greater receptivity now by oncologists in the use of integrative Susan Bauer-Wu, PhD, RN, FAAN Heather Greenlee, ND, PhD approaches such as exercise, acupuncture, and mindfulness medita- cates. Travel scholarships were awarded tion to address the needs of the whole to 12 patient advocates from the United patient during treatment and through- States and Canada. “The grant allowed us to expose these out survivorship and palliative care.” patient advocates to the best science in Clinical Practice Guidelines integrative oncology so that they could In addition to the record-breaking take the information back to their comnumber of scientific abstracts presented munities,” said Heather Greenlee, ND, at this year’s conference, this was the first PhD, President of SIO and Assistant year the SIO received a National Cancer Professor in the Department of EpideInstitute conference grant specifically to miology at the Mailman School of Public fund travel expenses for patient advo- Health at Columbia University in New York. One of the featured presentations at this year’s conference was the introduction of an integrative oncology practice tionnaire was used to categorize physiguideline for lung cancer that was develcal activity (as none vs moderate to oped by SIO members and published in vigorous) and a blood sample was taken CHEST.1 The guideline can also be found on the National Institutes of Health Nato determine telomere length. The intional Center for Complementary and vestigators concluded, “Lack of physiAlternative Medicine’s website at http:// cal activity is associated with shortened nccam.nih.gov/health/providers/clinitelomere length, warranting prospeccalpractice.htm. Next year, SIO will pubtive investigation of the potential role lish practice guidelines on the use of inof physical activity on cellular aging in tegrative therapies during breast cancer breast cancer survivors.” treatment in the Journal of the National Ginseng Cancer Institute. Miller SC, Durairaj P: Tumor resis“We are using the strictest standards tance, immuno-enhancement and life span issued by ASCO and the Institute of increase mediated by an extract of North Medicine in the development of guideAmerican ginseng. 10th International lines on the use of integrative therapies during breast cancer treatment for sympConference of the SIO. Abstract 20. Pretom management, preventing and amesented October 22, 2013. liorating treatment-related side effects, This controlled animal study tested and improving quality of life for breast immunoenhancement with dietary cancer patients,” said Dr. Greenlee. n CVT-E002, a proprietary extract from Disclosure: Drs. Greenlee and Bauer-Wu North American ginseng, for 11 months reported no potential conflicts of interest. in elderly mice. The researchers found that the CVT-E002 had a profound efReference fect on tumor resistance, significantly 1. Deng GE, Rausch SM, Jones LW, increased the numbers of immune cells, et al: Complementary therapies and inand prolonged life. tegrative medicine in lung cancer: DiagThe Best of SIO abstracts are availnosis and management of lung cancer, able at www.integrativeonc.org/index. 3rd ed: American College of Chest Phyphp/past-conferences-sec/114-10thsicians Evidence-Based Clinical Practice international-conference-of-the-sociGuidelines. Chest 143(5 suppl):e420Sety-for-integrative-oncology. e436S, 2013.

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. Results were censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There were 78 deaths and 121 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=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60 Not reached

7.9

40 20 0

ZELBORAF (n=337)

6 8 OS (months)

Dacarbazine (n=338)

HR=hazard ratio CI=confidence interval *Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2 † At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine. ‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001) Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

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

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

75%

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

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed 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 | DECEMBER 15, 2013

PAGE 76

10th International SIO Conference Society for Integrative Oncology Is Helping to Advance Evidence-Based, Comprehensive Integrative Health Care A Conversation With Heather Greenlee, ND, PhD By Jo Cavallo

eather Greenlee, ND, PhD, was named President of the Society for Integrative Oncology (SIO) at the

organization’s 10th International Conference in October. Dr. Greenlee is AsSafety:7" sistant Professor in the Department of

ZELBORAF ® (vemurafenib) tablet, oral 6 ADVERSE REACTIONS Initial U.S. Approval: 2011 6.1 Clinical Trials Experience This is a brief summary of information about ZELBORAF. Before Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot prescribing, please refer to the full Prescribing Information. be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable clinical practice. or metastatic melanoma with BRAF V600E mutation as detected by an This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 FDA-approved test. randomized (1:1) 675 treatment-naive patients with unresectable or Limitation of Use: ZELBORAF is not indicated for treatment of patients metastatic melanoma to receive ZELBORAF 960 mg orally twice daily with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior 5 WARNINGS AND PRECAUTIONS systemic therapy received treatment with ZELBORAF 960 mg orally 5.1 New Primary Malignancies twice daily. Cutaneous Malignancies Table 1 presents adverse reactions reported in at least 10% of patients Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma treated with ZELBORAF. The most common adverse reactions of any occurred at a higher incidence in patients receiving ZELBORAF compared grade (≥ 30% in either study) in ZELBORAF-treated patients were to those in the control arm in Trial 1. The incidence of cutaneous squamous arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse 24% compared to <1% in the dacarbazine arm [see Adverse Reactions reactions were cuSCC and rash. The incidence of Grade 4 adverse (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; reactions was ≤ 4% in both studies. approximately 33% of patients who developed a cuSCC while receiving The incidence of adverse events resulting in permanent discontinuation ZELBORAF experienced at least one additional occurrence with median of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% time between occurrences of 6 weeks. Potential risk factors associated for the dacarbazine arm. In Trial 2, the incidence of adverse events with cuSCC observed in clinical studies using ZELBORAF included age resulting in permanent discontinuation of study medication was 3% in (≥ 65 years), prior skin cancer, and chronic sun exposure. ZELBORAF-treated patients. The median duration of study treatment In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial patients receiving ZELBORAF compared to none of the patients receiving 1, and 5.7 months for ZELBORAF in Trial 2. dacarbazine. Reactions Reported in ≥ 10% of Patients Treated Perform dermatologic evaluations prior to initiation of therapy and every Table 1 Adverse with ZELBORAF* 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for Trial 2: Patients Trial 1: Treatment Naïve Patients 6 months following discontinuation of ZELBORAF. with Failure of at Non-Cutaneous Squamous Cell Carcinoma Least One Prior Systemic Therapy Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. ZELBORAF Dacarbazine ZELBORAF ADRs Monitor patients receiving ZELBORAF closely for signs or symptoms of n= 336 n= 287 n= 132 new non-cutaneous SCC. Grade All Grade Grade All All a Other Malignancies 3a Grades 3 Grades 3 Grades (%) (%) (%) (%) (%) (%) Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms Skin and subcutaneous [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF tissue disorders closely for signs or symptoms of other malignancies. Rash 37 8 2 0 52 7 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)]. 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)]. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)]. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

33 45 23 24 9 8 19 5 14

3 <1 1 1 2 0 0 <1 0

4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0

49 36 30 28 21 17 16 13 8

3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

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

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 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.

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF.

Main Objectives Please describe SIO’s mission. The mission of the Society for Integrative Oncology is to advance evidence-based, comprehensive integrative health care to improve the lives of people affected by cancer. We want to be the leading go-to organization for developing and cultivating the research behind integrative oncology. Our main objective is not just to encourage new high-quality research, but also to disseminate that research to everyone who needs the information, including other researchers, oncologists, patients, and patient advocates.

Short- and Long-Term Goals What are some goals you hope to accomplish over the next year? Recently, we held a strategic planning meeting with all of the past presidents of SIO as well as our current and outgoing board members. During that meeting, we discussed our long-term goal—to be recognized as the leading international resource and sciencebased professional organization in the field of integrative oncology. One of the key methods to accomplish that

Save the Date

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (<1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation

focuses on the use of lifestyle modifications and complementary and integrative medicine for breast cancer prevention and control. Before becoming President of the SIO, Dr. Greenlee served on its executive committee. She has received research funding from the National Institutes of Health (NIH) and is a member of SWOG (formerly the Southwest Oncology Group). The ASCO Post talked with Dr. Greenlee about the goals she hopes to accomplish over the next year as President of SIO and the biggest challenges she faces.

Safety:10"

5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

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

Epidemiology at the Mailman School of Public Health at Columbia University in New York. Dr. Greenlee’s research

The 11th International Conference of the Society for Integrative Oncology will be held in Houston, Texas, on October 26–28, 2014. The conference theme is Personalized Integrative Oncology: Targeted Approaches for Optimal Outcomes. Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

ASCOPost.com | DECEMBER 15, 2013

PAGE 77

10th International SIO Conference is for SIO to partner with other major oncology organizations, such as ASCO, through participation in their meetings as well as inviting them to participate in our annual conference.

specifically on the use of integrative therapies during breast cancer treatment for symptom management, to prevent and ameliorate treatment toxicities, and to improve quality of life.

There needs to be a paradigm shift in some institutions and medical communities, to recognize the potential benefit of an integrative approach to cancer care. —Heather Greenlee, ND, PhD

For example, this year we invited leaders from the American Society of Preventive Oncology (ASPO) to give a presentation on cancer survivorship research. And next year, we will have a session at ASPO’s conference on integrative oncology research. We are also planning to make presentations at the Oncology Nursing Society’s 2015 Annual Congress. Many of these groups are conducting research in integrative medicine, and we want to partner with them. Another goal is to publish new clinical practice guidelines for specific cancers. To date, SIO has published four different practice guidelines. Two were on the general use of integrative therapies in oncology settings and two were specifically for the management of patients with lung cancer. The next set of guidelines will focus

We will use the strictest standards established by ASCO and the Institute of Medicine for evaluating interventions and clinical strategies.

Perception Issues What are some of SIO’s biggest challenges? There needs to be a paradigm shift in some institutions and medical communities, to recognize the potential benefit of an integrative approach to cancer care. The field of integrative oncology isn’t going away, and we need to educate providers and researchers about integrative medicine’s role in cancer care. It is also important to understand that SIO is not interested in promoting “alternative” cancer care. Integrative oncology combines the best of conventional approaches to cancer treatment with the

best evidence-based integrative therapies. We want to advance the science.

Growing Field Is the amount of integrative medicine research in cancer care growing? The field is definitely growing. Within the National Institutes of Health, both the National Cancer Institute (NCI) and National Center for Complementary and Alternative Medicine (NCCAM) invest a significant amount of resources to studying integrative oncology. A great deal of integrative oncology research focuses on symptom management. For example, our research group at Columbia University is conducting clinical trials using acupuncture to help with aromatase inhibitor– induced joint pain. We are also studying the use of dietary supplements to prevent and/or treat chemotherapy toxicities.

Obstacles to Implementation What are the biggest impediments to the use of integrative medicine in oncology? There are several. The first is that a great deal of research still needs to be conducted to identify which integrative practices work, how they work, and what the best doses are, and to determine whether they are safe. In addition, most health-care professionals lack knowledge about the potential benefits and risks of integrative medicine, so we have to do a better job of educating oncologists, nurses,

and primary care physicians on the use of integrative medicine in clinical care. We also have to do a better job of educating patients about integrative medicine. There is a lot of misunderstanding and misinformation about integrative care and about what it can and cannot do. The new SIO guidelines will summarize the existing scientific evidence for integrative practices in specific cancers and will highlight where the knowledge gaps exist.

Ongoing Progress What progress have you seen over the past decade in advancing complementary medicine in oncology care, and what do expect to see in the future? The research base in integrative medicine has certainly grown, as has the amount of funding for research. The development and implementation of integrative services and integrative programs for cancer survivors within cancer centers across the country and internationally are also growing. Ten years ago, there weren’t many cancer survivorship programs. Now such programs exist almost everywhere, and integrative oncology is a key component in many of them. Both research and clinical care are being conducted via interdisciplinary teams. In the future, we will see more of that interdisciplinary research, which will lead to the best science to inform evidence-based practice. n Disclosure: Dr. Greenlee reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Chandrakanth Are, MBBS, FRCS, FACS, on Informed Consent see page 1

John Mendelsohn, MD, on the National Cancer Policy Summit see page 64

Ed Giampietro, on Receiving a Cancer Diagnosis see page 90

Omar Eton, MD, on the Massachusetts Society of Clinical Oncologists see page 97

Visit The ASCO Post online at ASCOPost.com

Brian J. Druker, MD, on Personalized Therapies for Cancer see page 80

Peter A. Ubel, MD, on Medical Costs of Cancer Care see page 98

The ASCO Post | DECEMBER 15, 2013

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Integrative Oncology By Jyothirmai Gubili, MS Editor, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center

Ginkgo biloba Common names: Fossil tree, maidenhair tree, kew tree, bai guo ye, yinhsing, ginkyo.

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. We chose omega-3 fatty acids for this issue because of their growing use by cancer patients. Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, and Jyothirmai Gubili, MS, Memorial SloanKettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, LAc, Memorial SloanKettering Cancer Center.

Overview

Ginkgo, one of the oldest living trees dating back 250 million years, is preva-

lent in China, Korea, and Japan. Beginning in 18th century, it began to be cultivated in many parts of the world for its aesthetic value. Known for its sturdiness, ginkgo is believed to be the only flora to have resprouted following the atomic bombing at Hiroshima. The therapeutic value of ginkgo was first described in the Chinese Materia Medica 5,000 years ago. The seeds were used in traditional Chinese medicine to treat brain, respiratory, and circulatory disorders, as well as sexual dysfunction, loss of hearing, and vertigo. Today, ginkgo leaf extract is used to enhance memory and to treat mild dementia, peripheral vascular disease, tinnitus, and sexual dysfunction. Current clinical evidence supports use of ginkgo for peripheral vascular disease. However, data on the herb’s potential to prevent dementia and Alzheimer’s disease are inconclusive. Ginkgo is among the top-selling herbal supplements in the United States and Europe. It is available in health food stores and online in the form of tablets, capsules, softgels, liquid extracts, and herbal tea.

GUEST EDITOR

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. Barrie R. Cassileth, MS, PhD mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http://itunes.apple.com/us/app/about-herbs/id554267162?mt=8.

The Science

Pharmacologically active constituents of ginkgo include flavonoids, diterpene lactones known as ginkgolides, and bilobalide, a sesquiterpene lactone. Several clinical trials have been conducted to determine the role of ginkgo in improving cognitive performance in both healthy adults and demented patients, but data are conflicting.1,2 According to data from the Ginkgo Evaluation of Memory (GEM) study,

the largest trial of ginkgo for dementia thus far, ginkgo is ineffective in decreasing the incidence of dementia or Alzheimer’s disease in elderly individuals.3 Similar findings were reported by

another group.4 Further, ginkgo did not slow down cognitive decline in older adults with normal cognition or with mild cognitive impairment.5 In other studies, ginkgo was less effective compared to the standard treatment for attention deficit hyperactivity disorder (ADHD) in children.6 Current evidence is mixed on ginkgo’s ability to decrease the severity of acute mountain sickness.7,8 More research is warranted. A few studies have also explored ginkgo’s anticancer potential. Epidemiologic and biologic data show that it reduces the risk of ovarian cancer.9 In patients with gastric cancer, oral administration of capsules containing ginkgo exocarp polysaccharides reduced the tumor area.10 But findings from the

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs

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Integrative Oncology OF NOTE Definitive data are needed to support ginkgo’s use as a memory enhancer. Physicians should be aware of the side effects and drug interactions associated with its use. GEM study, in which cancer was the secondary outcome, do not support use of ginkgo in reducing the risk of cancer.11 Ginkgo supplementation was also reported ineffective in preventing chemotherapy-associated cognitive dysfunction in a randomized controlled trial of patients with breast cancer.12

4. Vellas B, Coley N, Ousset P-J, et al: Longterm use of standardised ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): A randomised placebo-controlled trial. Lancet Neurol 11:851-859, 2012. 5. Snitz BE, O’Meara ES, Carlson MC, et al: Ginkgo biloba for preventing cognitive decline in older adults. A randomized trial. JAMA 302:2663-2670, 2009.

6. Salehi B, Imani R, Mohammadi MR, et al: Ginkgo biloba for attention-deficit/hyperactivity disorder in children and adolescents: A double blind, randomized controlled trial. Prog Neuropsychopharmacol Biol Psychiatry B:8.25” 34:76-80, 2010. 7. Chow T, Browne V,T:7.5” Heileson HL, et al: S:6.75” Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: A randomized,

placebo-controlled trial. Arch Intern Med 165:296-301, 2005. 8. Gertsch JH, Basnyat B, Johnson WE, et al: Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: The prevention of high altitude illness trial (PHAIT). continued on page 80

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

Adverse Effects

Seizures,13 and spontaneous bleeding,14 including hematomas,15,16 hyphema,17 and cerebral bleeding,18 have been reported.

Herb-Drug Interactions

Antipsychotics/prochlorperazine: Ginkgo may cause seizures when taken along with medications that lower the seizure threshold.13 Insulin: Ginkgo can alter insulin secretion and affect blood glucose levels.19 Cytochrome P450 substrates: Ginkgo can both inhibit and induce CYP450 enzymes but data are conflicting.20,21 P-glycoprotein substrates: Ginkgo inhibits P-glycoprotein and may interfere with drugs that are transported by P-glycoprotein.22 Efavirenz (antiretroviral agent): Ginkgo may inhibit its effects.23,24 Nonsteroidal anti-inflammatory drugs: Ginkgo can have additive anticoagulant/antiplatelet effects.25 Uridine 5’-diphospho-glucuronosyltransferase (UGT) substrates: Ginkgo modulates UGT enzymes in vitro and may increase the adverse effects of drugs metabolized by them.26 Disclosure: Ms. Gubili, Drs. Cassileth, and Yeung reported no potential conflicts of interest.

References 1. Lovera J, Bagert B, Smoot K, et al: Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: A randomized, placebo-controlled trial. Mult Scler 13:376-385, 2007. 2. Canter PH, Ernst E: Ginkgo biloba is not a smart drug: An updated systematic review of randomised clinical trials testing the nootropic effects of G. biloba extracts in healthy people. Hum Psychopharmacol 22:265-278, 2007. 3. DeKosky ST, Williamson JD, Fitzpatrick AL, et al: Ginkgo biloba for prevention of Dementia. A randomized controlled trial. JAMA 300:2253-2262, 2008.

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

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

Randomization 2:1 (Cabozantinib:Placebo)

Cabozantinib 60 mg QD

Placebo QD

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

The ASCO Post | DECEMBER 15, 2013

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Future of Oncology The Quest to Optimize Personalized Therapies for Cancer A Conversation With Brian J. Druker, MD By Jo Cavallo

Brian J. Druker, MD

n the late 1980s, Brian J. Druker, MD, was investigating the BCRABL tyrosine kinase as a target for therapeutic intervention for chronic myeloid leukemia (CML) in a laboratory at Dana-Farber Cancer Institute in Boston. By 1993, Dr. Druker had moved to Oregon Health & Science University in Portland, where he continued his research and found a compound called STI571 that could kill CML cells in vitro while preserving healthy cells. Five years later, Dr. Druker was conducting the first human clinical study of STI571, also known as imatinib mesylate (Gleevec). In one early-phase clinical trial, imatinib had restored normal blood counts in 53 of 54 interferon-resistant CML patients, a response rate rarely achieved in cancer with a single agent. In March 2001, imatinib was granted a U.S. Food and Drug Administration (FDA) expedited review and approved 2 months later. Many of the patients in those ear-

Gingko Biloba continued from page 79

BMJ 328:797, 2004. 9. Ye B, Aponte M, Dai Y, et al: Ginkgo biloba and ovarian cancer prevention: Epidemiological and biological evidence. Cancer Lett 251:43-52, 2007. 10. Xu AH, Chen HS, Sun BC, et al: Therapeutic mechanism of ginkgo biloba exocarp polysaccharides on gastric cancer. World J Gastroenterol 9:2424-2427, 2003. 11. Biggs ML, Sorkin BC, Nahin RL, et al: Ginkgo biloba and risk of cancer: Secondary analysis of the Ginkgo Evaluation of Memory (GEM) Study. Pharmacoepidemiol Drug Saf 19:694-698, 2010. 12. Barton DL, Burger K, Novotny PJ, et al: The use of Ginkgo biloba for the prevention of chemotherapy-related cognitive dysfunction

ly-phase clinical studies are alive today. Dr. Druker’s research proved that it was possible to transform life-threatening cancers into manageable chronic diseases, a concept that is prevalent today but was largely unthinkable 15 years ago. His work in the development of targeted cancer therapies has resulted in numerous awards, including the American Cancer Society Medal of Honor, the Charles F. Kettering Prize from the General Motors Cancer Research Foundation, the Lasker-Debakey Award for Clinical Medical Research, the Ernest Beutler Prize from the American Society of Hematology and, most recently, the Taubman Prize for Excellence in Translational Medical Science and the Albany Medical Center Prize in Medicine and Biomedical Research. The ASCO Post talked with Dr.

which you expressed optimism about the development of more effective targeted therapies for cancer. Why are you feeling so optimistic? Twenty years ago, if you asked a lung cancer specialist for his prognosis on patients, he would have said we have no cures for patients with metastatic disease. Similarly, there were no cures for patients with metastatic breast cancer or metastatic melanoma. Now, in lung cancer we have new agents like crizotinib (Xalkori) and erlotinib (Tarceva) that are producing rapid and dramatic responses in patients with metastatic disease. In melanoma, we are seeing Lazarus-like effects with the BRAF-targeted drugs vemurafenib (Zelboraf) and dabrafenib (Tafinlar). Unfortunately, we do see the rapid development of resis-

In melanoma, we are seeing Lazarus-like effects with the BRAF-targeted drugs vemurafenib (Zelboraf) and dabrafenib (Tafinlar).

nations of rational therapies. For example, in melanoma, when you combine dabrafenib with a MEK inhibitor, you get higher response rates with greater durability. To me, that’s really where we are headed. We are taking our understanding of the molecular drivers of cancer and the molecular basis of resistance, and we are seeing significant impacts. Another example of a breakthrough drug is enzalutamide (Xtandi) for prostate cancer. It was approved by the FDA based on an understanding of why men become resistant to antiandrogen therapy, and it is prolonging survival more than any other drug in a decade for prostate cancer. Those are the sorts of advances we are seeing, and that is why I am optimistic that this knowledge-based cancer therapy is going to be fundamentally different than what we have seen over the past 20 to 30 years.

Combination Strategies

In 2011, you gave a presentation called The End of Cancer Is Within Reach, in

tance to these drugs in the advanced metastatic setting. What people are beginning to realize is that by targeting these genetic drivers of cancer, we’re seeing responses we thought were impossible 2 decades ago. And we are figuring out why patients become resistant to therapy, so instead of thinking about chemotherapy combinations like we have done for decades, we are starting to use combi-

Targeted therapies as single agents have not been effective in controlling cancer and usually have to be combined with conventional chemotherapies. Is there a smarter way of utilizing these drugs? When I started along the path of developing [imatinib], people said single-agent therapy would never work; why bother investigating it? As it turns out, single-agent therapy does work; it just doesn’t have durability, so you could say the skeptics were right. The way that I look at it is this: Don’t

in women receiving adjuvant treatment for breast cancer, N00C9. Support Care Cancer 21:1185-1192, 2013. 13. Gregory PJ: Seizure associated with Ginkgo biloba? Ann Intern Med 134:344, 2001. 14. Matthews MK: Association of Ginkgo biloba with intracerebral hemorrhage. Neurology 50:1933-1934, 1998. 15. Rowin J, Lewis SL: Spontaneous bilateral subdural hematomas associated with chronic ginkgo biloba ingestion. Neurology 46:1775-1776, 1996. 16. Gilbert GJ: Ginkgo biloba. Neurology 48:1137, 1997. 17. Rosenblatt M, Mindel J: Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med 336:1108, 1997. 18. Pedroso JL, Henriques Aquino CC,

Escórcio Bezerra ML, et al: Ginkgo biloba and cerebral bleeding: A case report and critical review. Neurologist 17:89-90, 2011. 19. Kudolo GB: The effect of 3-month ingestion of Ginkgo biloba extract on pancreatic beta-cell function in response to glucose loading in normal glucose tolerant individuals. J Clin Pharmacol 40:647-654, 2000. 20. Lau AJ, Chang TK: Inhibition of human CYP2B6-catalyzed bupropion hydroxylation by Ginkgo biloba extract: Effect of terpene trilactones and flavonols. Drug Metab Dispos 37:1931-1937, 2009. 21. Hellum BH, Hu Z, Nilsen OG: Trade herbal products and induction of CYP2C19 and CYP2E1 in cultured human hepatocytes. Basic Clin Pharmacol Toxicol 105:58-63, 2009. 22. Fan L, Mao XQ, Tao GY, et al: Effect of

Schisandra chinensis extract and Ginkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers. Xenobiotica 39:249254, 2009. 23. Wiegman DJ, Brinkman K, Franssen EJ: Interaction of Ginkgo biloba with efavirenz. AIDS 23:1184-1185, 2009. 24. Naccarato M, Yoong D, Gough K: A potential drug-herbal interaction between Ginkgo biloba and efavirenz. J Int Assoc Physicians AIDS Care (Chic) 11:98-100, 2012. 25. Haller C, Kearney T, Bent S, et al: Dietary supplement adverse events: Report of a one-year poison center surveillance project. J Med Toxicol 4:84-92, 2008. 26. Mohamed ME, Frye RF: Effects of herbal supplements on drug glucuronidation. Review of clinical, animal, and in vitro studies. Planta Med 77:311-321, 2011.

Druker, Director of the Knight Cancer Institute at Oregon Health & Science University and JELD-WEN Chair of Leukemia Research, about his optimism for ending cancer and what is ahead in cancer therapies over the next decade.

Optimistic Outlook

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Future of Oncology you want to combine active agents in your treatment regimens, and don’t you want to have a rationale for why you are combining these drugs instead of saying they have some activity and nonoverlapping toxicities? That’s what we did for 40 years of combination chemotherapy. Now we are saying we need to shut down specific pathways that the cancer requires for its growth and survival, and then we should be able to kill the cancer effectively and durably. For now, we will continue to combine targeted therapies with conventional chemotherapies, but over the next 10 to 20 years, I suspect we will see a decrease in the number of chemotherapy drugs used and an increase in the number of combination targeted therapies used. In addition, we are likely to see combinations of the targeted therapies with immune therapeutics.

Controlled vs Cured Many of the first CML patients treated with imatinib in clinical trials are still alive. Are those patients cured of their cancer? Yes and no. Most people have to remain on active therapy, they take [imatinib] daily and they are fine. But what do you call that semantically? The general public may think of it as a cure, but most medical professionals would say, no, [imatinib] is an effective treatment but not a cure. I have been saying that the drug is an effective treatment that controls leukemia. For CML patients on [imatinib] for 15 years and doing fine, if they consider it a cure, why should I be a stickler for semantics?

Current Focus Please talk about your current research in leukemia. We are investigating the targeting of specific molecular drivers in leukemia. We are also moving rapidly to test combinations of treatment, including targeted therapy with standard chemotherapy or combinations of targeted agents. Our view is that we can bring genomic information into the clinic very rapidly, for example, in acute myeloid leukemia by targeting molecular drivers, understanding resistance mechanisms, and rapidly moving to combination therapy and showing that we can get higher response rates and greater durability. The goal is to move the cure rate from 30%, where it has been stuck for 40 years, to something significantly higher.

Looking Ahead Will it be possible to cure various types of cancer, or will cancer become a chronic disease that is managed over a lifetime? It would be a huge step forward if we could turn some of the metastatic cancers into manageable conditions. I would really like to see us move cancer

therapy into the cure category, which means you get treatment for a fixed amount of time, the cancer is gone, you stop treatment, and the cancer doesn’t come back. I am not sure whether that is a realistic goal over the next 10 years, but if you think about targeted cancer therapies, plus the immunotherapeutics

that are being developed, it may in fact be possible. n Disclosure: Oregon Health & Science University has clinical trial contracts with Novartis to pay for patient costs, nurse and data manager salaries, and institutional overhead; however, Dr. Druker does not derive salary, nor does his laboratory receive funds, from these contracts.

2013

CLINICAL CANCER ADVANCES The 2013 CCA Report is now available. Visit cancerprogress.net/CCA to see this year’s selection of top cancer research findings and policy updates. These advances will shape the future of care and have the greatest potential to improve patients’ lives.

Visit CancerProgress.Net/CCA today

The ASCO Post | DECEMBER 15, 2013

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In the Clinic

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

Indication On November 13, 2013, ibrutinib (Imbruvica) was granted accelerated approval for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.1,2 Approval was based on a multicenter, international, single-arm phase II trial with a primary endpoint of overall response rate.2,3 This indication is based on overall response rate; improvement in survival or disease-related symptoms has not been established. As a condition of accelerated approval, the sponsor is required to submit 24-month follow-up data for all patients in the single-arm trial and the results of a randomized controlled trial comparing ibrutinib plus bendamustine (Treanda)/rituximab (Rituxan) vs bendamustine/rituximab without ibrutinib in patients with newly diagnosed mantle cell lymphoma. In the study, 111 patients with at least one prior treatment received ibrutinib at 560 mg/d. Patients had a median age of 68 years (range, 40–84 years), 77% were male, 92% were Caucasian, 89% had Eastern Cooperative Oncology Group performance status of 0 or 1, median time from diagnosis was 42 months, 39% of subjects had at at least one tumor

OF NOTE Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways implicated in the pathogenesis of B-cell cancers.

≥ 5 cm, 49% had bone marrow involvement, and 54% had extranodal involvement. Patients had a median of three prior treatments (range, 1–5), including rituximab in 89%, hyperfractionated cyclophosphamide, vincristine, doxorubi-

cin, and dexamethasone in 30%, lenalidomide (Revlimid) in 24%, and stem cell transplantation in 11%. Median follow-up was 15.3 months, and median treatment duration was 8.3 months. The overall response rate was 65.8% (95% confidence interval [CI] = 56.2%–74.5%), with complete response in 17.1% of patients and partial response in 48.6%. Median duration of response was 17.5 months (95% CI = 15.8 months to not reached).

How It Works Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways implicated in the pathogenesis of B-cell cancers. Ibrutinib forms a covalent

OF NOTE Ibrutinib carries warnings/precautions for hemorrhage, infections, myelosuppression, renal toxicity, second primary malignancies, and embryo-fetal toxicity.

sidered as needed. If toxicities persist or recur after two dose reductions, ibrutinib should be discontinued. Coadministration of ibrutinib with strong or moderate CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole), and strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) should be avoided. Ibrutinib can be interrupted if short-term treatment (≤ 7

Ibrutinib for Mantle Cell Lymphoma ■■ Ibrutinib (Imbruvica) was granted accelerated approval for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. ■■ The recommended dose of ibrutinib is 560 mg (four 140-mg capsules) orally once daily.

bond with a cysteine residue in the Bruton’s tyrosine kinase active site, leading to inhibition of Bruton’s tyrosine kinase enzymatic activity. Bruton’s tyrosine kinase signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Preclinical studies indicate that ibrutinib inhibits malignant B-cell proliferation and survival in vivo and cell migration and substrate adhesion in vitro.

How It Is Given The recommended dose of ibrutinib is 560 mg (four 140-mg capsules) orally once daily. Ibrutinib treatment should be interrupted for any grade 3 or higher nonhematologic toxicity, grade 3 or higher neutropenia with infection or fever, and grade 4 hematologic toxicity. Once toxicity has resolved to grade 1 or baseline, treatment can be reinitiated at the starting dose. If toxicity recurs, the dose should be reduced by one capsule (140 mg/d) with a second reduction by 140 mg con-

days) with a strong CYP3A inhibitor is necessary, and the dose can be reduced to 140 mg/d if a moderate CYP3A inhibitor must be used. Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity. Ibrutinib should be avoided in patients with hepatic impairment.

Safety Profile The most common adverse events of any grade in the clinical trial were thrombocytopenia (57%), diarrhea (51%), neutropenia (47%), anemia (41%), fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%). The most common grade 3 or 4 adverse events were neutropenia (29%), thrombocytopenia (17%), anemia (9%), pneumonia (7%), and diarrhea,

abdominal pain, skin infections, and fatigue (5% each). Overall, 25% of patients had grade 3 or higher infections and 5% had grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Bleeding events of any grade, including bruising of any grade, occurred in 48% of patients. Ibrutinib carries warnings/precautions for hemorrhage, infections, myelosuppression, renal toxicity, second primary malignancies (including skin cancers and other carcinomas), and embryo-fetal toxicity. Patients must be monitored for bleeding and for fever and infections. Complete blood counts should be performed monthly. Renal function must be monitored and adequate hydration maintained. Women should be advised of potential fetal risk and to avoid pregnancy during therapy.

Cost Ibrutinib is estimated to cost approximately $10,900 per month of recommended therapy and $130,000 per year. n References 1. U.S. Food and Drug Administration: Ibrutinib. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm374857.htm. 2. IMBRUVICATM (ibrutinib) capsules prescribing information. Pharmacyclics, Inc, November 2013. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2013/205552lbl.pdf. 3. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507-516, 2013.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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2013–2014 Oncology Meetings January 2014 AACR-IASLC Joint Conference on the Molecular Origins of Lung Cancer January 6-9 • San Diego, California For more information: www.aacr.org

Clinical and Multidisciplinary Hematology and Oncology 2014: The 11th Annual Review January 24-26 • Scottsdale, Arizona For more information: www.mayo.edu/cme/internalmedicine-and-subspecialties2014s431 Melanoma 2014: 24th Annual Cutaneous Malignancy Update January 25-26 - San Diego, California For more information: med.edu@scrippshealth.org

2014 Gastrointestinal Cancers Symposium January 16-18 • San Francisco, California For more information: www.gicasym.org 10th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 18 • Orlando, Florida For more information: www.flasco.org/events?eventId=7103 10&EventViewMode=EventDetails American Association for Cancer Research-Prostate Cancer Foundation Conference on Advances in Prostate Cancer Research January 18-21 • San Diego, California For more information: www.aacr.org 1st World Congress in Controversies in Multiple Myeloma January 23-25 • Bangkok, Thailand For more information: www. comtecmed.com/comy/2014/

comtecmed.com/comy/2014/ JADPRO Live January 24-26 • St. Petersburg, Florida For more information: www.advancedpractitioner.com/ jadprolive

Clinical Genomics Boston 2014 January 28-30 • Boston, Massachusetts For more information: www.clinicalgenomics-usa.com

2014 Genitourinary Cancers Symposium: Celebrating 10 Years January 30-February 1 • San Francisco, California For more information: www.gucasym.org

February APOS 11th Annual Conference February 13-15 • Tampa, Florida For more information: www.apos-society.org/apos2014/

2013–2014

Multidisciplinary Head and Neck Cancer Symposium February 20-22 • Scottsdale, Arizona For more information: www.headandnecksymposium.org Society of Gynecological Oncology 2014 Winter Meeting February 20-22 - Breckenridge, Colorado For more information: www.sgo.org North Carolina Oncology Association/South Carolina Oncology Society Joint Membership Conference February 21-22 • Charlotte, North Carolina For more information: www.ncoa-northcarolina.com/ American Association for Cancer Research: RAS Oncogenes: From Biology to Therapy February 24-27 - Lake Buena Vista, Florida For more information: www.aacr.og

March 31st Annual Miami Breast Cancer Conference® March 6-9 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/31st-Annual-MiamiBreast-Cancer-Conference

European Society for Medical Oncology Sarcoma and GIST 2014 February 18-19 • Milan, Italy For more information: www.esmo.org

Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial SloanKettering Cancer Center March 7-10 • New York, New York For more information: www.mskcc.org/ hemoncreviewcourse

2014 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 19 - 23 – Orlando, Florida For more information: www.asbmt.org

38th Annual Meeting of the American Society of Preventive Oncology March 8-11 - Arlington, Virginia For more information: www.aspo.org

NCCN 19th Annual Conference: Advancing the Standard of Cancer Care™ March 13–15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp Society of Surgical Oncology Annual Cancer Symposium March 13 - 16 – Phoenix, Arizona For more information: www.surgonc.org 7th Annual Interdisciplinary Prostate Cancer Congress™ March 15 • New York, New York For more information: www.gotoper.com/conferences/ ipcc/meetings/7th-AnnualInterdisciplinary-Prostate-CancerCongress 24th Annual Interdisciplinary Breast Cancer Conference March 15-19 • Las Vegas, Nevada For more information: www.breastcare.org/ 9th European Breast Cancer Conference March 19-21 - Glasglow, Scotland For more information: www.ecco-org.eu Illinois Medical Oncology Society 2014 Membership Conference March 21 • Chicago, Illinois For more information: www.imos-illinois.com/ ELCC 2014 European Lung Cancer Conference March 26-29 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2014-Lung-Cancer ACCC 40th Annual National Meeting March 31-April 2 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ AM2014.asp

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2013–2014 Oncology Meetings April

2013–2014

August

Clinical Congress

ESTRO 33 April 4-8 • Vienna, Austria For more information: www.estro.org/congressesmeetings/items/estro-33

October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

ASCO 50th Annual Meeting May 30-June 3 • Chicago, Illinois For more information: http://am.asco.org

June American Association for Cancer Research Annual Meeting April 5-9 • San Diego, California For more information: www.aacr.org 15th Annual Meeting of the American Society of Breast Surgeons April 30-May 4 • Las Vegas, Nevada For more information: www.breastsurgeons.org/index.php

May Oncology Nursing Society 39th Annual Congress May 1-4 • Anaheim, California For more information: www.ons.org Accelerating Anticancer Agent Development and Validation Workshop May 7-9 • Bethesda, Maryland For more information: www.acceleratingworkshop.org/ ASPHO’s 27th Annual Meeting May 14-17 • Chicago, Illinois For more information: www.aspho.org Oral Oncology: Oncologic Dentistry and Maxillofacial Prosthetics Symposium May 15-17 • Houston, Texas For more information: www.mdanderson.org/conferences 2014 State of the Art Radiation Therapy: Practical Treatment, Biology and Imaging May 16-18 • San Antonio, Texas For more information: www.astro.org

American College of Surgeons

6th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone Disease June 28-July 2 • Oxford, United Kingdom For more information: www.oxfordbonepharm.org/ 16th International Symposium on Pediatric Neuro-Oncology June 28-July 2 • Singapore For more information: www.ispno2014.com

July 12th Annual Meeting of the Japanese Society of Medical Oncology July 17-19 • Fukuoka, Japan For more information: www.congre.co.jp/jsmo2014/en/ 5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org/

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois

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

For more information: http:// thoracicsymposium.org

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundationsymposium.org Diagnostic Error in Medicine 5th

American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org

International Conference

European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress

aspx/80028747

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29 - October 2 • Cambridge, Massachusetts For more information: http:// steelelab.mgh.harvard.edu

For more information: http://www.

October ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org

November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail.

Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida mayo.edu/cme/surgical-specialties2014s306 EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org RSNA 2014 Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

The ASCO Post | DECEMBER 15, 2013

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Patient’s Corner

Cancer Has Given Me a Greater Appreciation for Life Getting a cancer diagnosis was shocking, but it has made me a more positive and productive person. By Ed Giampietro, as told to Jo Cavallo

’ve been blessed with good health for most of my life, and I was careful to keep it that way. I don’t smoke, I eat a healthy diet, and I maintain a healthy weight. I also was fortunate to be born with pretty good genes and have no family history of cancer. In fact, except for an occasional flare-up of gout, I’ve never had any serious illnesses. So it was a complete shock in the fall of 2009 when my wife Ann Marie and I came home from having dinner out and I found blood in my urine.

urine. It felt as though the tumor was sucking the life out of me. I was told I needed a radical ne-

phrectomy and that one of my ribs would need to be removed. The biopsy showed that the tumor was stage II

kidney cancer. My doctor said that he removed all signs of the cancer and that I wouldn’t need further treatment.

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

46% 1-YEAR survival rate*

24% 2-YEAR survival rate*

Some patients were still alive up to 4.5 years2 I have always been a positive person, but the experience of having cancer has made me even more determined to live a purposeful life.

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

Median overall survival was 10 months in the YERVOY arm3

—Ed Giampietro

At first I thought it was probably a bladder infection and made an appointment the next morning to see my primary care physician. Although she didn’t say anything at the time, I was sure she suspected that I had something more serious than a bladder infection. She ordered an ultrasound test for the next day, which was followed by a CT scan and other diagnostic tests. Finally, I was told that there was a 12-cm tumor sitting on my right kidney and that there was a high probability that it was cancer.

Coping With Cancer Metastases Until blood appeared in my urine, I hadn’t had any symptoms that anything was wrong. But soon after the diagnosis, I started experiencing chronic shortness of breath, an irritating cough, and small blood clots in my

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

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

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

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

ASCOPost.com | DECEMBER 15, 2013

PAGE 91

Patient’s Corner

But a month later, when I went back for a follow-up CT scan, the test showed hundreds of nodules on both lungs—the cancer had metastasized. Now I was scared. The diagnosis was changed to stage IV disease, and I was offered treatment with high-dose interleukin-2 (Proleukin). Although my prog-

nosis wasn’t good, and I had just a 7% to 15% chance for a durable full recovery, I underwent the treatment, and within a few months the tumors starting shrinking. Today, I am cancer-free.

Encouraging Words While I am so thankful to my oncology team for taking such good

care of my medical needs, I wish that they had paid more attention to my emotional needs. I was looking for some encouraging words while I was going through treatment—and even now that I’m in remission—but they never came. I try to put myself in my doctors’ shoes and realize how difficult it must

durable long-term survival in metastatic melanoma

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

Indication

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

See experts discuss redefining treatment goals for metastatic melanoma Find out at www.RedefineTreatmentGoals2.com

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

Please see detailed Important Safety Information, including Boxed WARNING regarding immune-mediated side effects, and brief summary of Full Prescribing Information on adjacent pages. ©2013 Bristol-Myers Squibb Company. All rights reserved. 731US13BR02884-01-01 10/13

be to treat cancer patients, especially when their disease is as advanced as mine was, and you can’t be sure of the outcome. I know that if I hadn’t gotten such great medical treatment, I wouldn’t still be here, but I felt that the lack of an emotional connection was the missing piece in my care. continued on page 92

The ASCO Post | DECEMBER 15, 2013

PAGE 92

Patient’s Corner

Cancer Has Given Me a Greater Appreciation for Life continued from page 91

Living the Best Possible Life I have always been a positive person, but the experience of having cancer has made me even more determined to live a purposeful life. I don’t concern myself with life’s small incon-

veniences, and I don’t have patience for chronic complainers. I am so grateful for having survived cancer, I decided to help others going through a similar circumstance and joined Imerman Angels, a one-on-one cancer support group that matches a newly diagnosed patient with a survivor of the same type of cancer. So

far, I have talked with a dozen kidney cancer patients around the country, and the experience has been very gratifying. Now that I’ve been a survivor for 4 years, I don’t live in constant fear that the cancer will recur, but I know that it is a possibility. If I am faced with a recurrence, I will once again put my trust

in my oncology team and be open to any treatments they recommend. In the meantime, I’m living the best life I can, and I don’t take anything for granted. n Ed Giampietro is an operations manager for a global technology company in Foxboro, Massachusetts.

Important Important Safety Safety Information Information WARNING: WARNING: IMMUNE-MEDIATED IMMUNE-MEDIATED ADVERSE ADVERSE REACTIONS REACTIONS YERVOY YERVOY (ipilimumab) (ipilimumab) can can result result in in severe severe and and fatal fatal immune-mediated immune-mediated adverse adverse reactions reactions due due to to T-cell T-cell activation activation and and proliferation. proliferation. These These immune-mediated immune-mediated reactions reactions may may involve involve any any organ organ system; system; however, however, the the most most common common severe severe immune-mediated immune-mediated adverse adverse reactions reactions are are enterocolitis, enterocolitis, hepatitis, hepatitis, dermatitis dermatitis (including (including toxic toxic epidermal epidermal necrolysis), necrolysis), neuropathy, neuropathy, and and endocrinopathy. endocrinopathy. The The majority majority of of these these immune-mediated immune-mediated reactions reactions initially initially manifested manifested during during treatment; treatment; however, however, aa minority minority occurred occurred weeks weeks to to months months after after discontinuation discontinuation of of YERVOY. YERVOY. Assess Assess patients patients for for signs signs and and symptoms symptoms of of enterocolitis, enterocolitis, dermatitis, dermatitis, neuropathy, neuropathy, and and endocrinopathy endocrinopathy and and evaluate evaluate clinical clinical chemistries chemistries including including liver liver function function tests tests (LFTs) (LFTs) and and thyroid thyroid function function tests tests at at baseline baseline and and before before each each dose. dose. Permanently Permanently discontinue discontinue YERVOY YERVOY and and initiate initiate systemic systemic high-dose high-dose corticosteroid corticosteroid therapy therapy for for severe severe immune-mediated immune-mediated reactions. reactions. Recommended Recommended Dose Dose Modifications Modifications Withhold Withholddose dosefor forany anymoderate moderateimmune-mediated immune-mediatedadverse adversereactions reactionsor orfor forsymptomatic symptomatic endocrinopathy endocrinopathyuntil untilreturn returnto tobaseline, baseline,improvement improvementto tomild mildseverity, severity,or orcomplete completeresolution, resolution, and andpatient patientisisreceiving receiving<7.5 <7.5mg mgprednisone prednisoneor orequivalent equivalentper perday. day. Permanently Permanentlydiscontinue discontinueYERVOY YERVOYfor forany anyof ofthe thefollowing: following: ••Persistent Persistentmoderate moderateadverse adversereactions reactionsor orinability inabilityto toreduce reducecorticosteroid corticosteroiddose doseto to7.5 7.5mg mg prednisone prednisoneor orequivalent equivalentper perday day ••Failure Failureto tocomplete completefull fulltreatment treatmentcourse coursewithin within16 16weeks weeksfrom fromadministration administrationof offirst firstdose dose ••Severe Severeor orlife-threatening life-threateningadverse adversereactions, reactions,including includingany anyof ofthe thefollowing: following: ––Colitis Colitiswith withabdominal abdominalpain, pain,fever, fever,ileus, ileus,or orperitoneal peritonealsigns; signs;increase increasein instool stoolfrequency frequency (≥7 (≥7over overbaseline), baseline),stool stoolincontinence, incontinence,need needfor forintravenous intravenoushydration hydrationfor for>24 >24hours, hours, gastrointestinal gastrointestinalhemorrhage, hemorrhage,and andgastrointestinal gastrointestinalperforation perforation ––AST ASTor orALT ALT>5× >5×the theupper upperlimit limitof ofnormal normal(ULN) (ULN)or ortotal totalbilirubin bilirubin>3× >3×the theULN ULN ––Stevens-Johnson Stevens-Johnsonsyndrome, syndrome,toxic toxicepidermal epidermalnecrolysis, necrolysis,or orrash rashcomplicated complicatedby byfull-thickness full-thickness dermal dermalulceration ulcerationor ornecrotic, necrotic,bullous, bullous,or orhemorrhagic hemorrhagicmanifestations manifestations ––Severe Severemotor motoror orsensory sensoryneuropathy, neuropathy,Guillain-Barré Guillain-Barrésyndrome, syndrome,or ormyasthenia myastheniagravis gravis ––Severe Severeimmune-mediated immune-mediatedreactions reactionsinvolving involvingany anyorgan organsystem system ––Immune-mediated Immune-mediatedocular oculardisease diseasewhich whichisisunresponsive unresponsiveto totopical topicalimmunosuppressive immunosuppressivetherapy therapy Immune-mediated Immune-mediated Enterocolitis: Enterocolitis: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY-treated YERVOY-treatedpatients, patients,severe, severe,life-threatening, life-threatening,or orfatal fatal(diarrhea (diarrheaof of ≥7 ≥7stools stoolsabove abovebaseline, baseline,fever, fever,ileus, ileus,peritoneal peritonealsigns; signs;Grade Grade3-5) 3-5)immune-mediated immune-mediatedenterocolitis enterocolitis occurred occurredin in34 34(7%) (7%)and andmoderate moderate(diarrhea (diarrheawith withup upto to66stools stoolsabove abovebaseline, baseline,abdominal abdominalpain, pain, mucus mucusor orblood bloodin instool; stool;Grade Grade2) 2)enterocolitis enterocolitisoccurred occurredin in28 28(5%) (5%)patients patients ••Across Acrossall allYERVOY-treated YERVOY-treatedpatients patients(n=511), (n=511),55(1%) (1%)developed developedintestinal intestinalperforation, perforation,44(0.8%) (0.8%)died died as asaaresult resultof ofcomplications, complications,and and26 26(5%) (5%)were werehospitalized hospitalizedfor forsevere severeenterocolitis enterocolitis ••Infliximab Infliximabwas wasadministered administeredto to55of of62 62(8%) (8%)patients patientswith withmoderate, moderate,severe, severe,or orlife-threatening life-threatening immune-mediated immune-mediatedenterocolitis enterocolitisfollowing followinginadequate inadequateresponse responseto tocorticosteroids corticosteroids ••Monitor Monitorpatients patientsfor forsigns signsand andsymptoms symptomsof ofenterocolitis enterocolitis(such (suchas asdiarrhea, diarrhea,abdominal abdominalpain, pain, mucus mucusor orblood bloodin instool, stool,with withor orwithout withoutfever) fever)and andof ofbowel bowelperforation perforation(such (suchas asperitoneal peritonealsigns signs and andileus). ileus).In Insymptomatic symptomaticpatients, patients,rule ruleout outinfectious infectiousetiologies etiologiesand andconsider considerendoscopic endoscopic evaluation evaluationfor forpersistent persistentor orsevere severesymptoms symptoms ••Permanently Permanentlydiscontinue discontinueYERVOY YERVOYin inpatients patientswith withsevere severeenterocolitis enterocolitisand andinitiate initiatesystemic systemic corticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayof ofprednisone prednisoneor orequivalent). equivalent).Upon Uponimprovement improvementto to≤Grade ≤Grade1, 1,initiate initiate corticosteroid corticosteroidtaper taperand andcontinue continueover overat atleast least11month. month.In Inclinical clinicaltrials, trials,rapid rapidcorticosteroid corticosteroidtapering tapering resulted resultedin inrecurrence recurrenceor orworsening worseningsymptoms symptomsof ofenterocolitis enterocolitisin insome somepatients patients ••Withhold WithholdYERVOY YERVOYfor formoderate moderateenterocolitis; enterocolitis;administer administeranti-diarrheal anti-diarrhealtreatment treatmentand, and,ififpersistent persistent for for>1 >1week, week,initiate initiatesystemic systemiccorticosteroids corticosteroids(0.5 (0.5mg/kg/day mg/kg/dayprednisone prednisoneor orequivalent) equivalent) Important Safety Information continued on following page.

ASCOPost.com | DECEMBER 15, 2013

PAGE 93

Announcements

NIH Announces New Co-Chairs of Panel on Antiretroviral Guidelines

he National Institutes of Health recently announced several changes in leadership on the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. The panel, a working group of the NIH Office of AIDS Research Advisory Commit-

tee (OARAC), consists of approximately 40 representatives from NIH, the Centers for Disease Control and Prevention, the Food and Drug Administration, and the Health Resources and Services Administration, as well as scientists and clinicians from academia and primary care medical

practices, and HIV/AIDS community representatives. The panel is charged with regularly updating HIV treatment guidelines based on advances in HIV therapy. The guidelines serve as the standard of medical care for treating HIV-infected patients in the United States.

Important Important Safety Safety Information Information (cont’d) (cont’d) Immune-mediated Immune-mediated Hepatitis: Hepatitis: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY YERVOY(ipilimumab)-treated (ipilimumab)-treatedpatients, patients,severe, severe,life-threatening, life-threatening,or or fatal fatalhepatotoxicity hepatotoxicity(AST (ASTor orALT ALTelevations elevations>5× >5×the theULN ULNor ortotal totalbilirubin bilirubinelevations elevations>3x >3xthe theULN; ULN; Grade Grade3–5) 3–5)occurred occurredin in88(2%) (2%)patients, patients,with withfatal fatalhepatic hepaticfailure failurein in0.2% 0.2%and andhospitalization hospitalizationin in0.4% 0.4% ••13 13(2.5%) (2.5%)additional additionalYERVOY-treated YERVOY-treatedpatients patientsexperienced experiencedmoderate moderatehepatotoxicity hepatotoxicitymanifested manifestedby by LFT LFTabnormalities abnormalities(AST (ASTor orALT ALTelevations elevations>2.5× >2.5×but but≤5× ≤5×the theULN ULNor ortotal totalbilirubin bilirubinelevation elevation>1.5× >1.5× but but≤3× ≤3×the theULN; ULN;Grade Grade2) 2) ••Monitor MonitorLFTs LFTs(hepatic (hepatictransaminase transaminaseand andbilirubin bilirubinlevels) levels)and andassess assesspatients patientsfor forsigns signsand and symptoms symptomsof ofhepatotoxicity hepatotoxicitybefore beforeeach eachdose doseof ofYERVOY. YERVOY.In Inpatients patientswith withhepatotoxicity, hepatotoxicity,rule ruleout out infectious infectiousor ormalignant malignantcauses causesand andincrease increasefrequency frequencyof ofLFT LFTmonitoring monitoringuntil untilresolution resolution ••Permanently Permanentlydiscontinue discontinueYERVOY YERVOYin inpatients patientswith withGrade Grade3-5 3-5hepatotoxicity hepatotoxicityand andadminister administersystemic systemic corticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayof ofprednisone prednisoneor orequivalent). equivalent).When WhenLFTs LFTsshow showsustained sustained improvement improvementor orreturn returnto tobaseline, baseline,initiate initiatecorticosteroid corticosteroidtapering taperingand andcontinue continueover over11month. month. Across Acrossthe theclinical clinicaldevelopment developmentprogram programfor forYERVOY, YERVOY,mycophenolate mycophenolatetreatment treatmenthas hasbeen been administered administeredin inpatients patientswith withpersistent persistentsevere severehepatitis hepatitisdespite despitehigh-dose high-dosecorticosteroids corticosteroids ••Withhold WithholdYERVOY YERVOYin inpatients patientswith withGrade Grade22hepatotoxicity hepatotoxicity Immune-mediated Immune-mediated Dermatitis: Dermatitis: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY-treated YERVOY-treatedpatients, patients,severe, severe,life-threatening, life-threatening,or orfatal fatal immune-mediated immune-mediateddermatitis dermatitis(e.g., (e.g.,Stevens-Johnson Stevens-Johnsonsyndrome, syndrome,toxic toxicepidermal epidermalnecrolysis, necrolysis,or orrash rash complicated complicatedby byfull fullthickness thicknessdermal dermalulceration, ulceration,or ornecrotic, necrotic,bullous, bullous,or orhemorrhagic hemorrhagicmanifestations; manifestations; Grade Grade3–5) 3–5)occurred occurredin in13 13(2.5%) (2.5%)patients patients ––11(0.2%) (0.2%)patient patientdied diedas asaaresult resultof oftoxic toxicepidermal epidermalnecrolysis necrolysis ––11additional additionalpatient patientrequired requiredhospitalization hospitalizationfor forsevere severedermatitis dermatitis ••There Therewere were63 63(12%) (12%)YERVOY-treated YERVOY-treatedpatients patientswith withmoderate moderate(Grade (Grade2) 2)dermatitis dermatitis ••Monitor Monitorpatients patientsfor forsigns signsand andsymptoms symptomsof ofdermatitis dermatitissuch suchas asrash rashand andpruritus. pruritus.Unless Unlessan an alternate alternateetiology etiologyhas hasbeen beenidentified, identified,signs signsor orsymptoms symptomsof ofdermatitis dermatitisshould shouldbe beconsidered considered immune-mediated immune-mediated ••Permanently Permanentlydiscontinue discontinueYERVOY YERVOYin inpatients patientswith withsevere, severe,life-threatening, life-threatening,or orfatal fatalimmune-mediated immune-mediated dermatitis dermatitis(Grade (Grade3-5). 3-5).Administer Administersystemic systemiccorticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayof ofprednisone prednisoneor or equivalent). equivalent).When Whendermatitis dermatitisisiscontrolled, controlled,corticosteroid corticosteroidtapering taperingshould shouldoccur occurover overaaperiod periodof ofat at least least11month. month.Withhold WithholdYERVOY YERVOYin inpatients patientswith withmoderate moderateto tosevere severesigns signsand andsymptoms symptoms ••Treat Treatmild mildto tomoderate moderatedermatitis dermatitis(e.g., (e.g.,localized localizedrash rashand andpruritus) pruritus)symptomatically. symptomatically.Administer Administer topical topicalor orsystemic systemiccorticosteroids corticosteroidsififthere thereisisno noimprovement improvementwithin within11week week Immune-mediated Immune-mediated Neuropathies: Neuropathies: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY-treated YERVOY-treatedpatients, patients,11case caseof offatal fatalGuillain-Barré Guillain-Barrésyndrome syndrome and and11case caseof ofsevere severe(Grade (Grade3) 3)peripheral peripheralmotor motorneuropathy neuropathywere werereported reported ••Across Acrossthe theclinical clinicaldevelopment developmentprogram programof ofYERVOY, YERVOY,myasthenia myastheniagravis gravisand andadditional additionalcases casesof of Guillain-Barré Guillain-Barrésyndrome syndromehave havebeen beenreported reported ••Monitor Monitorfor forsymptoms symptomsof ofmotor motoror orsensory sensoryneuropathy neuropathysuch suchas asunilateral unilateralor orbilateral bilateralweakness, weakness, sensory sensoryalterations, alterations,or orparesthesia. paresthesia.Permanently Permanentlydiscontinue discontinueYERVOY YERVOYin inpatients patientswith withsevere severe neuropathy neuropathy(interfering (interferingwith withdaily dailyactivities) activities)such suchas asGuillain-Barré–like Guillain-Barré–likesyndromes syndromes ••Institute Institutemedical medicalintervention interventionas asappropriate appropriatefor formanagement managementof ofsevere severeneuropathy. neuropathy.Consider Consider initiation initiationof ofsystemic systemiccorticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayof ofprednisone prednisoneor orequivalent) equivalent)for forsevere severe neuropathies. neuropathies.Withhold WithholdYERVOY YERVOYin inpatients patientswith withmoderate moderateneuropathy neuropathy(not (notinterfering interferingwith with daily dailyactivities) activities) Immune-mediated Immune-mediated Endocrinopathies: Endocrinopathies: ••In Inthe thepivotal pivotalPhase Phase33study studyin inYERVOY-treated YERVOY-treatedpatients, patients,severe severeto tolife-threatening life-threateningimmuneimmunemediated mediatedendocrinopathies endocrinopathies(requiring (requiringhospitalization, hospitalization,urgent urgentmedical medicalintervention, intervention,or orinterfering interferingwith with activities activitiesof ofdaily dailyliving; living;Grade Grade3-4) 3-4)occurred occurredin in99(1.8%) (1.8%)patients patients Important ImportantSafety SafetyInformation Informationcontinued continuedon onfollowing followingpage. page.

The following panel leadership changes were announced at a recent OARAC meeting: John G. Bartlett, MD, will retire from his position as Panel Co-Chair at the end of 2013, a position he has held since the continued on page 94

The ASCO Post | DECEMBER 15, 2013

PAGE 94

Announcement

Antiretroviral Guidelines Panel Co-Chairs continued from page 93

panel’s creation in 1996. Dr. Bartlett is Professor Emeritus of Medicine in the Division of Infectious Diseases at The Johns Hopkins University School of Medicine in Baltimore. He served as Chief of the Infectious Diseases

Division for 26 years before stepping down in 1996. He is a member of the Institute of Medicine, a master of the American College of Physicians, and Past President of the Infectious Diseases Society of America. Roy M. Gulick, MD, MPH, has been named as one of two new Panel Co-Chairs. Currently a Professor of Medicine and Chief of the Division of Infectious Diseases at Weill

Medical College of Cornell University in New York, Dr. Gulick served as a panel member from 2002 to March 2013. An expert on antiretroviral treatment strategies, new antiretroviral agents, clinical trial design and clinical management of HIV infection, Dr. Gulick currently serves as

Roy M. Gulick, MD, MPH

Martin S. Hirsch, MD

Important ImportantSafety SafetyInformation Information(cont’d) (cont’d) Immune-mediated Immune-mediatedEndocrinopathies Endocrinopathies(cont’d): (cont’d): ––All All99patients patientshad hadhypopituitarism, hypopituitarism,and andsome somehad hadadditional additionalconcomitant concomitantendocrinopathies endocrinopathiessuch such asasadrenal adrenalinsufficiency, insufficiency,hypogonadism, hypogonadism,and andhypothyroidism hypothyroidism ––66ofofthe the99patients patientswere werehospitalized hospitalizedfor forsevere severeendocrinopathies endocrinopathies ••Moderate Moderateendocrinopathy endocrinopathy(requiring (requiringhormone hormonereplacement replacementorormedical medicalintervention; intervention;Grade Grade2)2) occurred occurredinin12 12(2.3%) (2.3%)YERVOY YERVOY(ipilimumab)-treated (ipilimumab)-treatedpatients patientsand andconsisted consistedofofhypothyroidism, hypothyroidism, adrenal adrenalinsufficiency, insufficiency,hypopituitarism, hypopituitarism,and and11case caseeach eachofofhyperthyroidism hyperthyroidismand andCushing’s Cushing’ssyndrome syndrome ••Median Mediantime timetotoonset onsetofofmoderate moderatetotosevere severeimmune-mediated immune-mediatedendocrinopathy endocrinopathywas was11 11weeks weeksand and ranged rangedup uptoto19.3 19.3weeks weeksafter afterthe theinitiation initiationofofYERVOY YERVOY ••Monitor Monitorpatients patientsfor forclinical clinicalsigns signsand andsymptoms symptomsofofhypophysitis, hypophysitis,adrenal adrenalinsufficiency insufficiency(including (including adrenal adrenalcrisis), crisis),and andhyperhyper-ororhypothyroidism hypothyroidism ––Patients Patientsmay maypresent presentwith withfatigue, fatigue,headache, headache,mental mentalstatus statuschanges, changes,abdominal abdominalpain, pain,unusual unusual bowel bowelhabits, habits,and andhypotension, hypotension,orornonspecific nonspecificsymptoms symptomswhich whichmay mayresemble resembleother othercauses causessuch such asasbrain brainmetastasis metastasisororunderlying underlyingdisease. disease.Unless Unlessan analternate alternateetiology etiologyhas hasbeen beenidentified, identified,signs signs ororsymptoms symptomsshould shouldbe beconsidered consideredimmune-mediated immune-mediated ––Monitor Monitorthyroid thyroidfunction functiontests testsand andclinical clinicalchemistries chemistriesatatthe thestart startofoftreatment, treatment,before beforeeach eachdose, dose, and andasasclinically clinicallyindicated indicatedbased basedon onsymptoms. symptoms.InInaalimited limitednumber numberofofpatients, patients,hypophysitis hypophysitiswas was diagnosed diagnosedby byimaging imagingstudies studiesthrough throughenlargement enlargementofofthe thepituitary pituitarygland gland ••Withhold WithholdYERVOY YERVOYininsymptomatic symptomaticpatients. patients.Initiate Initiatesystemic systemiccorticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayofof prednisone prednisoneororequivalent) equivalent)and andinitiate initiateappropriate appropriatehormone hormonereplacement replacementtherapy. therapy.Long-term Long-term hormone hormonereplacement replacementtherapy therapymay maybe benecessary necessary Other OtherImmune-mediated Immune-mediatedAdverse AdverseReactions, Reactions,Including IncludingOcular OcularManifestations: Manifestations: ••InInthe thepivotal pivotalPhase Phase33study studyininYERVOY-treated YERVOY-treatedpatients, patients,clinically clinicallysignificant significantimmune-mediated immune-mediated adverse adversereactions reactionsseen seeninin<1% <1%were: were:nephritis, nephritis,pneumonitis, pneumonitis,meningitis, meningitis,pericarditis, pericarditis,uveitis, uveitis,iritis, iritis, and andhemolytic hemolyticanemia anemia ••Across Acrossthe theclinical clinicaldevelopment developmentprogram programfor forYERVOY, YERVOY,likely likelyimmune-mediated immune-mediatedadverse adversereactions reactions also alsoreported reportedwith with<1% <1%incidence incidencewere: were:myocarditis, myocarditis,angiopathy, angiopathy,temporal temporalarteritis, arteritis,vasculitis, vasculitis, polymyalgia polymyalgiarheumatica, rheumatica,conjunctivitis, conjunctivitis,blepharitis, blepharitis,episcleritis, episcleritis,scleritis, scleritis,leukocytoclastic leukocytoclasticvasculitis, vasculitis, erythema erythemamultiforme, multiforme,psoriasis, psoriasis,pancreatitis, pancreatitis,arthritis, arthritis,autoimmune autoimmunethyroiditis, thyroiditis,sarcoidosis, sarcoidosis, neurosensory neurosensoryhypoacusis, hypoacusis,autoimmune autoimmunecentral centralneuropathy neuropathy(encephalitis), (encephalitis),myositis, myositis,polymyositis, polymyositis, and andocular ocularmyositis myositis ••Permanently Permanentlydiscontinue discontinueYERVOY YERVOYfor forclinically clinicallysignificant significantororsevere severeimmune-mediated immune-mediatedadverse adverse reactions. reactions.Initiate Initiatesystemic systemiccorticosteroids corticosteroids(1-2 (1-2mg/kg/day mg/kg/dayofofprednisone prednisoneororequivalent) equivalent)for forsevere severe immune-mediated immune-mediatedadverse adversereactions reactions ••Administer Administercorticosteroid corticosteroideye eyedrops dropsfor foruveitis, uveitis,iritis, iritis,ororepiscleritis. episcleritis.Permanently Permanentlydiscontinue discontinue YERVOY YERVOYfor forimmune-mediated immune-mediatedocular oculardisease diseaseunresponsive unresponsivetotolocal localimmunosuppressive immunosuppressivetherapy therapy Pregnancy Pregnancy&&Nursing: Nursing: ••YERVOY YERVOYisisclassified classifiedasaspregnancy pregnancycategory categoryC.C.There Thereare areno noadequate adequateand andwell-controlled well-controlledstudies studies ofofYERVOY YERVOYininpregnant pregnantwomen. women.Use UseYERVOY YERVOYduring duringpregnancy pregnancyonly onlyififthe thepotential potentialbenefit benefitjustifies justifies the thepotential potentialrisk risktotothe thefetus fetus ••Human HumanIgG1 IgG1isisknown knowntotocross crossthe theplacental placentalbarrier barrierand andYERVOY YERVOYisisan anIgG1; IgG1;therefore, therefore,YERVOY YERVOY has hasthe thepotential potentialtotobe betransmitted transmittedfrom fromthe themother mothertotothe thedeveloping developingfetus fetus ••ItItisisnot notknown knownwhether whetherYERVOY YERVOYisissecreted secretedininhuman humanmilk. milk.Because Becausemany manydrugs drugsare aresecreted secretedinin human humanmilk milkand andbecause becauseofofthe thepotential potentialfor forserious seriousadverse adversereactions reactionsininnursing nursinginfants infantsfrom from YERVOY, YERVOY,aadecision decisionshould shouldbe bemade madewhether whethertotodiscontinue discontinuenursing nursingorortotodiscontinue discontinueYERVOY YERVOY Common CommonAdverse AdverseReactions: Reactions: ••The Themost mostcommon commonadverse adversereactions reactions(≥5%) (≥5%)ininpatients patientswho whoreceived receivedYERVOY YERVOYatat33mg/kg mg/kgwere were fatigue fatigue(41%), (41%),diarrhea diarrhea(32%), (32%),pruritus pruritus(31%), (31%),rash rash(29%), (29%),and andcolitis colitis(8%) (8%) Please Pleasesee seebrief briefsummary summaryofofFull FullPrescribing PrescribingInformation, Information,including includingBoxed BoxedWARNING WARNINGregarding regardingimmune-mediated immune-mediatedside sideeffects, effects,ononfollowing followingpages. pages. References: References:1. 1.Hodi HodiFS,FS,O’Day O’DaySJ,SJ,McDermott McDermottDF,DF,etetal.al.Improved Improvedsurvival survivalwith withipilimumab ipilimumabin inpatients patientswith withmetastatic metastaticmelanoma. melanoma.N NEngl EnglJ Med. J Med.2010;363(8):711-723. 2010;363(8):711-723. YERVOYpackage packageinsert. insert.Princeton, Princeton,NJ:NJ:Bristol-Myers Bristol-MyersSquibb SquibbCompany. Company.3.3.Data Dataononfile. file.YERV YERV008. 008.Bristol-Myers Bristol-MyersSquibb SquibbCompany. Company.Princeton, Princeton,NJ.NJ.April April2011. 2011. 2.2.YERVOY

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Announcements

principal investigator of the Cornell HIV Clinical Trials Unit, part of the NIH-funded AIDS Clinical Trials Group (ACTG). Additionally, he is Co-Chair of the Forum for Collaborative HIV Research, a board member of the International AIDS Society-USA, and a member of the American Society of Clinical Investigation. Dr. Gulick served as chairman of the FDA Antiviral Drugs Advi-

sory Committee from 2001 to 2004. Martin S. Hirsch, MD, has been named as the second new Panel CoChair. Dr. Hirsch currently is a Professor of Medicine at Harvard Medical School, Professor of Immunology and Infectious Diseases at the Harvard School of Public Health, and a physician at Massachusetts General Hospital, Boston. Serving on the

® (ipilimumab) ® (ipilimumab) YERVOY YERVOY Injection, Injection, forfor intravenous intravenous infusion infusion

Brief Brief Summary Summary of Prescribing of Prescribing Information. Information. ForFor complete complete prescribing prescribing information information consult consult official official package package insert. insert. WARNING: WARNING: IMMUNE-MEDIATED IMMUNE-MEDIATED ADVERSE ADVERSE REACTIONS REACTIONS YERVOY YERVOY (ipilimumab) (ipilimumab) cancan result result in in severe severe andand fatal fatal immune-mediated immune-mediated adverse adverse reactions reactions duedue to to T-cell T-cell activation activation andand proliferation. proliferation. These These immune-mediated immune-mediated reactions reactions may may involve involve anyany organ organ system; system; however, however, thethe most most common common severe severe immune-mediated immune-mediated adverse adverse reactions reactions areare enterocolitis, enterocolitis, hepatitis, hepatitis, dermatitis dermatitis (including (including toxic toxic epidermal epidermal necrolysis), necrolysis), neuropathy, neuropathy, andand endocrinopathy. endocrinopathy. TheThe majority majority of of these these immune-mediated immune-mediated reactions reactions initially initially manifested manifested during during treatment; treatment; however, however, a a minority minority occurred occurred weeks weeks to to months months after after discontinuation discontinuation of of YERVOY. YERVOY. Permanently Permanently discontinue discontinue YERVOY YERVOY andand initiate initiate systemic systemic high-dose high-dose corticosteroid corticosteroid therapy therapy forfor severe severe immune-mediated immune-mediated reactions. reactions. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in in FullFull Prescribing Prescribing Information.] Information.] Assess Assesspatients patientsforforsigns signsandandsymptoms symptomsof ofenterocolitis, enterocolitis,dermatitis, dermatitis,neuropathy, neuropathy,andand endocrinopathy endocrinopathy andand evaluate evaluate clinical clinical chemistries chemistries including including liver liver function function tests tests andand thyroid thyroid function function tests tests at at baseline baseline andand before before each each dose. dose. [See [See Warnings Warnings andand Precautions.] Precautions.] INDICATIONS INDICATIONS AND AND USAGE USAGE YERVOY YERVOY (ipilimumab) (ipilimumab) is indicated is indicated forfor thethe treatment treatment of unresectable of unresectable or metastatic or metastatic melanoma. melanoma. CONTRAINDICATIONS CONTRAINDICATIONS None. None. WARNINGS WARNINGS AND AND PRECAUTIONS PRECAUTIONS YERVOY YERVOY cancan result result in severe in severe andand fatal fatal immune-mediated immune-mediated reactions reactions duedue to T-cell to T-cell activation activation andand proliferation. proliferation. [See [See Boxed Boxed Warning.] Warning.] Immune-mediated Immune-mediated Enterocolitis Enterocolitis In In Study Study 1, 1, severe, severe, life-threatening, life-threatening, or or fatal fatal (diarrhea (diarrhea of of 7 or 7 or more more stools stools above above baseline, baseline, fever, fever, ileus, ileus, peritoneal peritoneal signs; signs; Grade Grade 3–5) 3–5) immune-mediated immune-mediated enterocolitis enterocolitis occurred occurred in 34 in 34 (7%) (7%) YERVOY-treated YERVOY-treated patients, patients, andand moderate moderate (diarrhea (diarrhea with with up up to 6tostools 6 stools above above baseline, baseline, abdominal abdominal pain, pain, mucus mucus or blood or blood in stool; in stool; Grade Grade 2) enterocolitis 2) enterocolitis occurred occurred in 28 in 28 (5%) (5%) YERVOY-treated YERVOY-treated patients. patients. Across Across all all YERVOY-treated YERVOY-treated patients patients (n=511), (n=511), 5 (1%) 5 (1%) patients patients developed developed intestinal intestinal perforation, perforation, 4 (0.8%) 4 (0.8%) patients patients died died as as a result a result of complications, of complications, andand 2626 (5%) (5%) patients patients were were hospitalized hospitalized forfor severe severe enterocolitis. enterocolitis. TheThe median median time time to to onset onset was was 7.47.4 weeks weeks (range: (range: 1.6–13.4) 1.6–13.4) andand 6.36.3 weeks weeks (range: (range: 0.3–18.9) 0.3–18.9) after after thethe initiation initiation of YERVOY of YERVOY forfor patients patients with with Grade Grade 3–53–5 enterocolitis enterocolitis andand with with Grade Grade 2 enterocolitis, 2 enterocolitis, respectively. respectively. Twenty-nine Twenty-nine patients patients (85%) (85%) with with Grade Grade 3–53–5 enterocolitis enterocolitis were were treated treated with with high-dose high-dose (≥40 (≥40 mgmg prednisone prednisone equivalent equivalent perper day) day) corticosteroids, corticosteroids, with with a median a median dose dose of of 8080 mg/day mg/day of of prednisone prednisone or or equivalent; equivalent; thethe median median duration duration of treatment of treatment was was 2.32.3 weeks weeks (ranging (ranging up up to 13.9 to 13.9 weeks) weeks) followed followed by by corticosteroid corticosteroid taper. taper. Of Of thethe 2828 patients patients with with moderate moderate enterocolitis, enterocolitis, 46% 46% were were notnot treated treated with with systemic systemic corticosteroids, corticosteroids, 29% 29% were were treated treated with with <40 <40 mgmg prednisone prednisone or or equivalent equivalent perper dayday forfor a median a median duration duration of of 5.15.1 weeks, weeks, andand 25% 25% were were treated treated with with high-dose high-dose corticosteroids corticosteroids forfor a median a median duration duration of 10 of 10 days days prior prior to corticosteroid to corticosteroid taper. taper. Infliximab Infliximab was was administered administered to 5to of5 the of the 6262 patients patients (8%) (8%) with with moderate, moderate, severe, severe, or or life-threatening life-threatening immune-mediated immune-mediated enterocolitis enterocolitis following following inadequate inadequate response response to corticosteroids. to corticosteroids. Of Of thethe 3434 patients patients with with Grade Grade 3–53–5 enterocolitis, enterocolitis, 74% 74% experienced experienced complete complete resolution, resolution, 3%3% experienced experienced improvement improvement to to Grade Grade 2 severity, 2 severity, andand 24% 24% diddid notnot improve. improve. Among Among thethe 2828 patients patients with with Grade Grade 2 2 enterocolitis, enterocolitis, 79% 79% experienced experienced complete complete resolution, resolution, 11% 11% improved, improved, andand 11% 11% diddid notnot improve. improve. Monitor Monitor patients patients forfor signs signs andand symptoms symptoms of of enterocolitis enterocolitis (such (such as as diarrhea, diarrhea, abdominal abdominal pain, pain, mucus mucus or or blood blood in in stool, stool, with with or or without without fever) fever) andand of of bowel bowel perforation perforation (such (such as as peritoneal peritoneal signs signs andand ileus). ileus). In In symptomatic symptomatic patients, patients, rulerule outout infectious infectious etiologies etiologies andand consider consider endoscopic endoscopic evaluation evaluation forfor persistent persistent or or severe severe symptoms. symptoms. Permanently Permanently discontinue discontinue YERVOY YERVOY in patients in patients with with severe severe enterocolitis enterocolitis andand initiate initiate systemic systemic corticosteroids corticosteroids at at a dose a dose of 1of to1 2to mg/kg/day 2 mg/kg/day of prednisone of prednisone or or equivalent. equivalent. Upon Upon improvement improvement to Grade to Grade 1 or 1 or less, less, initiate initiate corticosteroid corticosteroid taper taper andand continue continue to to taper taper over over at at least least 1 month. 1 month. In In clinical clinical trials, trials, rapid rapid corticosteroid corticosteroid tapering tapering resulted resulted in recurrence in recurrence or worsening or worsening symptoms symptoms of enterocolitis of enterocolitis in some in some patients. patients. Withhold Withhold YERVOY YERVOY dosing dosing forfor moderate moderate enterocolitis; enterocolitis; administer administer anti-diarrheal anti-diarrheal treatment treatment and, and, if persistent if persistent forfor more more than than 1 week, 1 week, initiate initiate systemic systemic corticosteroids corticosteroids at aatdose a dose of 0.5 of 0.5 mg/kg/day mg/kg/day prednisone prednisone or equivalent. or equivalent. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] Immune-mediated Immune-mediated Hepatitis Hepatitis In Study In Study 1, severe, 1, severe, life-threatening, life-threatening, or or fatal fatal hepatotoxicity hepatotoxicity (AST (AST or ALT or ALT elevations elevations of more of more than than 5 times 5 times thethe upper upper limit limit of normal of normal or or total total bilirubin bilirubin elevations elevations more more than than 3 times 3 times thethe upper upper limit limit of normal; of normal; Grade Grade 3–5) 3–5) occurred occurred in 8in(2%) 8 (2%) YERVOY-treated YERVOY-treated patients, patients, with with fatal fatal hepatic hepatic failure failure in 0.2% in 0.2% andand hospitalization hospitalization in 0.4% in 0.4% of of YERVOY-treated YERVOY-treated patients. patients. AnAn additional additional 1313 (2.5%) (2.5%) patients patients experienced experienced moderate moderate hepatotoxicity hepatotoxicity manifested manifested by by liver liver function function testtest abnormalities abnormalities (AST (AST or ALT or ALT elevations elevations of more of more than than 2.52.5 times times butbut notnot more more than than 5 times 5 times thethe upper upper limit limit of normal of normal or or total total bilirubin bilirubin elevation elevation of more of more than than 1.51.5 times times butbut notnot more more than than 3 times 3 times thethe upper upper limit limit of normal; of normal; Grade Grade 2).2). TheThe underlying underlying pathology pathology was was notnot ascertained ascertained in all in all patients patients butbut in some in some instances instances included included immune-mediated immune-mediated hepatitis. hepatitis. There There were were insufficient insufficient numbers numbers of patients of patients with with biopsybiopsyproven proven hepatitis hepatitis to characterize to characterize thethe clinical clinical course course of this of this event. event. Monitor Monitor liver liver function function tests tests (hepatic (hepatic transaminase transaminase andand bilirubin bilirubin levels) levels) andand assess assess patients patients forfor signs signs andand symptoms symptoms of hepatotoxicity of hepatotoxicity before before each each dose dose of YERVOY. of YERVOY. In patients In patients with with hepatotoxicity, hepatotoxicity, rulerule outout infectious infectious or malignant or malignant causes causes andand increase increase frequency frequency of liver of liver function function testtest monitoring monitoring until until resolution. resolution. Permanently Permanently discontinue discontinue YERVOY YERVOY in in patients patients with with Grade Grade 3–53–5 hepatotoxicity hepatotoxicity andand administer administer systemic systemic corticosteroids corticosteroids at at a dose a dose of of 1 to 1 to 2 mg/kg/day 2 mg/kg/day of of prednisone prednisone or or equivalent. equivalent. When When liver liver function function tests tests show show sustained sustained improvement improvement or or return return to to baseline, baseline, initiate initiate corticosteroid corticosteroid tapering tapering andand continue continue to to taper taper over over 1 month. 1 month. Across Across thethe clinical clinical development development program program forfor YERVOY, YERVOY, mycophenolate mycophenolate treatment treatment hashas been been administered administered in patients in patients who who have have persistent persistent severe severe hepatitis hepatitis despite despite high-dose high-dose corticosteroids. corticosteroids. Withhold Withhold YERVOY YERVOY in patients in patients with with Grade Grade 2 hepatotoxicity. 2 hepatotoxicity. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] Immune-mediated Immune-mediated Dermatitis Dermatitis In Study In Study 1, severe, 1, severe, life-threatening, life-threatening, or fatal or fatal immune-mediated immune-mediated dermatitis dermatitis (eg,(eg, Stevens-Johnson Stevens-Johnson syndrome, syndrome, toxic toxic epidermal epidermal necrolysis, necrolysis, or or rash rash complicated complicated by by fullfull thickness thickness dermal dermal ulceration, ulceration, or or necrotic, necrotic, bullous, bullous, or or hemorrhagic hemorrhagic manifestations; manifestations; Grade Grade 3–5) 3–5) occurred occurred in in 1313 (2.5%) (2.5%) YERVOY-treated YERVOY-treated patients. patients. OneOne (0.2%) (0.2%) patient patient died died as as a result a result of toxic of toxic epidermal epidermal necrolysis necrolysis andand oneone additional additional patient patient required required hospitalization hospitalization forfor severe severe dermatitis. dermatitis. There There were were 6363 (12%) (12%) patients patients with with moderate moderate (Grade (Grade 2) dermatitis. 2) dermatitis.

Yrv0513pbs_731US13PBS02301wip2.indd Yrv0513pbs_731US13PBS02301wip2.indd1 1

panel from 1996 to 2012, Dr. Hirsch contributed to guidelines on managing drug resistance and other topics. His laboratory was the first to demonstrate that certain combinations of antiretrovirals had synergistic anti-HIV activity and was central to bringing these findings into large-scale human clinical trials performed within the ACTG. Dr. Hirsch was the first chair

of the ACTG and served as director of the Harvard AIDS Clinical Trials Unit from 1986 to 2003. Dr. Hirsch is also editor-inchief of the Journal of Infectious Diseases. Dr. Gulick and Dr. Hirsch will work alongside the third Panel Co-Chair H. Clifford Lane, MD, NIAID’s Clinical Director. Dr. Lane has served as a Panel CoChair since 2004. n

TheThe median median time time to to onset onset of of moderate, moderate, severe, severe, or or life-threatening life-threatening immune-mediated immune-mediated dermatitis dermatitis was was 3.13.1 weeks weeks andand ranged ranged up up to 17.3 to 17.3 weeks weeks from from thethe initiation initiation of YERVOY of YERVOY (ipilimumab). (ipilimumab). Seven Seven (54%) (54%) YERVOY-treated YERVOY-treated patients patients with with severe severe dermatitis dermatitis received received high-dose high-dose corticosteroids corticosteroids (median (median dose dose 6060 mgmg prednisone/day prednisone/day or or equivalent) equivalent) forfor up up to 14.9 to 14.9 weeks weeks followed followed by by corticosteroid corticosteroid taper. taper. Of Of these these 7 patients, 7 patients, 6 had 6 had complete complete resolution; resolution; time time to resolution to resolution ranged ranged up up to 15.6 to 15.6 weeks. weeks. Of Of thethe 6363 patients patients with with moderate moderate dermatitis, dermatitis, 2525 (40%) (40%) were were treated treated with with systemic systemic corticosteroids corticosteroids (median (median of of 6060 mg/day mg/day of of prednisone prednisone or or equivalent) equivalent) forfor a median a median of of 2.12.1 weeks, weeks, 7 (11%) 7 (11%) were were treated treated with with only only topical topical corticosteroids, corticosteroids, andand 3131 (49%) (49%) diddid notnot receive receive systemic systemic or or topical topical corticosteroids. corticosteroids. Forty-four Forty-four (70%) (70%) patients patients with with moderate moderate dermatitis dermatitis were were reported reported to to have have complete complete resolution, resolution, 7 (11%) 7 (11%) improved improved to to mild mild (Grade (Grade 1) severity, 1) severity, andand 1212 (19%) (19%) hadhad no no reported reported improvement. improvement. Monitor Monitor patients patients forfor signs signs andand symptoms symptoms of of dermatitis dermatitis such such as as rash rash andand pruritus. pruritus. Unless Unless an an alternate alternate etiology etiology hashas been been identified, identified, signs signs or symptoms or symptoms of dermatitis of dermatitis should should be be considered considered immune-mediated. immune-mediated. Permanently Permanently discontinue discontinue YERVOY YERVOY in patients in patients with with Stevens-Johnson Stevens-Johnson syndrome, syndrome, toxic toxic epidermal epidermal necrolysis, necrolysis, or rash or rash complicated complicated by by fullfull thickness thickness dermal dermal ulceration, ulceration, or necrotic, or necrotic, bullous, bullous, or hemorrhagic or hemorrhagic manifestations. manifestations. Administer Administer systemic systemic corticosteroids corticosteroids at at a dose a dose of of 1 to 1 to 2 mg/kg/day 2 mg/kg/day of of prednisone prednisone or or equivalent. equivalent. When When dermatitis dermatitis is controlled, is controlled, corticosteroid corticosteroid tapering tapering should should occur occur over over a period a period of of at at least least 1 month. 1 month. Withhold Withhold YERVOY YERVOY dosing dosing in patients in patients with with moderate moderate to severe to severe signs signs andand symptoms. symptoms. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] ForFor mild mild to to moderate moderate dermatitis, dermatitis, such such as as localized localized rash rash andand pruritus, pruritus, treat treat symptomatically. symptomatically. Administer Administer topical topical or systemic or systemic corticosteroids corticosteroids if there if there is no is no improvement improvement of symptoms of symptoms within within 1 week. 1 week. Immune-mediated Immune-mediated Neuropathies Neuropathies In In Study Study 1, 1, 1 case 1 case of of fatal fatal Guillain-Barré Guillain-Barré syndrome syndrome andand 1 case 1 case of of severe severe (Grade (Grade 3) 3) peripheral peripheral motor motor neuropathy neuropathy were were reported. reported. Across Across thethe clinical clinical development development program program of of YERVOY, YERVOY, myasthenia myasthenia gravis gravis andand additional additional cases cases of Guillain-Barré of Guillain-Barré syndrome syndrome have have been been reported. reported. Monitor Monitor forfor symptoms symptoms of of motor motor or or sensory sensory neuropathy neuropathy such such as as unilateral unilateral or or bilateral bilateral weakness, weakness, sensory sensory alterations, alterations, or paresthesia. or paresthesia. Permanently Permanently discontinue discontinue YERVOY YERVOY in patients in patients with with severe severe neuropathy neuropathy (interfering (interfering with with daily daily activities) activities) such such as as Guillain-Barré-like Guillain-Barré-like syndromes. syndromes. Institute Institute medical medical intervention intervention as as appropriate appropriate forfor management management of of severe severe neuropathy. neuropathy. Consider Consider initiation initiation of of systemic systemic corticosteroids corticosteroids at at a dose a dose of of 1 to 1 to 2 mg/kg/day 2 mg/kg/day prednisone prednisone or or equivalent equivalent forfor severe severe neuropathies. neuropathies. Withhold Withhold YERVOY YERVOY dosing dosing in patients in patients with with moderate moderate neuropathy neuropathy (not(not interfering interfering with with daily daily activities). activities). [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in in FullFull Prescribing Prescribing Information.] Information.] Immune-mediated Immune-mediated Endocrinopathies Endocrinopathies In InStudy Study1, 1,severe severeto tolife-threatening life-threateningimmune-mediated immune-mediatedendocrinopathies endocrinopathies(requiring (requiringhospitalization, hospitalization, urgent urgent medical medical intervention, intervention, or or interfering interfering with with activities activities of of daily daily living; living; Grade Grade 3–4) 3–4) occurred occurred in 9in (1.8%) 9 (1.8%) YERVOY-treated YERVOY-treatedpatients. patients. All All9 9patients patientshadhadhypopituitarism hypopituitarismandandsome somehadhadadditional additionalconcomitant concomitant endocrinopathies endocrinopathies such such as as adrenal adrenal insufficiency, insufficiency, hypogonadism, hypogonadism, andand hypothyroidism. hypothyroidism. SixSix of of thethe 9 patients 9 patients were were hospitalized hospitalized forfor severe severe endocrinopathies. endocrinopathies. Moderate Moderate endocrinopathy endocrinopathy (requiring (requiring hormone hormone replacement replacement or or medical medical intervention; intervention; Grade Grade 2) occurred 2) occurred in 12 in 12 (2.3%) (2.3%) patients patients andand consisted consisted of hypothyroidism, of hypothyroidism, adrenal adrenal insufficiency, insufficiency, hypopituitarism, hypopituitarism, andand 1 case 1 case each each of of hyperthyroidism hyperthyroidism andand Cushing’s Cushing’s syndrome. syndrome. TheThe median median time time to to onset onset of of moderate moderate to to severe severe immune-mediated immune-mediated endocrinopathy endocrinopathy was was 1111 weeks weeks andand ranged ranged up up to to 19.3 19.3 weeks weeks after after thethe initiation initiation of YERVOY. of YERVOY. Of Of thethe 2121 patients patients with with moderate moderate to to life-threatening life-threatening endocrinopathy, endocrinopathy, 1717 patients patients required required long-term long-term hormone hormone replacement replacement therapy therapy including, including, most most commonly, commonly, adrenal adrenal hormones hormones (n=10) (n=10) andand thyroid thyroid hormones hormones (n=13). (n=13). Monitor Monitor patients patients forfor clinical clinical signs signs andand symptoms symptoms of of hypophysitis, hypophysitis, adrenal adrenal insufficiency insufficiency (including (including adrenal adrenal crisis), crisis), andand hyperhyperor hypothyroidism. or hypothyroidism. Patients Patients may may present present with with fatigue, fatigue, headache, headache, mental mental status status changes, changes, abdominal abdominal pain, pain, unusual unusual bowel bowel habits, habits, andand hypotension, hypotension, or or nonspecific nonspecific symptoms symptoms which which may may resemble resemble other other causes causes such such as as brain brain metastasis metastasis or or underlying underlying disease. disease. Unless Unless an an alternate alternate etiology etiology hashas been been identified, identified, signs signs or symptoms or symptoms of endocrinopathies of endocrinopathies should should be be considered considered immune-mediated. immune-mediated. Monitor Monitor thyroid thyroid function function tests tests andand clinical clinical chemistries chemistries at at thethe start start of of treatment, treatment, before before each each dose, dose, andand as as clinically clinically indicated indicated based based on on symptoms. symptoms. In aIn limited a limited number number of of patients, patients, hypophysitis hypophysitis was was diagnosed diagnosed by by imaging imaging studies studies through through enlargement enlargement of the of the pituitary pituitary gland. gland. Withhold Withhold YERVOY YERVOY dosing dosing in in symptomatic symptomatic patients. patients. Initiate Initiate systemic systemic corticosteroids corticosteroids at at a dose a dose of of 1 to 1 to 2 mg/kg/day 2 mg/kg/day of of prednisone prednisone or or equivalent, equivalent, andand initiate initiate appropriate appropriate hormone hormone replacement replacement therapy. therapy. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] Other Other Immune-mediated Immune-mediated Adverse Adverse Reactions, Reactions, Including Including Ocular Ocular Manifestations Manifestations TheThe following following clinically clinically significant significant immune-mediated immune-mediated adverse adverse reactions reactions were were seen seen in in lessless than than 1%1% of of YERVOY-treated YERVOY-treated patients patients in in Study Study 1: 1: nephritis, nephritis, pneumonitis, pneumonitis, meningitis, meningitis, pericarditis, pericarditis, uveitis, uveitis, iritis, iritis, andand hemolytic hemolytic anemia. anemia. Across Across thethe clinical clinical development development program program forfor YERVOY, YERVOY, thethe following following likely likely immune-mediated immune-mediated adverse adverse reactions reactions were were also also reported reported with with lessless than than 1%1% incidence: incidence: myocarditis, myocarditis, angiopathy, angiopathy, temporal temporal arteritis, arteritis, vasculitis, vasculitis,polymyalgia polymyalgiarheumatica, rheumatica,conjunctivitis, conjunctivitis,blepharitis, blepharitis,episcleritis, episcleritis,scleritis, scleritis,leukocytoclastic leukocytoclastic vasculitis, vasculitis, erythema erythemamultiforme, multiforme, psoriasis, psoriasis, pancreatitis, pancreatitis, arthritis, arthritis, autoimmune autoimmunethyroiditis, thyroiditis, sarcoidosis, sarcoidosis, neurosensory neurosensoryhypoacusis, hypoacusis, autoimmune autoimmunecentral centralneuropathy neuropathy(encephalitis), (encephalitis), myositis, myositis, polymyositis, polymyositis, andand ocular ocular myositis. myositis. Permanently Permanently discontinue discontinue YERVOY YERVOY forfor clinically clinically significant significant or or severe severe immune-mediated immune-mediated adverse adverse reactions. reactions. Initiate Initiate systemic systemic corticosteroids corticosteroids at aatdose a dose of 1ofto1 2tomg/kg/day 2 mg/kg/day prednisone prednisone or equivalent or equivalent forfor severe severe immuneimmunemediated mediated adverse adverse reactions. reactions. Administer Administer corticosteroid corticosteroid eyeeye drops drops to to patients patients who who develop develop uveitis, uveitis, iritis, iritis, or or episcleritis. episcleritis. Permanently Permanently discontinue discontinue YERVOY YERVOY forfor immune-mediated immune-mediated ocular ocular disease disease thatthat is unresponsive is unresponsive to local to local immunosuppressive immunosuppressive therapy. therapy. [See [See Dosage Dosage andand Administration Administration (2.2) (2.2) in Full in Full Prescribing Prescribing Information.] Information.] ADVERSE ADVERSE REACTIONS REACTIONS TheThe following following adverse adverse reactions reactions areare discussed discussed in greater in greater detail detail in other in other sections sections of the of the labeling. labeling. • •Immune-mediated Immune-mediated enterocolitis enterocolitis [see [see Warnings Warnings andand Precautions]. Precautions]. • •Immune-mediated Immune-mediated hepatitis hepatitis [see [see Warnings Warnings andand Precautions]. Precautions]. • •Immune-mediated Immune-mediated dermatitis dermatitis [see [see Warnings Warnings andand Precautions]. Precautions]. • •Immune-mediated Immune-mediated neuropathies neuropathies [see [see Warnings Warnings andand Precautions]. Precautions]. • •Immune-mediated Immune-mediated endocrinopathies endocrinopathies [see [see Warnings Warnings andand Precautions]. Precautions]. • •Other Other immune-mediated immune-mediated adverse adverse reactions, reactions, including including ocular ocular manifestations manifestations [see [see Warnings Warnings andand Precautions]. Precautions].

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Letters to the Editor

Conflict of Interest Reconsidered

Post. Dr. Weisenthal seems to be suggesting that an article in the September issue, regarding a Best of ASCO presentation by Melinda L. Telli, MD, supports (in opposition, by the way, to current ASCO guidelines) the routine clinical application of chemosensitivity assays. I don’t

read with interest the letter from Larry Weisenthal, MD, PhD, on “PlatinumBased Treatment of Triple-Negtive Breast Cancer,” which appeared in the October 15 issue of The ASCO

really think Dr. Telli was saying that. That point aside, the reason I am writing is that Dr. Weisenthal reported “no potential conflicts of interest” with the publication of his letter. On further research it appears that Dr. Weisenthal makes his living selling chemosensitiv-

ity assays; most people would identify that as a conflict of interest. n —Joseph Mason, Jr, MD San Jose, California

Dr. Weisenthal Replies

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for 4 doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information.] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range: 1–4 doses). YERVOY was discontinued for adverse reactions in 10% of patients. The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events. Table 1:

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3–5

Any Grade

Grade 3–5

Any Grade

Grade 3–5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

No formal pharmacokinetic drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy

In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition, at exposure levels either 2.6 or 7.2 times higher by AUC than the exposures at the clinical dose of 3 mg/kg of ipilimumab. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, the ipilimumab treated groups experienced higher incidences of severe toxicities including abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner compared to controls. [See Nonclinical Toxicology (13.2) in Full Prescribing Information.] Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Nursing Mothers

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Table 2:

DRUG INTERACTIONS

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Percentage (%) of Patientsa

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

Including fatal outcome. Including intestinal perforation. c Underlying etiology not established. b

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

It is not known whether ipilimumab is secreted in human milk. In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at the recommended dose, ipilimumab was present in milk at concentrations of 0.1 and 0.4 mcg/mL, representing a ratio of up to 0.3% of the serum concentration of the drug. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother. Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients. Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No dose adjustment is needed for patients with renal impairment. [See Clinical Pharmacology (12.3) in Full Prescribing Information.] Hepatic Impairment No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 × to 1.5 × the upper limit of normal [ULN] or AST >ULN). YERVOY has not been studied in patients with moderate (TB >1.5 × to 3.0 × ULN and any AST) or severe (TB >3 × ULN and any AST) hepatic impairment. [See Clinical Pharmacology (12.3) in Full Prescribing Information.] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. •

Inform patients of the potential risk of immune-mediated adverse reactions.

• Advise patients to read the YERVOY Medication Guide before each YERVOY infusion. •

Advise women that YERVOY may cause fetal harm.

•

Advise nursing mothers not to breastfeed while taking YERVOY.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1281558A4

Rev May 2013 731US13PBS02301

r. Mason states that I implied that Dr. Telli supports the routine application of chemosensitivity assays. I have no knowledge regarding Dr. Telli’s views on this subject, nor did I in any way attempt to represent her views, much less imply that she was supportive of anything relating to chemosensitivity assays. Dr. Mason also raises the issue of conflict of interest. I am an expert in chemosensitivity testing, with 35 years of largely full-time experience with the relevant technologies. Dr. Telli stated that her group was working on predictive markers to identify the best candidates for platinum treatment in breast cancer. I quoted our data presented at the 2009 Breast Cancer Symposium, which prospectively identified the best candidates for such treatment as being patients with triple-negative disease and a Bloom-Richardson score of 9/9. My laboratory provides neither marker studies for triple-negative disease nor Bloom-Richardson scoring.

Obvious vs Nonobvious Conflicts Let’s imagine that I were a pathologist, who pointed out to Dr. Telli that there was prior work suggesting that the above routine pathology markers could be useful in identifying candidates for platinum treatment. Would this be a conflict of interest? Dr. Mason seems to be implying that any expert/specialist who provides a service related to his/her comment should declare a conflict of interest. Thus, a radiotherapist commenting on a surgical study should declare a conflict of interest, a chemotherapist commenting on a radiotherapy study should declare a conflict of interest, and so forth. In my case, it was obvious from my letter that I performed chemosensitivity testing, as I quoted my own work in this field! In a similar vein, pathologists, radiotherapists, and chemotherapists generally make note of their own specialties in their comments, as workers in a particular field typically have the most relevant knowledge base, and their conflicts of interest continued on page 109

Yrv0513pbs_731US13PBS02301wip2.indd 2

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ASCO State Affiliates Focus on the Massachusetts Society of Clinical Oncologists By Jo Cavallo rier to update their policy regarding the use of antiemetics in oncology so they conform to ASCO and National Comprehensive Cancer Network (NCCN) guidelines. The ASCO Post talked with MSCO’s President, Omar Eton, MD, about the importance of being an ASCO State Affiliate and the Society’s future goals.

Massachusetts Society of Clinical Oncologists

More Effective Care Delivery Omar Eton, MD

he Massachusetts Society of Clinical Oncologists (MSCO) is among the oldest and largest of ASCO’s State Affiliates. Based in the same building as the Massachusetts Medical Society in Waltham, MSCO was founded in 1985 and has a growing membership of 160 members, including medical, surgical, and radiation oncologists as well as oncology fellows. Among the most politically active societies, MSCO realized two major victories last year. One was passage of the state’s oral chemotherapy parity law, an effort that took more than 2 years to accomplish. The second success was the negotiation with a major insurance carrier to include payment for evaluation and management services when provided on the same day as drug infusion services. Currently, MSCO is negotiating with Medicare and a local insurance car-

Why is it important for MSCO to be an ASCO State Affiliate? It is our obligation as oncologists to provide cancer patients with the most effective treatment and support; deliver care in a coordinated,

logging in billing code data that is not central to patients’ needs. With increasingly limited resources, oncologists are functioning more and more as technicians and need to take back their

Our most important goal is to protect patients from the unintended consequences of regulation and rationing of care that are deleterious to patient outcome. —Omar Eton, MD

cost-effective manner; and provide new solutions to improve treatment and care. While local societies have worked on delivery of care within state-specific parameters, this work has been fragmented and redundant across states. The result is a misalignment between regulations and effective delivery of care. Rather than focusing on the medical care of their patients, oncologists spend inordinate amounts of time

Fast Facts ■■ The Massachusetts Society of Clinical Oncologists (MSCO) was founded in 1985. ■■ The current President is Omar Eton, MD. ■■ The Society has 160 members, including oncologists, hematologists, and other cancer specialists working in community practices, hospitals, and other health-care facilities. ■■ The purpose of the Society is to foster the dissemination of information on the diagnosis, care, and treatment of cancer; to encourage and make available continuing education that addresses the needs of oncologists; to encourage the improvement of community facilities relating to the care and treatment of patients in hospitals and in other health facilities; and to participate in any activity relating to the medical care and treatment of patients with cancer. ■■ MSCO holds an annual educational meeting every fall that includes a specific topic and guest speaker and monthly Board of Director meetings to address organizational issues and new business. The Society also holds two corporate roundtable meetings each year in which members and stakeholders from pharmaceutical and insurance companies and government agencies can discuss common problems and possible solutions.

leadership role as effective captains of their team. Oncologists are looking to ASCO to establish best practices culled from across the country, and ASCO is responding by providing the latest tools for oncologists to ensure and measure quality, to provide the best value in each patient’s care. State societies and ASCO are working more closely than ever to generate clear messages so we can exercise sufficient clout on a local and national level to influence health-care policy. Unless we represent ourselves effectively, we will continue to experience imposed restrictions by business people and lawmakers. Two years ago, ASCO created the State Affiliate Council, which meets in person twice a year to discuss important legislative and practice-changing matters. Since then, members have begun sharing information between meetings electronically, allowing professionals to hone their messages with regional and national officials.

Access to Multispecialty Services Many State Affiliates are concerned about private oncology practices being sold to large health-care organizations. Is that an issue in Massachusetts? Private oncology practices are becoming a rarity in Massachusetts,

potentially resulting in access issues for patients who have to travel long distances for care. While navigator programs are succeeding in managing this vulnerability, long distance commuting remains disruptive and risky for patients who are undergoing treatment with even the most routine regimens that have toxicities. Tighter coordination of care is now vital to avoid a spike in unnecessary hospitalizations. On the other hand, as practices are sold to hospital groups, there are economies of scale and patients are gaining access to expeditious multispecialty services, often conveniently housed in one place. This is an important development, given the increasingly multidisciplinary care patients now require.

Key Goals MSCO has had several significant accomplishments in 2013. What are your future goals? In today’s medical environment, it is important to have a place where people from all fields, including oncology, pharmaceutical, health insurance, and government, can meet to discuss issues, such as new legislation, third-party reimbursement, and barriers to quality patient care, and that’s what we provide. MSCO members meet monthly and we also sponsor corporate roundtables and annual meetings. We also keep members informed on the latest developments affecting patient care through electronic communications, and we are building our website to include the latest disease-specific presentations by oncology experts in various specialties. We seek to develop the next generation of leaders in oncology by providing a venue for inter-institutional dialogue resulting in enhanced situational awarecontinued on page 99

The ASCO Post | DECEMBER 15, 2013

PAGE 98

In the News Cost of Care

Disclosing Medical Costs Can Help Avoid ‘Financial Toxicity’ By Charlotte Bath

igh costs of cancer treatments can be an “undisclosed toxicity” that can harm a patient’s overall health and well-being, according to an article in The New England Journal of Medicine.1 High medical bills can not only cause stress and anxiety but may also compel patients to cut back on spending for other basic needs— such as food, leading to less healthy diets—or to take medications less frequently than prescribed. “This is a very frequent cause of nonadherence,” the article’s lead author, Peter A. Ubel, MD, Professor of Business, Public Policy, and Medicine at Duke University, Durham, North Carolina, said in an interview with The ASCO Post. “It is a medical problem. Patients may not be showing up for tests or taking their pills because they can’t afford it. Dr. Ubel also tackled the issue of physicians rarely discussing medical intervention costs in an op-ed article he wrote for The New York Times.2

Not Always Easy to Know “Because treatments can be ‘financially toxic,’ imposing out-of-pocket costs that may impair patients’ wellbeing, we contend that physicians need to disclose the financial consequences of treatment alternatives just

as they inform patients about treatments’ side effects,” Dr. Ubel and colleagues wrote. They acknowledged that “it is very difficult, and often impossible for the clinician to know the actual out-of-pocket costs for each patient, since costs vary by intervention, insurer, location of care, choice of pharmacy or radiology service, and

While discussing costs of medical treatment would add time in an already tight schedule, Dr. Ubel challenged physicians to “think about how much time we spend trying to adjust medicines and revisit problems that we later found out occurred because patients were taking the pills every other day because they couldn’t af-

[T]hink about how much time we spend trying to adjust medicines and revisit problems that we later found out occurred because patients were taking the pills every other day because they couldn’t afford them. —Peter A. Ubel, MD

so on,” but added, “some general information is known.” To those who say that they can’t disclose costs to patients because they themselves don’t know the prices, Dr. Ubel responds, “But you have an idea. For treatments you prescribe or use frequently, you have a pretty good idea. You know that some things are likely to cost your patients next to nothing and some things can cost a lot. That is a good starting point.”

ford them.” A recent study found that found 24% of cancer patients avoided filling prescriptions to save money, 19% partially filled prescriptions, and 20% took less than the prescribed amount of medication. In addition, 46% reduced the amount spent on food and clothing.3

Cheaper Alternatives “Patients experience unnecessary financial distress when physicians do

Expect Questions From Patients

ot discussing the costs of medical interventions could result in “financial toxicity” for patients who have trouble paying out-of-pocket costs, as well as problems adhering to expensive treatment regimens. “The problem is perhaps starkest in cancer care, but it applies to all complex illness,” noted a recent article in The New England Journal of Medicine.1

Uncomfortable Discussion Among the challenges to a frank discussion of costs, according to the article, “patients and physicians face social barriers in discussing costs of care. No doubt, many doctors and patients find discussions of money uncomfortable; they have not been coached in having that discussion.” The way you talk about money, advised the article’s lead author,

Peter A. Ubel, MD, in an interview with The ASCO Post, “is the way you talk about any cost or benefit of treatment. And you need to make sure that patients understand you are not judging their value as a person or assuming anything about their financial situation.” As an example, he offered this approach to the conversation: “I know that some of my patients have been stressed out and burdened by the cost of medical care. I want to make sure to talk to you about treatment costs before you get burdened.” Dr. Ubel is Professor of Business, Public Policy, and Medicine at Duke University, Durham, North Carolina.

Patients Taking the Lead In a follow-up op-ed piece in The New York Times,2 Dr. Ubel added that “patients should not be afraid to take

the lead and ask how much a pill or procedure will cost.” That is happening already, he said. He has begun a study on that issue and said that while “I don’t have precise data on it yet, I can tell you my early study of this shows that patients probably bring up costs at least as often as physicians and probably more often, although typically it is to complain about costs they have already incurred.” n

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

References 1. Ubel PA, Abernathy AP, Zafar SY: Full disclosure—out-of-pocket costs as side effects. N Engl J Med 369:14841486, 2013. 2. Ubel PA: Doctor, first tell me what it costs. New York Times. November 3, 2013.

not inform them of alternative treatments that are less expensive but equally or nearly as effective,” Dr. Ubel and colleagues wrote in The New England Journal of Medicine. “We discovered this phenomenon when interviewing a convenience sample of breast-cancer survivors who had participated in a national study of financial burden. Many women reported discussing treatmentrelated costs with their physicians only after they had begun to experience financial distress.” Physicians should be aware of these cheaper alternatives “because they used to be the main treatment before newer, more expensive ones came along,” Dr. Ubel told The ASCO Post. “They might be out of the habit of using these alternative treatments and some doctors won’t think that they are reasonable alternatives because they are no longer the ‘best’ treatment, but I just want to redefine ‘best,’ because best is what fits a patient’s goal the closest. And sometimes the patient’s goal might be to trade off a little bit of medical benefit to protect his or her financial interest.” Determining what is best for particular patients should also factor in type and frequency of testing. “Frequent MRI and CT scan imaging to follow-up on tumor progress can all be very expensive, and awareness of those costs might make you change which tests you use or how frequently you look,” Dr. Ubel said.

‘Not Financial Counselors’ During a talk at a medical school, a medical student asked Dr. Ubel, “Am I supposed to be a financial counselor, too?” After the talk, the student went up to him and said, “If I had known this was part of medicine, I would never have become a doctor. This is not about becoming a doctor.” As Dr. Ubel noted, “He expressed absolute visceral distress at the thought that this would be part of what he would do.” Given the potential medical consequences of undisclosed financial toxicity, “I think the more we think about this as a medical topic instead of a financial topic, the better,” Dr. Ubel said. “Doctors don’t want to feel like they are financial counselors. That is why we use phrases like financial toxcontinued on page 99

ASCOPost.com | DECEMBER 15, 2013

PAGE 99

Announcements

Avoid Financial Toxicity continued from page 98

icity and think of it as a treatment side effect. We want people to really think about this in medical terms.”

Making It Easier to Estimate Costs Efforts by insurance companies to develop technologies to better estimate costs, as well as price-transparency legislation passed in several states, may make it easier to avoid financial toxicity. “I do think that those things are on the horizon and are going to happen in the next handful of years,” Dr. Ubel said. “If patients don’t already know the prices, they will quickly be able to figure them out. I would not be surprised if some electronic medical records start routinely including cost and price information so doctors are aware of it, especially in health systems such as accountable care organizations that are trying to control costs.” In the op-ed piece in The New York Times, Dr. Ubel stated, “The Affordable Care Act will have only a modest impact on patient exposure to health-care costs because the limits it sets on outof-pocket costs are still high compared with most people’s resources.” Whether or not disclosure of medical costs will have an impact on medical costs, “only time will tell,” Dr. Ubel said, but at least patients would have the information needed to make informed choices. “And I would predict that more frequent discussions of cost would reduce spending,” Dr. Ubel added. n

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

References 1. Ubel PA, Abernathy AP, Zafar SY: Full disclosure—out-of-pocket costs as side effects. N Engl J Med 369:1484-1486, 2013. 2. Ubel PA: Doctor, first tell me what it costs. New York Times. November 3, 2013. 3. Zafar SY, Peppercorn JM, Schrag D, et al: The financial toxicity of cancer treatment: A pilot study assessing out-ofpocket expenses and the insured cancer patient’s experience. Oncologist 18:381390, 2013.

Steven T. Rosen, MD, Named Provost and Chief Scientific Officer of City of Hope

ity of Hope has selected Steven T. Rosen, MD, the Director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine, as its first Provost and Chief Scientific Officer. Dr. Rosen will set the scientific direction of City of Hope as it embarks on a new era of strategic growth, shaping the re-

vision will create the environment necessary to accelerate the pace of meaningful discoveries that extend both quality and length of life.”

Collaborative Efforts Dr. Rosen will work closely and collaboratively with City of Hope’s scientists, clinicians, and administrative leaders to develop strategies that

City of Hope is one of the great treasures in American medicine, with some of the most important discoveries of the last decades coming from its investigators, both in terms of scientific observations as well as clinical advances.

There, he not only led one of the nation’s most distinguished cancer centers for more than two decades, he simultaneously provided care for hundreds of patients with blood cancers and oversaw a basic science laboratory and clinical research team credited with improving the treatment of patients with blood cancers. Dr. Rosen also has served as an advisor to the National Cancer Institute and the American Cancer Society, among other institutions. He has written more than 400 papers, reports, editorials and books.

Unique Opportunity

search and educational vision for the $1.2-billion independent biomedical research, treatment, and education institution. “City of Hope has established our reputation as an academic medical institution, known for leadingedge research, superior outcomes, and compassionate, patient-focused care,” said President and soon-tobe Chief Executive Officer Robert Stone. “Dr. Rosen’s experience and

contribute to City of Hope’s mission of transforming basic science into practical benefits for patients suffering from cancer and other life-threatening diseases. He will be responsible for the Comprehensive Cancer Center, the Beckman Research Institute, and the Irell & Manella Graduate School of Biological Sciences. At Northwestern, Dr. Rosen is widely recognized for bringing the cancer center to national prominence.

“I feel privileged to join such a prestigious institution with so many accomplished and talented scientists, clinicians and administrative leaders,” Dr. Rosen said. “City of Hope is one of the great treasures in American medicine, with some of the most important discoveries of the last decades coming from its investigators, both in terms of scientific observations as well as clinical advances.” “This is a unique opportunity to work with leaders as accomplished as Robert Stone, as well as the remarkable medical and nursing staff and incredibly talented scientists,” he added. Dr. Rosen will assume his new duties on March 1, 2014. n

Massachusetts Society of Clinical Oncology

outcome. We also want to reduce barriers that have been pervasively impeding clinical development, while increasing opportunities for greater participation in clinical trials that advance the personalized treatment of cancer and improve the delivery of care. These are our primary goals, but we also want to increase our constructive collaboration with the key stakeholders in health care. As the population ages there will be increasing numbers of patients with cancer who will need high-

quality and personalized care. The Patient Protection and Affordable Care Act has firmly set the patient at the center of gravity, finally facilitating better collaboration among providers, insurance companies, regulators, and patients. We are hopeful that over the next 4 or 5 years, oncologists and their patients will be in a better place. With some patience and better engagement, we have faith that we can accomplish the ultimate goal of producing better and more cost-effective oncology care. n

—Steven T. Rosen, MD

continued from page 97

ness, and by sponsoring poster sessions for trainees. If we continue to grow, we envision supporting grants to find better ways to deliver oncology care and to help practices manage newly mandated quality initiatives. Our most important goal is to protect patients from the unintended consequences of regulation and rationing of care that are deleterious to patient

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6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events. Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment. Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment. Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

for the treatment of advanced RCC after failure of one prior systemic therapy

What truly matters to you in 2nd-line mRCC?

EVIDENCE In the phase 3, head-to-head study of exclusively 2nd-line patients with mRCC...

INLYTA was the 1st agent to demonstrate

SUPERIOR EFFICACY to sorafenib

Primary endpoint: PFS HR=0.67 (95% CI: 0.54, 0.81; P<.0001)

6.7

months

4.7

months

median PFS

INLYTA

sorafenib

(n=361) (n=362) 95% CI: 6.3, 8.6 and 4.6, 5.6, respectively

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

Data are from a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokinecontaining regimen). Patients were randomized to either INLYTA (5 mg twice daily ) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety and tolerability.1,2

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be coadministered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions]. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients

AXU606812

(7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment. Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib INLYTA Sorafenib (N=359) (N=355) All Grade All Grade Gradesb 3/4 Gradesb 3/4 % % % % Diarrhea 55 11 53 7 Hypertension 40 16 29 11 Fatigue 39 11 32 5 Decreased appetite 34 5 29 4 Nausea 32 3 22 1 Dysphonia 31 0 14 0 Palmar-plantar erythrodysesthesia syndrome 27 5 51 16 Weight decreased 25 2 21 1 Vomiting 24 3 17 1 Asthenia 21 5 14 3 Constipation 20 1 20 1 Hypothyroidism 19 <1 8 0 Cough 15 1 17 1 Mucosal inflammation 15 1 12 1 Arthralgia 15 2 11 1 Stomatitis 15 1 12 <1 Dyspnea 15 3 12 3 Abdominal pain 14 2 11 1 Headache 14 1 11 0 Pain in extremity 13 1 14 1 Rash 13 <1 32 4 Proteinuria 11 3 7 2 Dysgeusia 11 0 8 0 Dry skin 10 0 11 0 Dyspepsia 10 0 2 0 Pruritus 7 0 12 0 Alopecia 4 0 32 0 Erythema 2 0 10 <1 a Percentages are treatment-emergent, all-causality events b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 Adverse Reactiona

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%). The following table presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

Hematology Hemoglobin decreased 320 35 <1 316 52 4 Lymphocytes (absolute) decreased 317 33 3 309 36 4 Platelets decreased 312 15 <1 310 14 0 White blood cells decreased 320 11 0 315 16 <1 Chemistry Creatinine increased 336 55 0 318 41 <1 Bicarbonate decreased 314 44 <1 291 43 0 Hypocalcemia 336 39 1 319 59 2 ALP increased 336 30 1 319 34 1 Hyperglycemia 336 28 2 319 23 2 Lipase increased 338 27 5 319 46 15 Amylase increased 338 25 2 319 33 2 ALT increased 331 22 <1 313 22 2 AST increased 331 20 <1 311 25 1 Hypernatremia 338 17 1 319 13 1 Hypoalbuminemia 337 15 <1 319 18 1 Hyperkalemia 333 15 3 314 10 3 Hypoglycemia 336 11 <1 319 8 <1 Hyponatremia 338 13 4 319 11 2 Hypophosphatemia 336 13 2 318 49 16 a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib). DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/ kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were ≥65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only September 2013

References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc, New York, NY. mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

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Emerging Clinical Data on Cancer Management GASTRIC CANCER Disease-Free Survival Is Acceptable Surrogate for Overall Survival in Trials of Adjuvant Chemotherapy Disease-free survival is an acceptable surrogate for overall survival in trials of cytotoxic agents for gastric cancer in the adjuvant setting, the GASTRIC group concluded after conducting a meta-analysis of data from 3,288 individual patients enrolled in 14 randomized clinical trials. The trials compared adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer. “Surrogacy of [disease-free survival] was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints,” authors explained in an article in the Journal of the National Cancer Institute. While overall survival “is considered the gold standard endpoint” in investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, using overall survival as the endpoint “requires an extended follow-up period,” the authors noted. In addition, “its measurement is potentially diluted by nonmalignant causes of death and therapies for recurrent/advanced disease.” Results of the meta-analysis “show a very tight individual-level association between [disease-free and overall survival] (Spearman rank correlation coefficient = 0.974; 95% confidence interval = 0.971–0.976), indicating that in individual patients, [disease-free survival] is highly predictive of [overall survival]. The strong correlation between [the two endpoints] can be partly attributed to the short time from relapse to death in gastric cancer (median of < 12 months across all the included trials). Further, 16% of all the analyzed patients died without documented relapse and, therefore, had the same [disease-free and overall survival],” the researchers wrote. A very high trial-level association between the effects of adjuvant chemotherapy on disease-free and overall survival “indicates that almost all of the variability in the treatment effects on [overall survival] can be explained by the treatment effects on [disease-free survival],” the authors added.

External Validation An external validation using data from six trials found that the “hazard

ratios for [overall survival] predicted according to [disease-free survival] were in very good agreement with those actually observed for [overall survival],” the researchers reported. The project was initiated and partially funded by the French Institut National du Cancer. The GASTRC Group is international and includes representation from several U.S. medical centers. The corresponding author for the study is Koji Oba, PhD, of Hokkaido University Hospital in Sapporo, Japan. Depending on follow-up, using diseasefree rather than overall survival as the primary endpoint in future clinical trials of adjuvant chemotherapies could reduce the duration of trials by 15% to 30%, as well as costs, according to the authors. They pointed out that since they only investigated cytotoxic agents, “future trials investigating agents with different mechanisms of actions, such as [targeted] therapy, will require separate validation of the surrogacy relation before it is applied routinely.” Oba K, et al: J Natl Cancer Inst 105:16001607, 2013.

MULTIPLE MYELOMA Three-Drug Regimen Produces High Response Rate in Relapsed/ Refractory Myeloma A phase II trial to evaluate the combination of bendamustine (Treanda) with bortezomib (Velcade) and dexamethasone in patients with relapsed/refractory multiple myeloma “showed a remarkable response rate of 60.9%,” and when minor responses were included, 75.9%,” researchers reported in Blood. “The short time to response (31 days) and to best response (111 days) is clinically relevant, because rapid tumor control usually corresponds with fast improvement of clinical symptoms,” the investigators noted. The 79 study patients were enrolled at nine participating centers in Austria and the Czech Republic. The patients’ median age was 64. Most had stage I (34.2%) or stage II disease (39.2%).The median number of prior treatment lines was two. Treatment consisted of bendamustine at 70 mg/m2 on days 1 and 4, bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 intravenously, and dexamethasone at 20 mg on days 1, 4, 8, and 11. Cycles were repeated every 4 weeks until a maximum of eight cycles. In patients with no response, treatment was discontinued at cycle 4, the investigators explained.

Key Data Complete response occurred in 12 patients, very good partial response in 16 patients, and partial response in 20 patients, yielding the overall response rate of 60.9%. Adding the minor responses in 12 patients resulted in the overall response rate of 75.9%. The overall response rate was similar in patients who had been previously exposed to bortezomib, lenalidomide (Revlimid), and to both bortezomib and lenalidomide. The overall response rate was lower for patients with adverse cytogenetic features than for those without such aberrations, as defined by fluorescence in situ hybridization (53% vs 67%). Progression-free survival was 9.7 months and overall survival was 25.6 months, and these endpoints did not differ significantly according to adverse cytogenetic features. “Multivariate analysis showed high LDH, ≥ 3 prior treatment lines, and low platelet counts correlating with short survival,” the investigators noted. The treatment regimen was relatively well tolerated, although grade 3/4 hematologic toxicities were seen in up to one-third of patients, the authors noted. Grade 3–5 infections were noted in 23% of patients, two of whom had fatal outcomes. “Hence, G-CSF [Neupogen] prophylaxis should be considered particularly in elderly frail patients. Herpes zoster prophylaxis is mandatory but clinical virus reactivation may occur even during adequate prophylaxis,” the authors commented. Grade ≤ 2 polyneuropathy increased with duration of therapy, from 19% at

baseline to 52% at cycle 8. Other nonhematologic side effects, mostly grade 1/2, included insomnia/fatigue, nausea, emesis, and constipation. Ludwig H, et al: Blood. November 13, 2013 (early release online).

CANCER SCREENING Using Life Expectancy, Not Age, to Make Cancer Screening Decisions Can Maximize Potential Benefits Using life expectancy, rather than chronologic age, to inform decisions about whether to continue cancer screening for older persons can maximize the potential benefits of screening, while minimizing the harms, according to results of a populationbased cohort study of 407,749 people over 66 without a history of cancer. “Persons with higher levels of comorbidity had shorter life expectancies, whereas those with no comorbid conditions, including the very elderly, had favorable life expectancies relative to an average person of the same chronological age,” Hyunsoon Cho, PhD, of the National Cancer Institute, and colleagues reported in the Annals of Internal Medicine. “Comorbidity-adjusted life expectancy may help physicians tailor recommendations for stopping or continuing cancer screening for individual patients,” the researchers concluded. Patients without a history of cancer were identified from a random 5% sample of Medicare beneficiaries residing in Surveillance, Epidemiology, and End

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In the Literature

Results (SEER) cancer registry areas. More than 30% of the cohort members had one or more comorbid conditions. Information was not available on functional status and severity of comorbidity, “which might influence life expectancy in elderly persons,” the investigators cautioned. The researchers used a three-step approach to estimate life expectancy by comorbidity. The first step included estimating the effect of comorbid conditions on survival and constructing a comorbidity score, using this score to classify comorbidity status as no, low/ medium, or high comorbidity. The second step involved estimating age-specific survival curves for each of those comorbidity status groups and the three most common comorbid conditions—diabetes, chronic obstructive pulmonary disease, and congestive heart failure. The final step was to estimate comorbidity-adjusted life expectancy.

Death Hazards “Of all comorbid conditions examined, AIDS was associated with the highest risk for death [hazard ratio = 3.66, 95% confidence interval (CI) = 2.72– 4.92]. Persons with diabetes, [chronic obstructive pulmonary disease], and [congestive heart failure] had, respectively, at least a 1.45, 1.76, and 2.27 times greater hazard of dying compared with those with no comorbidity. The hazard of death for persons in the high comorbidity group was at least 1.76 times greater than that of persons in the no-comorbidity group,” the researchers reported. “Relative to the life expectancy of the average U.S. population, the estimated life expectancy for persons aged 75 years with no comorbidity was approximately 3 years longer, but for persons with high comorbidity, it was approximately 3 years shorter. As age increases, the effect of comorbidity on life expectancy decreases,” the investigators added. The authors concluded that their study findings and methods “may aid physicians and other health practitioners in individualizing recommendations for cancer screening in elderly persons (that is, to continue screening in persons with sufficient life expectancy who might benefit or to stop screening among those for whom benefits are unlikely). Even with additional information about life expectancy,” the authors added, “discussions about continuing or stopping screening are complex and will need to be informed by patient preferences.” Cho H, et al: Ann Intern Med 159:667676, 2013.

PHYSICIAN COMMUNICATION

Nekhlyudov L, et al: J Oncol Pract. November 12, 2013 (early release online).

Oncologists Need to Inform Primary Care Physicians About Late and Long-Term Effects of Chemotherapy

Promoting Timely Referral to Reproductive Specialists for Patients Concerned About Fertility

A nationally representative survey of 1,130 oncologists and 1,072 primary care physicians found that primary care physicians had limited awareness of late or longterm effects of chemotherapy agents. This was attributed to primary care physicians not typically encountering chemotherapy agents and/or their late/long-term effects in their clinical practices or perusing relevant literature. “In the transition of patients from oncology to primary care settings, [primary care physicians] should be informed about potential [late/long-term effects] so that they are better prepared to recognize and address them among the cancer survivors in their care,” Larissa Nekhlyudov, MD, MPH, of Harvard Medical School and Harvard Vanguard Medical Associates, Boston, and colleagues wrote in the Journal of Oncology Practice. Physicians responding to the Survey of Physician Attitudes Regarding the Care of Cancer Survivors (SPARCCS) were asked to describe the late and long-term effects they had either observed or seen reported for chemotherapy agents used to treat breast and colon cancers. Most of the responding physicians were white men who were trained in the United States and board-certified. Among the primary care physician group, 40% were family practitioners, another 40% were internists, and 20% were obstetricians/gynecologists.

Updated clinical guidelines published this year by ASCO “give oncology care providers an opportunity to partner with their reproductive specialist colleagues to ensure that the clinical and psychosocial needs of patients with cancer are addressed as close to the time of diagnosis as possible,” according to an article in the Journal of Oncology Practice. Previous guidelines, published in 2006, stated that oncologists should be prepared to either “discuss fertility preservation options or refer patients who are interested to reproductive specialists.” The updated guidelines “extend the responsibility for discussion and referral for fertility preservation beyond the medical oncologist to explicitly include other physician specialties (eg, surgeons, radiation oncologists) and allied health-care professionals (eg, nurses, social workers) in the oncology care setting,” Susan T. Vadaparampil, PhD, and Gwendolyn P. Quinn, PhD, of the Moffit Cancer Center and University of South Florida, Tampa, explained. The new guidelines also stress the importance of discussing fertility-preservation options and referring to reproductive specialists early, before cancer treatment begins. “As such, the need for cancer care institutions to establish formal or informal relationships with reproductive specialists to facilitate ongoing communication serves to ensure timely access to fertility preservation consults and/or services,” the authors wrote.

Major Findings “Almost all oncologists (95%) reported awareness of cardiac dysfunction as [a late/ long-term effect] of doxorubicin and peripheral neuropathy as [a late/long-term effect] of paclitaxel (97%) and oxaliplatin (97%). These [late/long-term effects] were reported by 55%, 27%, and 22% of primary care physicians, respectively,” the researchers found. “Most oncologists reported awareness of premature menopause (71%) and secondary malignancies (62%) as [late/longterm effects] of cyclophosphamide, compared with only 15% and 17% of [primary care physicians], respectively. Main [late/ long-term effects] associated with all four agents were identified by 65% of oncologists and only 6% of [primary care physicians],” they added. “Education for all providers caring for the growing population of cancer survivors is needed,” the authors concluded.

Unique Juncture The updated guidelines recognize the point of transition between pediatric and adult oncology care settings may be a unique juncture at which communication between oncology providers and reproductive specialists is needed,” the authors stated. The guidelines cite studies suggesting that adult survivors of pediatric cancer wish they had been informed of fertility options or feel regret about not having options. Along with established methods of fertility preservation, such as sperm and oocyte cryopreservation, the guidelines suggest “that providers present other investigational methods (eg, ovarian and testicular tissue cryopreservation,” the authors noted. “The revised guidelines also encour-

age clinicians to document discussions about fertility preservation in the medical record, suggesting important changes in the perception of fertility preservation discussions as a quality of care indicator,” the authors stated. Vadaparampil ST, Quinn GP: J Oncol Pract 9:300-302, 2013.

SMOKING Young Tobacco Consumers Frequently Use Products Other Than Cigarettes “A substantial proportion of youth tobacco use occurs with products other than cigarettes, so monitoring and prevention of youth tobacco use needs to incorporate other products, including new and emerging products,” according to the Morbidity and Mortality Weekly Report, published by the Centers for Disease Control and Prevention. Analysis of data from the 2012 National Youth Tobacco Survey found that the prevalence of current tobacco product use was 6.7% among middle school students and 23.3% among high school students. Current use was defined as using the tobacco product on 1 or more of the last 30 days. The survey sample size was 24,685 students. While cigarettes were the most commonly used tobacco product, followed by cigars, “from 2011 to 2012, electronic cigarette use increased significantly among middle school (0.6% to 1.1%) and high school (1.5% to 2.8%) students, and hookah use increased among high school students (4.1% to 5.4%),” the authors reported. “The increase in use of electronic cigarettes and hookah tobacco could be attributed to low price, an increase in marketing, availability, and visibility of these products, and the perception that these tobacco products might be ‘safer’ alternatives to cigarettes,” an editorial note speculated. Cigars, electronic cigarettes (or e-cigarettes), hookah tobacco, and some other new types of tobacco products are not currently subject to regulation by the U.S. Food and Drug Administration (FDA) regulation. “FDA has stated it intends to issue a proposed rule that would deem products meeting the statutory definition of a ‘tobacco product’ to be subject to the Federal Food, Drug, and Cosmetic Act,” according to the editorial note. (For more information on electronic or e-cigarettes, see “What You Need to Know About E-Cigarettes,” The ASCO Post, October 15, 2013.) n Arrazola RA, et al: MMWR 62:893897, 2013.

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The ASCO Post | DECEMBER 15, 2013

PAGE 106

In Memoriam

Peter Jacobs, MD, Storied South African Hematology Pioneer Dies By Ronald Piana “We make a living by what we get. We make a life by what we give.” —Winston S. Churchill

he remarkable medical career of Peter Jacobs, MD, in large part, traces the oncologic history of South Africa. During the decades of political and social unrest that engulfed his native land, Dr. Jacobs treated countless thousands of

private practice and developed the world renowned Bone Marrow Transplant Unit at Cape Town’s Constantiaberg Hospital, which he headed until his final retirement in February 2011. Wim de Villiers, MD, University of Cape Town, noted, “Dr. Jacobs’ energy and work ethic were legendary in the faculty during his years in office, and he will be fondly remembered by scores of students who benefited from his approach to both undergraduate and postgraduate teaching during his long academic career.”

A Life Fully Lived

Peter Jacobs, MD

patients with cancer from every economic and racial stratum, and his groundbreaking research was central to the development of hematology as a discipline in South Africa. After a long illness, Dr. Jacobs died on November 18, 2013, at the age of 79. Colleagues from around the world remembered him not only for his vast contributions to oncology, but equally for his humanism and generous friendship. Dr. Jacobs was born in South Africa on March 21, 1934, but grew up in Rhodesia, which is now Zimbabwe. He returned to South Africa to pursue a career in medicine, attending the University of the Witwatersrand in Johannesburg. After graduating medical school, Dr. Jacobs trained in internal medicine and hematology, and studied in South Africa, the United Kingdom, and the United States. In the course of his career, he also earned a PhD in iron metabolism and was elected to Fellowship in the Royal Society of South Africa, Royal College of Physicians, Royal College of Pathologists, the American Society of Clinical Pathologists, and the American College of Physicians. In 1972, Dr. Jacobs became the founding Head of the Hematology Department at the University of Cape Town, a post he held until 1994. He then continued in

From his days in high school and throughout much of his undergraduate study, Dr. Jacobs worked as a lab assistant and technician, which nurtured his passion for clinical research. Dr. Jacobs also had experiences that sounded as if they were ripped from the pages of an adventure novel. In March 2010, his associate and friend, James O. Armitage, MD, University of Nebraska Medical Center, Omaha, wrote a letter supporting the nomination of Dr. Jacobs for Mastership in the American College of Physicians, in which he opened a candid window into Dr. Jacobs’ youth. He noted, “There is probably no other candidate this year for Mastership in the American College of Physicians who earned the money to attend medical school by working as a game control officer, whose responsibility it was to track down and destroy dangerous animals that were killing humans or ruining crops.” In an interview, Dr. Armitage elaborated on Dr. Jacobs’ adventurous past. “Peter had great stories about being a game control officer. One time he tracked a leopard that had been marauding the nearby villages. The big cat had gone into a cave, so Peter followed with a flashlight and a shotgun, because it would be a close-quarters shot. He said that he was concerned that the leopard might get the jump on him in the dark, but Peter got him first.” Dr. Armitage also noted that Dr. Jacobs was an avid reader of the rough-andtumble American Western writer Louis

L’Amour. “He never really said why he liked L’Amour so much, but I always figured there might be some connection between the Wild West that L’Amour wrote about and the Africa that Peter grew up in,” said Dr. Armitage. Dr. Armitage added that Dr. Jacobs’ original contributions included leading the development of a method for reducing graft-vs-host disease with allogeneic transplantation using alemtuzumab (Campath) mixed with the bone marrow before reinfusion into the patient. “Peter’s work has led to 252 original scientific publications in peer-reviewed journals and numerous awards. However, I think he would be most proud that his work made it possible for many South Africans of all races and economic backgrounds to be cured of what would have otherwise been fatal diseases,” said Dr. Armitage.

International Oncology Ambassador Fellow South African and mentee, Matthew Seftel, MD, MBChB, MPH, MRCP, FRCPC, University of Manitoba, said, “Dr. Jacobs’ major achievement was the introduction of experimental and clinical blood and bone marrow transplantation. Throughout his career, he trained and mentored countless physicians and basic scientists, and in the midst of political and economic instability in South Africa, many of these trainees progressed to academic careers worldwide,” he added. “His longstanding interest in lymphoma was influenced in recent years by the region’s HIV epidemic,” Dr. Seftel continued. “Despite these challenges, he continued to practice medicine with a tireless, orderly, and scholarly approach. Lymphoma experts of international repute regularly attended his biennial South African Lymphoma Study Group meetings. In 2009, the South African Academy of Arts and Science awarded him the centenary medal in recognition of his outstanding national and international academic profile.” From Canada, long-term colleague

 In Memoriam

Peter Jacobs, MD

March 21, 1934 – November 18, 2013 

Joseph M. Connors, MD, BC Cancer Agency Centre for Lymphoid Cancer, remembered Dr. Jacobs with the following reflections: “Dr. Peter Jacobs was an inspiration to all of us who endeavor to help lymphoma patients even in the most challenging circumstances. With a career spanning the entire history of hematology and medical oncology in South Africa from the 1960s until now, he worked tirelessly to bring the best of modern health care to those with hematologic malignancies. My every encounter with Peter was an inspiration. All of us should aspire to emulate his compassion for patients and his commitment to education and learning. We have lost an irreplaceable colleague.” From Germany, colleague Volker Dielh, MD, PhD, Founder and Honorary Chairman of the German Hodgkin Study Group said, “Peter Jacobs was one of the most passionate, engaged, and knowledge-hungry doctors I have known. There were no meetings for malignant lymphomas in which Peter was not sitting in the first row from early in the morning until the last talk in the evening, listening intensively and taking notes for his practice, in order to give the best treatment possible for the many lymphoma and leukemia patients for whom he lived and fought. Nearly every month, I got an e-mail from Peter, asking for help with a very special and difficult patient with a completely unusual leukemia or an absurd lymphoma, or he asked for advice on the third- or fourth-line therapy of a patient who had become a dear friend.” Dr. Jacobs lived a full and vibrant life, caring for patients with cancer and conducting research under conditions that, at times, would probably be hard for young oncology fellows to fully comprehend. It is beyond the scope of this essay to fully capture the life of Peter Jacobs, the doctor and the man. However, Dr. Armitage offered a simple tribute that we all might strive for: “Peter was simply a man you wanted as your friend.” And if you were diagnosed with cancer, he was a man you wanted as your doctor. n

ASCOPost.com | DECEMBER 15, 2013

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Opinion

Consent and Compassion continued from page 1

be considered an enormous benefit. Shared decision-making is supposed to ensure that both parties partake of all of the burdens equally. In reality, we know very well that in the majority of situations, we share the information and the patient bears the burden, leaving them alone for decision-making. Similarly, somewhere

workup, including a computed tomography scan, reveals pneumatosis, suggestive of ischemic bowel. She is emaciated, malnourished, dehydrated, and does not appear to be a good candidate for any operation, let alone an operation of this magnitude. The families of both patients are very w supportive, cooperative, and willing to do anything or everything to make their kin better.

Anything but a Clear Answer How do we go about approaching these patients and their families about the various operative and nonoperative treatment options? How do we obtain consent for these major procedures, if an operative intervention is decided upon? How do we explain the risks and benefits of the proposed procedures/ interventions? How do we explain that sometimes the best operation is actually none? Adherence to the well-accepted principles of informed consent and shared decision-making do not guarantee ease of solution.1-3 These scenarios are very common, as most of us can attest from personal experiences, which usually consist of patient/family education about risks and benefits, but ultimately they weave through an agonizing labyrinth that leads to anything but a clear answer—while the families demand nothing short of a clear answer. We can only expect a rise in these situations due to the increasing number of aging baby boomers.4

Trust and Compassion Years ago, the very fact that patients came to see the physician implied that they had given consent to be examined and treated. This was possible due to the bedrock of trust that the patient and the physician placed in their relationship. The physician’s emphasis was on patient care and nothing else, and the families placed their faith in the physician and no one else. This level of trust permitted compassion to flourish, which made it easier to deal with all the medical and nonmedical issues at hand. Due to various factors, including risk of litigation and the consequent need for patients to be completely educated, we have shifted to the principles of informed consent and shared decisionmaking. Informed consent has ushered in a world where patients and families are supposed to be made as informed as the responsible physician, which should

along this path from “simple consent” to “informed consent,” we have noticed a phenomenon whereby the plethora of information provided erodes or, in some instances, substitutes for the true personal bond between the parties. When this happens, trust in the relationship can be one of the elements that is compromised. When trust is in

short measure, compassion often suffers the same fate. A lack of compassion, the fundamental building block of the patient-physician relationship, can only make it more difficult for both parties.

Personal Touch In discussions with the patient and continued on page 108

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Opinion

Consent and Compassion continued from page 107

family, we try to provide data from the recent literature, describing the landmark randomized controlled trials, phase III studies, levels of evidence or lack thereof, and so on, presuming that they comprehend it all. This makes us feel safe, since we feel like we have satisfied the legal requirements that are being constantly drummed into us by the risk management teams. Where does that leave the patient and families? Informed, maybe. Trusting, maybe. But have we achieved the level of compassion needed to make them feel comfortable and not alone in a difficult situation—not always. Science can offer an everlasting fountain of information, but it does not usually instill compassion. Compassion comes from the personal touch, which most patients and families are very astute to detect when present. There is no science to teach how to obtain a “shared” and “informed” consent that is also “compassionate.” It is more of an art—that is, the art of human communication—whereby we communicate well enough to keep patients informed but also be honest enough to retain the personal side. We try to keep the information simple so that they can understand what we are trying to convey. We stand as a bulwark for them to lean on in their difficult times. We make it known that this decision is not for “me” or “you” to make, but will be made together as “us,” on this unexpected journey that fate has destined us to travel together.

Useful Algorithm After going through so many of these heartbreakingly painful experiences, I have come to realize that an algorithm along this pathway might be helpful. Depending on their individual style and comfort level, other physicians may prefer any of several other potential algorithms that could be used. But

I have found this algorithm useful for my style of practice. This is not based on any randomized controlled trial or level I evidence, since the circle of compassion does not always fit into the rigid squares of science. After completing the exam and disclosing the diagnosis and treatment options, it usually helps to tell patients that they fall into one of three groups regarding the need for intervention: group I needs the intervention, group II does not need the intervention, and group III represents those cases where we are not sure whether they need it or not. This is based on the willingness to admit to patients that we are not masters of all (or, in fact, any) medical ailments. It may well be that

categorization would give the patient and family a measure of what lies ahead in terms they can clearly understand, which makes it easier to move on to the next phase.

Shared Decision Next we tell them, this is a decision that will be made by “us”—not by “me” or “you.” This makes the patient and family realize that we are not dictating care and allows them to feel comfortable about truly being an integral part of the treatment plan, which is how it should always be. The role-playing is described as follows: my job is to give you all the medical information we have and be available for all your needs and questions, your job is to under-

Patients come to us with fear of the disease, some trust, and the hope of obtaining answers. It is our solemn duty to not only dispel the fear, establish complete trust, and provide answers, but also to offer compassion.

some or many of our patients fall into group III. But at least they will be aware of our honesty and realize where we all stand, thereby tempering their expectations. Depending on which group they fall into, the next step would be to tell them about the risk-benefit stratification: For group I, benefits outweigh risks; for group II, risks outweigh benefits; and for group III, risks are equal to benefits. This is a simple algorithm that is very easy for almost everyone to understand. The 92-year-old patient described at the beginning of this piece would fall into group I for treatment and between groups II and III for risk stratification, regardless of the final decision. This

The ASCO Post Wants to Hear from You

fertile for seeds of trust. Patients and families are more likely to trust your compassion, sincerity, and honesty than your medical knowledge. By this stage, the patient and family appreciate the compassion in our efforts to share their burden of decision-making. This is far better than drowning them with information alone, which may actually prevent them from finding the comfort of compassion.

Solemn Duty The purpose of the consent process is to inform patients and families of the proposed treatment in detail. The provision of adequate or excessive information does not absolve us of the responsibility of remaining compassionate and having the willingness to share their burden. Patients come to us with fear of the disease, some trust, and the hope of obtaining answers. It is our solemn duty to not only dispel the fear, establish complete trust, and provide answers, but also to offer compassion. The ultimate consent should be not only informed, but compassionately informed. n

—Chandrakanth Are, MBBS, FRCS, FACS

Disclaimer: Dr. Are reported no potential conflicts of interest.

stand the situation, and our job is to share the burden, so as to reach a decision together that we all think is the most beneficial. At this stage, some patients and families pose this difficult question: What would you do if it were you? I wish more patients asked this, but failing that, we should always try to volunteer an answer. This is the time to be utterly honest about what one thinks, although it may be difficult at times in the current legal environment. When you are honest, patients and families immediately realize it and are very appreciative of your sincerity. This leads to the ideal physician-patient relationship based on compassion. Once compassion sets in, the ground is

References 1. Whitney SN, Holmes-Rovner M, Brody H, et al: Beyond shared decision making: An expanded typology of medical decisions. Med Decis Making 28:699-705, 2008. 2. Lantos J: Informed consent. The whole truth for patients? Cancer 1:28112815, 1993. 3. McGuire AL, McCullough LB, Weller SC, et al: Missed expectations? Physicians’ view of patients’ participation in medical decision-making. Med Care 43:466-470, 2005. 4. U.S. Census Bureau: Statistical abstract of the United States: 2008, Section 1: Population. Available at www.census.gov/ prod/2007pubs/08abstract/pop.pdf. Accessed November 4, 2013.

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

ASCOPost.com | DECEMBER 15, 2013

PAGE 109

Letters to the Editor

Dr. Weisenthal’s Reply continued from page 96

are likewise obvious. One generally makes a formal conflict of interest declaration when one’s conflict is not obvious, eg, most typically in disclosing a relationship to an entity not obviously related to one’s medical practice, such as a relationship with an outside pharmaceutical company. I am going to hazard a guess that Dr. Mason would state that the difference between an oncologist providing chemosensitivity testing and a pathologist providing estrogen receptor testing is that the former testing is considered to be “investigational/not recognized by ASCO,” whereas the latter is considered to be noninvestigational/recognized. But is this a fair distinction?

trial ever performed to “validate” estrogen receptor testing4 (estrogen receptor negativity being the most powerful contributor to platinum sensitivity in patients with triple-negative disease in our 2009 study).5 Comparing the chemosensitivity test study with the estrogen receptor study, the former had a greater number

of patients and stronger predictive correlations, and used real-world test conditions (real-time processing and prospective reporting, as opposed to post hoc batch-processing and retrospective reporting). Additionally, for the first time ever in all studies of predictive markers used for treatment selection in cancer, the chemosensitivity study

showed an improved clinical outcome for patients randomly assigned to testguided treatment selection vs non–testguided treatment selection. (Patients in the empiric therapy arm had a 2.5-fold greater probability of being dead at 1 year, compared to the patients in the test-directed arm.) continued on page 110

NP FOR s A YOU ND R PA s

Double Standard? To date, ASCO has provided two formal reviews of chemosensitivity testing.1,2 In both reviews, the sole criterion being assessed was “efficacy,” meaning the existing data relating to the question of whether the use of this testing improves clinical outcomes. In both reviews, no attempt was made to assess the considerable data documenting the accuracy of chemosensitivity testing, where test accuracy is the only criterion ever used to “validate” any predictive laboratory technology, specifically including the triple-negative tests (ie, for estrogen receptor, progesterone receptor, and HER2). This double standard has had the effect of halting virtually all progress in the field of chemosensitivity testing since the late 1980s. Critics have labeled the technology “investigational” and have then failed to support the investigations they have demanded, as readily evidenced by the complete absence of NIH grant–supported publications in the American literature over the past 2 decades. The technologies are largely in the public domain and labor-intensive, and there has accordingly been no serious private sector money to compete with pharmaceutical company funding for clinical trials.

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New Development Just this year, however, there has been a new development. A large-scale (777-patient) prospective, randomized trial in chronic lymphocytic leukemia was published, supported by the British Leukemia Research Fund.3 I would ask fair reviewers to compare and contrast the quality and results of this trial with what is the self-proclaimed “best”

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The ASCO Post | DECEMBER 15, 2013

Letters to the Editor

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Dr. Weisenthal’s Reply continued from page 109

Lost Opportunity

I view the lack of support and overt hostility to chemosensitivity testing as being the single greatest lost opportunity in clinical cancer research over the past 25 years. As a postscript, there was a nonfunctioning link to our 2009 ASCO Breast Symposium presentation relating to platinum therapy in triple-negative breast cancer in my original comment, as published. Here is the correct link, presenting our abstract and most important data: http://meetinglibrary. asco.org/content/40486-70 n —Larry Weisenthal, MD Huntington Beach, California References 1. Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology Technology Assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22:3631-3638, 2004. 2. Burstein HJ, Mangu PB, Somerfield MR, et al: American Society of Clinical

Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol 29:3328-3330, 2011. 3. Matutes E, Bosanquet AG, Wade R, et al: The use of individualized tumor response testing in treatment selection: Second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. Leukemia 27:507-510, 2013. 4. Elledge RM, Green S, Pugh R, et al: Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group Study. Int J Cancer 89:111-117, 2000. 5. Weisenthal L: Activity of cisplatin in triple-negative breast cancer in comparison to other cancer types in fresh tumor cell culture assay using a cell death endpoint. 2009 Breast Cancer Symposium. Abstract 61. Presented October 8-10, 2009. Disclaimer: This letter represents the views of the author and may not necessarily reflect the views of ASCO.

Perception of Bias

am a veteran member of ASCO (> 33 years) and a regular reader of The ASCO Post Evening News, which usually provides very interesting information. A recent issue contained an article about a review presented by Tony Reid, MD, PhD, at a Best of ASCO meeting on “Important Findings in Metastatic Colorectal Cancer” (from The ASCO Post, October 15, 2013). Reading this article, I already had the impression of a bias in favor of bevacizumab (Avastin). I was, therefore, not surprised to read a disclosure statement at the end of the article indicating that Dr. Reid

e appreciate Dr. Herrmann’s concerns in regard to conflict of interest. The ASCO Post makes every effort to present news and data in an objective and fair manner. Often we invite an independent expert in a particular area to share his or her perspective to lend more insight to a report. We recognize that some individuals may have relationships with industry that could be perceived as a potential conflict of interest. Contributors to The ASCO Post are encouraged to disclose

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None.

has been a consultant to Genentech, the manufacturer of bevacizumab. I find it extremely disappointing that The ASCO Post accepts colleagues for such a task even if they have a clear conflict of interest. Because I am quite familiar with the subject discussed in the previously mentioned article, I have my own opinion based on the scientific evidence. However, if I read articles about other areas, where I may be less knowledgeable, how do I know that the opinion given is unbiased? —Richard Herrmann, MD Basel, Switzerland

The ASCO Post Replies

Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

any such relationship, and a formal disclosure statement is then printed with the respective article. We believe that by promoting transparency and providing independent expert perspective for news published in The ASCO Post, readers will be equipped to form their own opinions in regard to the perception of bias. n —James O. Armitage, MD, Editor-in-Chief and Cara H. Glynn, Editorial Director The ASCO Post

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC)

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

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Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). [See Warnings and Precautions (5.8).]

Arm 2 IFL+ + Avastin (n = 392) 87%

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Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

Arm 1 IFL+ + Placebo (n = 396) 74%

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

Indications

Most common adverse events

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastintreated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

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Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.