TAP Vol 6 Issue 19

Novel Drugs in Advanced RCC 1, 3, 50 | Federal Regulations/U.S. Research

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| Necitumumab in Squamous NSCLC

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VOLUME 6, ISSUE 19

OCTOBER 25, 2015

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

European Cancer Congress

Discussing Financial Toxicity With Patients Who Have Cancer

Nivolumab Produces Survival Benefit in Advanced Renal Cell Carcinoma

By Caroline Helwick

By Jonas A. de Souza, MD

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atients with advanced renal cell carcinoma treated with nivolumab (Opdivo) were 27% less likely to die than those receiving everolimus (Afinitor), in a planned interim analysis of the open-label phase III CheckMate 025 trial.1 These positive results prompted an early termination of the study by the data safety monitoring committee.

These study findings were presented at the 2015 European Cancer Congress in Vienna, Austria, by Padmanee Sharma, MD, PhD, Scientific Director of the Immunotherapy Platform and Professor of Genitourinary Medical Oncology and Immunology at MD Anderson Cancer Center, Houston. The study results were reported by first author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, and published simultaneously in The New England Journal of Medicine.2 See page 50 for more details on CheckMate 025 from the published paper.

“CheckMate 025 met its primary endpoint, dem-

Patient: “Doc, how much are these drugs going to cost me?”

Physician: “They are expensive, and you can see our financial counselor to help you understand the costs.”

Robert J. Motzer, MD

Padmanee Sharma, MD, PhD

onstrating superior overall survival with nivolumab vs everolimus,” Dr. Sharma announced.

“CheckMate 025 is the first and only study in which immunotherapy with an immune checkpoint inhibitor, used after prior treatment has failed, has shown a benefit in overall survival among patients with advanced kidney cancer. The findings are likely to change the treatment of patients whose disease has progressed on continued on page 4

European Cancer Congress

Ovarian Suppression During Chemotherapy Preserves Fertility in Young Women With Breast Cancer

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ancer care is not a black-and-white endeavor, and costs are considered a distasteful subject to be passed over in tactful silence. The surprise lesson from my oncology practice is that patients themselves often have become increasingly interested in knowing how the therapies we prescribe will affect their continued on page 130

Dr. de Souza is Assistant Professor of Medicine at The University of Chicago and winner of the Costs of Care and ABIM Foundation Teaching Value and Choosing Wisely® Challenge.

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

MORE IN THIS ISSUE

By Alice Goodman everal studies have addressed the risks and benefits of ovarian suppression during chemotherapy for breast cancer in women of childbearing age. A new meta-analysis of randomized trials found that it prevented premature ovarian failure and was associated with a higher number of pregnancies post chemotherapy without apparent negative consequence on prognosis. The study was presented

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at the 2015 European Cancer Congress and published to coincide with the presentation in Annals of Oncology.1,2

Attractive Option

“I hope our study will lead to ovarian suppression being deemed a valid option to be offered to patients for preservation of ovarian function and fertility,” stated Matteo Lambertini, MD, a coauthor of the study I hope our study will lead to ovarian and a fellow in medical oncology at IRCCS AOU San suppression being deemed a valid Martino-IST, Genoa, Italy. option to be offered to [breast cancer] Lucia Del Mastro, MD, of the same institution, is the patients for preservation of ovarian corresponding author. function and fertility.

A diagnosis of breast —Matteo Lambertini, MD cancer can be a major chal-

Oncology Meetings Coverage European Cancer Congress ���������������� 3–20 Breast Cancer Symposium ��������������� 23–24 World Conference on Lung Cancer ��� 25–32 Palliative Care in Oncology ������������� 33–38 National Academies of Sciences, Engineering, and Medicine ����������������������47 Direct From ASCO �������������������������� 39–42 Integrative Medicine: Scam Alert ��������� 44 Cancer During Pregnancy �����������������������63 High-Risk Ovarian Cancer ���������������������� 76 Pioneers in Oncology ������������������������������ 94

continued on page 20

October is Breast Cancer Awareness Month.

A Harborside Press® Publication

The ASCO Post | OCTOBER 25, 2015

PAGE 2

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ASCOPost.com | OCTOBER 25, 2015

PAGE 3

European Cancer Congress Genitourinary Oncology

Phase III METEOR Trial Finds Cabozantinib Improves ProgressionFree Survival vs Everolimus in Advanced Renal Cell Carcinoma

By Alice Goodman

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abozantinib (Cometriq) nearly doubled progression-free survival compared with standard everolimus (Afinitor) therapy in patients with advanced renal cell carcinoma, according to the phase III METEOR trial.1 Additionally, a preplanned interim analysis found an encouraging trend toward overall survival in patients treated with cabozantinib.

“I am very excited by this outcome. This study can change the standard of care for patients with advanced kidney cancer who have received prior standard therapy targeting the VEGF [vascular endothelial growth factor] receptor,” said Toni Choueiri, MD, Associate Professor of Medicine at Harvard Medical School and Kidney Cancer Center Director at The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston. “Cabozantinib is an option for second-line therapy of renal cell carcinoma.”

Dr. Choueiri presented these results of the METEOR trial at the 2015 European Cancer Congress, and they were published online in The New England Journal of Medi-

cine to coincide with his presentation.2 See page 50 for more details on the METEOR trial as reported in the published paper.

Although drugs that target the VEGF receptor (VEGFR) are now standard treatment for advanced renal cell carcinoma, resistance to these drugs is a major challenge, Dr. Choueiri explained.

Cabozantinib, approved for the treatment of advanced thyroid cancer, is an oral small-molecule multitargeted inhibitor of tyrosine kinases, including MET, VEGFRs, and AXL. Increased expression of both MET and AXL is associated with the development of resistance and poor prognosis in renal cell carcinoma, suggesting that cabozantinib is worthy of study in renal cell carcinoma, Dr. Choueiri told listeners.

METEOR Trial Details The METEOR trial enrolled 658 patients diagnosed with advanced renal cell carcinoma and clear cell histology from 173 centers in 26 countries; all patients

EXPERT POINT OF VIEW

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ora N. Sternberg, MD, FACP, Chief of Medical Oncology at San Camillo Forlanini Hospital, Rome, Italy, discussed the implications of the METEOR trial. Everolimus (Afinitor) is considered standard secondline therapy, with a benchmark progression-free survival of 4.9 months in the RECORD-1 trial, she explained. In that trial, there was no difference in overall survival between everolimus and placebo, due to the fact that 80% of patients in the placebo arm crossed over to receive everolimus.

“The primary endpoint of a 42% reduction in risk of disease progression or death observed in METEOR with cabozantinib [Cometriq] is encouraging, with practically double progression-free survival,” Dr. Sternberg told listeners.

“The overall survival trend is encouraging, but the data are not yet mature.”

“Cabozantinib was developed to target the AXL and MET receptors and kinases associated with resistance and poor prognosis. The mechanism of action of cabozantinib is different from that of everolimus and is designed to overcome resistance to other tyrosine kinase inhibtors. The safety of cabozantinib is acceptable, and it is a new option for second- or later-line therapy of advanced renal cell carcinoma,” she stated.

Greatest Benefit Dr. Sternberg pointed out that patients treated with only one prior VEGF-targeted agent had the greatest benefit from cabozantinib, along with moderate- and favorable-risk patients. “A biomarker to predict response to cabozantinib would be important, but currently we don’t have one. Keep in mind that the results apply to the type of patients enrolled in this trial, but the efficacy was impressive with cabozantinib vs everolimus,” she concluded.

Dr. Sternberg was a principal investigator in both the METEOR trial and the CheckMate 025 trial of nivolumab (Opdivo) in renal cell carcinoma [see page 1 for more details on the CheckMate 025 trial]. n Disclosure: Dr. Sternberg has received research funding or honoraria from Pfizer, Novartis, Bayer, AVEO, Roche, BMS, Exelexis, and GSK.

This study can change the standard of care for patients with advanced kidney cancer who have received prior standard therapy targeting the VEGF receptor.

—Toni Choueiri, MD

had received at least one prior VEGFRtargeted tyrosine kinase inhibitor and had radiographic progression within 6 months after the most recent dose.

No crossover was allowed in the trial, which met its primary endpoint of progression-free survival. Patients were randomly assigned 1:1 to oral cabozantinib at 60 mg/d or oral everolimus at 10 mg/d and treated as long as benefit was observed or until the development of unacceptable toxicity. No crossover was allowed.

The study met its primary endpoint of progression-free survival. Median progression-free survival—as assessed by an independent radiology review committee—was 7.4 months for cabozantinib vs 3.8 months for everolimus, representing a 42% reduction in risk of progression or death (P < .001). Objective tumor responses were observed in 21% of the cabozantinib group vs 5% of patients treated with everolimus.

At a prespecified interim analysis of overall survival, a trend toward longer survival was seen with cabozantinib vs everolimus (a 37% reduction in risk of death favoring cabozantinib, P = .005).

The survival trend favored cabozantinib despite more frequent use of subsequent anticancer therapies in the everolimus group (47% of patients) compared with cabozantinib (38% of patients), he noted.

“We think this interim overall survival, although immature, is very encouraging,” Dr. Choueiri said. “Putting this in context, in patients with renal cell carcinoma treated with other drugs, cabozantinib compares favorably with everolimus, axitinib [Inlyta], and sorafenib

[Nexavar] in patients previously treated with only sunitinib [Sutent].”

Median duration of treatment was 7.6 months for cabozantinib and 4.4 months for everolimus.

Adverse Events “Dose reductions were more frequent with cabozantinib to manage adverse events [60% vs 25% of patients who received everolimus], underlining the need for careful adverse-event monitoring, as is the case with other VEGFR inhibitors. But the rate of discontinuation due to treatment-related adverse events was similar in both arms, around 10%,” Dr. Choueiri said.

The most common adverse events with cabozantinib were diarrhea, fatigue, nausea, decreased appetite, palmar-plantar syndrome, and hypertension. Higher rates of pneumonitis, peripheral edema, anemia, and hypoglycemia were observed with cabozantinib than with everolimus. n

Disclosure: The study was supported by Exelixis. Dr. Choueiri has served as a consult/ advisor for AVEO, GlaxoSmithKline, Novartis, Pfizer, and Exelixis and has received research funding from Pfizer.

References 1. Choueiri T, Escudier B, Powles T, et al: Cabozantinib versus everolimus in patients with advanced renal cell carcinoma. 2015 European Cancer Congress. Abstract 4LBA. Presented September 26, 2015.

2. Choueiri TK, Escudier B, Powles T, et al: Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. September 25, 2015 (early release online).

Cabozantinib vs Everolimus in Advanced Renal Cell Carcinoma ■■ Progression-free survival was nearly doubled by treatment with cabozantinib vs everolimus in patients with pretreated advanced renal cell carcinoma.

■■ More dose reductions for side effects were needed with cabozantinib, suggesting the need for careful monitoring during treatment, as with other tyrosine kinase inhibitors.

The ASCO Post | OCTOBER 25, 2015

PAGE 4

European Cancer Congress Nivolumab continued from page 1

prior treatment,” she predicted.

Patients taking nivolumab, an inhibitor of the programmed cell death protein 1 (PD-1), had a median overall survival of 25 months, compared with 19.6 months for those taking the tyrosine kinase inhibitor everolimus.

The international trial recruited 821 patients with advanced renal cell carcinoma of clear cell histology who had received previous antiangiogenic drugs (72% had one prior treatment). Patients were randomized to receive nivolumab at 3 mg/kg intravenously every 2 weeks or everolimus at 10 mg orally once a day.

Patients were followed for at least 14 months. At the July 2015 data cutoff, 17% of the nivolumab arm and 7% of the everolimus arm remained on treatment, whereas 45% and 54%, respectively, had died.

Overall Survival Benefit The hazard ratio (HR) for death (from any cause) with nivolumab vs everolimus was 0.73 (P = .002), which met the prespecified criterion for superi-

ority “with a highly significant P value,” Dr. Sharma reported. “The overall survival curves separated early and remained separated for the duration of the study.”

Numerous subgroups benefitted, including patients deemed to be at poor risk, she added.

Other Key Outcomes Objective response rates were almost fivefold higher with nivolumab as well, 25% vs 5% (P < .0001). In each arm, complete responses were observed in 1%, and the median duration of response was 12 months.

“Among responders, there were patients with a long duration of response, including some who went off treatment but still continued to have a response,” Dr. Sharma indicated.

Median progression-free survival was 4.6 months with nivolumab and 4.4 months with everolimus (HR = 0.88; P = .11). The observation that the curves diverged after the median was reached suggests a potential delayed treatment effect with immunotherapy, she added.

The investigators further explored

CheckMate 025 is the first and only study in which immunotherapy with an immune checkpoint inhibitor, used after prior treatment has failed, has shown a benefit in overall survival among patients with advanced kidney cancer.

—Padmanee Sharma, MD

this finding with an ad hoc sensitivity analysis among patients who did not experience disease progression or death by 6 months (35% with nivolumab and 31% with everolimus). In this analysis, median progression-free survival was 15.6 months with nivolumab, vs 11.7 months with everolimus (HR = 0.64).

Nivolumab was effective irrespective of the expression of the PD-1 ligand, PDL1, suggesting that PD-L1 expression should not be used to select patients for this treatment, Dr. Sharma said. Hazard ratios were 0.79 for patients with PD-L1 expression ≥ 1% and 0.77 for those with continued on page 5

Immune Checkpoint Inhibition in Advanced Renal Cell Carcinoma ■■ In the second-line treatment of advanced renal cell carcinoma, nivolumab reduced mortality by 27% compared with everolimus in the phase III CheckMate 025 trial.

■■ Median overall survival was 25 months with nivolumab and 19.6 months with everolimus.

■■ The benefit was seen regardless of PD-L1 expression.

EXPERT POINT OF VIEW

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ora N. Sternberg, MD, FACP, Chief of Medical Oncology at San Camillo Forlanini Hospital in Rome, Italy, formally discussed CheckMate 025 at the Presidential Session of the 2015 European Cancer Congress as well as findings from the METEOR trial of cabozantinib (Cometriq) in

a new benchmark for patients with previously treated metastatic renal cell carcinoma.”

Immunotherapy not only provides significant tumor shrinkage but can also stabilize disease, which translates into long-term survival benefits, she pointed out.

We now have two new interesting agents [nivolumab and cabazantinib] with different mechanisms of action.

This is an exciting time for immunotherapeutics and for drugs targeting VEGF resistance.

—Cora N. Sternberg, MD, FACP

metastatic renal cell carcinoma (see full details of the METEOR trial on page 3).

“We now have two new interesting agents with different mechanisms of action,” she noted. “This is an exciting time for immunotherapeutics and for drugs targeting VEGF [vascular endothelial growth factor] resistance.”

The overall survival benefit of 25 months with nivolumab, she said, “sets

“We know that with immunotherapy, the kinetics of response differ from [those of] targeted therapy, and we can often see responses after therapy has been stopped,” added Dr. Sternberg.

First-Time Survival Difference Because of this observation, patients in CheckMate 025 were allowed to remain on nivolumab even when they appeared to be progressing,

“which was wise,” and the study’s endpoint was, “correctly,” overall survival, she commented.

She emphasized that the median overall survival of 25 months—a 5.4-month difference vs everolimus— is the first time a survival difference has been observed in the second-line treatment of metastatic renal cell carcinoma. “This is an important new result,” she remarked.

Clinical Implications Dr. Sternberg further indicated that the lack of difference in progressionfree survival is not surprising when viewed in context with ipilimumab (Yervoy) data in melanoma. “You see no separation of the curves in the first 3 months, but separation starts to occur after that, and overall survival is increased…. The progression-free survival may not reflect the clinical benefit of nivolumab, due to its mechanism of action. This is what we can expect to see with immunotherapy.”

This pseudoprogression, and the challenges in evaluating response on treatment, could prove problematic for clinicians “in deciding how to counsel patients and on when to stop therapy,” she predicted.

She also noted that perhaps not all

patients will benefit equally from immunotherapy. In CheckMate 025, the most benefit was seen in patients with only one prior antiangiogenic regimen and in poor-risk patients. Little to no benefit was observed among favorable-risk patients, those treated in the third-line setting, and the elderly (> 75 years). The reasons for these differences are not clear.

Also unclear is why PD-L1 (programmed cell death-ligand 1) expression did not predict survival. More information on PD-L1 as a potential biomarker in this tumor would be of real interest, she said, especially in light of the intratumoral heterogeneity of this malignancy.

Referring to possibly having nivolumab and also cabazantinib in the treatment arsenal, Dr. Sternberg concluded: “Our task is to integrate the results of drugs with novel mechanisms of action—to understand whether we should use them in combination, in sequence, as maintenance therapy, or as adjuvant or neoadjuvant treatment. We also need proper patient selection.” n Disclosure: Dr. Sternberg has received research funding or honoraria from Pfizer, Novartis, Bayer, AVEO, Roche, BMS, Exelexis, and GSK.

ASCOPost.com | OCTOBER 25, 2015

PAGE 5

European Cancer Congress Thoracic Oncology

Atezolizumab Makes Inroads in Non–Small Cell Lung Cancer

By Alice Goodman

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he anti–PD-L1 (programmed cell death-ligand 1) antibody atezolizumab (formerly known as MPDL3280A) achieved encouraging outcomes in patients with non–small lung cancer (NSCLC) in two different trials: POPLAR1 and BIRCH.2 PD-L1 has emerged as a predictive biomarker for atezolizumab response in both trials, which were presented at the 2015 Eu-

II trial that compared atezolizumab vs standard docetaxel in 287 patients with advanced NSCLC that progressed on prior platinum therapy. Patients were treated with atezolizumab until loss of clinical benefit and until disease progression in the docetaxel arm.

The primary analysis presented by Dr. Vansteenkiste was on efficacy, safety, and predictive biomarkers.

It is to be expected that atezolizumab, like other PD-1 and PD-L1 antibodies, will substantially change treatment strategies of patients with refractory lung cancer.

—Martin Reck, MD

ropean Cancer Congress and are part of a huge development program for this investigational immunotherapy.

According to ESMO spokesperson Martin Reck, MD, of the Hospital Grosshansdorf, Germany, “Atezolizumab is the second checkpoint inhibitor to show superior efficacy and better tolerability compared to second-line chemotherapy in patients with pretreated NSCLC. Therefore, it is to be expected that atezolizumab, like other PD-1 and PD-L1 antibodies, will substantially change treatment strategies of patients with refractory lung cancer.”

Atezolizumab is an immunotherapy that inhibits PD-L1/PD-1 and PD-L1/ B7 interactions and can restore antitumor T-cell activity and enhance T-cell priming. PD-L1 is thought to be a predictive biomarker and was measured with a proprietary SP142 assay sensitive and specific for PD-L1 expression on both tumor cells (TC) and immune cells (IC).

POPLAR Trial Details “POPLAR demonstrated significant improvements in overall survival for unselected patients treated with atezolizumab vs docetaxel, reflecting a 27% improvement. Higher PD-L1 expression was associated with improved overall survival,” said lead author Johan Vansteenkiste, MD, PhD, of the University Hospitals Leuven, Belgium, who presented the trial results.

POPLAR was a randomized phase

Nivolumab continued from page 4

PD-L1 expression < 1%.

No New Safety Signals Treatment-related adverse events of any grade were observed in 79% of those who received nivolumab and 88% of those who received everolimus; grade 3-4 events occurred in 19% and 37%, re-

Johan Vansteenkiste, MD, PhD

Patients in POPLAR were stratified according to their level of PD-L1 expression: TC3 and/or IC3 were considered high expressors; TC2/3 and/ or IC2/3 were intermediate to high expressors. TC1/2/3 and/or IC1/2/3 were deemed “any expressors,” and TC0 spectively. The most common grade 3-4 events were fatigue with nivolumab (2%) and anemia with everolimus (8%). Toxicities led to treatment discontinuations in 8% and 13%, respectively, and two patients taking everolimus died as a result of toxicity. There were no treatment-related deaths on the nivolu­mab arm.

The mean change from baseline in quality-of-life scores on the Functional

and IC0 were deemed nonexpressors.

Baseline demographic and disease characteristics were well balanced between the two treatment arms. About two-thirds of patients had nonsquamous histology, and two-thirds received one prior platinum-containing regimen.

POPLAR Trial Results Atezolizumab significantly improved overall survival from a median of 9.7 months with docetaxel to 12.6 months (P = .04), reflecting a 27% improvement favoring the anti–PD-L1 antibody. “At a minimum follow-up of 13 months, the emerging picture suggests that the separation of survival curves will be ongoing,” Dr. Vansteenkiste told listeners.

Median survival was even better in high expressors of PD-L1 (ie, TC3 or IC3). “We saw the benefit of increasing gradient according to expression of PDL1,” he said, “with a 41% improvement in tumors with both TC3/IC3. In non– PD-L1 expressors, the survival curves are superimposed.”

“PD-L1 staining of tumor cells and immune cells is an independent predictor of survival improvement,” he noted.

The same phenomenon was observed for progression-free survival, with even a steeper gradient in improvement according to the intensity of PDL1 expression.

Treatment-emergent grades 3-4 adverse events were 11% with atezolizu­ mab vs 39% with docetaxel. The rate of grade 5 adverse events was 4% in both treatment arms. More patients in the docetaxel arm withdrew due to adverse events: 22% vs 8% for atezolizumab.

Alopecia, nausea, vomiting, and febrile neutropenia were more common with docetaxel, whereas immune-related events, such as dyspnea, pyrexia, arthralgia, musculoskeletal pain, and pneumonia, were more common with atezolizumab.

Assessment of Cancer Therapy–Kidney Symptom Index increased over time and differed significantly from the everolimus group at each assessment through week 76 (P < .05). “We saw a consistent improvement in quality of life with nivolumab vs everolimus,” Dr. Sharma reported. n Disclosure: Dr. Sharma has been a consultant for Amgen, AstraZeneca/MedImmune, BristolMyers Squibb, and GlaxoSmithKline and has

Dr. Vansteenkiste said the results of the phase III OAK trial of second-line atezolizumab patients with NSCLC are eagerly awaited. Multiple phase III trials that include atezolizumab in combination with other therapies are planned.

BIRCH Trial Details POPLAR was not enriched for PDL1 expression, whereas the BIRCH trial was a single-arm study of first-line or subsequent therapy that enrolled only PD-L1–positive patients with advanced or metastatic NSCLC (no brain metastasis allowed).

Benjamin Besse, MD

“The BIRCH trial found clinically meaningful results with atezolizumab monotherapy in PD-L1–selected patients with advanced NSCLC. The majority of responses are ongoing. Overall survival data are not mature. Six-month overall survival correlates with POPLAR results in second- and third-line therapy,” said lead author Benjamin Besse, MD, of Gustave Roussy, Paris.

“The safety profile of atezolizumab is consistent with previous trials, with no unexpected signals or differences in toxicity across cohorts.”

“Higher PD-L1 expression correlates with higher responses and may identify NSCLC patients who are likely to benefit from atezolizumab therapy,” he added.

The study was stratified into three cohorts: Cohort 1 was treated with firstline atezolizumab until disease progression (n = 142); cohort 2 was treated continued on page 6

been a consultant and founder with stock in Jounce Therapeutics.

References 1. Sharma P, et al: CheckMate 025. 2015 European Cancer Congress. Abstract 3LBA. Presented September 26, 2015.

2. Motzer RJ, et al: Nivolumab vs ev­ero­ limus in advanced renal-cell carcinoma. N Engl J Med. Sept 25, 2015 (early release online).

The ASCO Post | OCTOBER 25, 2015

PAGE 6

European Cancer Congress Atezolizumab continued from page 5

with second-line atezolizumab after one prior platinum-containing therapy (n = 271); and cohort 3 was treated with third-line and higher atezolizumab (n = 254). These 667 patients were recruited from 100 sites in 19 countries.

The proprietary SP142 assay was used to prescreen more than 3,000 patients for PD-L1 positivity; 34% were found to be PD-L1 expressors, classified as TC2/3 and/or IC2/3. Of the overall eligible population, 46% were classified as high PD-L1 expressors (ie, TC3 or IC3).

Baseline clinical and pathologic characteristics were well balanced between the three treatment cohorts. Median age was 64 years, 59% were male, 72% had nonsquamous histology, 12% had EGFR mutations, and 33% had KRAS mutations.

BIRCH Trial Results Overall response rates to atezolizumab were 17% in cohorts 2 and 3 and 19% in cohort 1. Overall response rates among high PD-L1 expressors were 27%, 24%, and 26%, in cohorts 1, 2, and 3, respectively. The majority of responses are ongoing.

Six-month overall survival was 82%, 76%, and 71% in cohorts 1, 2, and 3, respectively, and was higher when restricted to TC3 and IC3 patients (high expressors).

Six-month progression-free survival was 40%, 29%, and 31%, in cohorts 1, 2, and 3, respectively. Among TC3 or IC3 tumors, 6-month progressionfree survival was 48%, 34%, and 39%, respectively, in cohorts 1, 2, and 3, ­respectively.

Of all patients, 11% had grades 3 or 4 treatment-related adverse events, which led to treatment discontinuation in 5%. Common adverse events included fatigue, diarrhea, nausea, pruritus, pyrexia, and decreased appetite.

Adverse events of special interest were reported in 26% of patients; the majority were grades 1 and 2. The most frequently occurring grade 3 and 4 adverse events of special interest were pneumonitis (1.5%, one fatal case), increased aspartate transaminase levels (0.8%), colitis (0.5%), hypothyroidism, and rash (0.3% for each). n Disclosure: The POPLAR and BIRCH trials were sponsored by Genentech. Dr. Reck has

POPLAR and BIRCH Trials With Atezolizumab ■■ Atezolizumab improved outcomes in NSCLC in two separate randomized trials: the POPLAR and BIRCH trials.

■■ In both trials, the magnitude of PD-L1 positivity was associated with improved response and outcomes.

■■ The safety profile of atezolizumab was consistent with previous trials, with no unexpected signals or differences in toxicity across cohort.

■■ Atezolizumab is the second immunotherapy to show positive benefits in NSCLC, coming on the heels of nivolumab, an anti–PD-1 agent already approved for NSCLC. ■■ Use of PD-L1 staining as a biomarker for response to immunotherapies such as atezolizumab and nivolumab needs to be confirmed in randomized, controlled trials.

received honoraria for lectures and consultancy from Hoffmann-La Roche, Lilly, BMS, MSD, AstraZeneca, Boehringer Ingelheim, Novartis, and Pfizer. Drs. Vansteenkiste and Besse reported no potential conflicts of interest.

References 1. Vansteenkiste J, Fehrenbacher L, Spira AI, et al: Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety,

and predictive biomarkers from a randomized phase II study (POPLAR). 2015 European Cancer Congress. Abstract 14LBA. Presented on September 27, 2015.

2. Besse B, Johnson M, Jänne PA, et al: Phase II singl-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1selected non-small cell cancer. 2015 European Cancer Congress. Abstract 16LBA. Presented on September 27, 2015.

EXPERT POINT OF VIEW

“T

his is the first time we have seen data from the BIRCH trial in these three different cohorts using biomarker expression on tumor cells and immune cells,” said formal discussant Luis Paz-Ares, MD, Professor Medicine at the Hospital Universitario 12 de Octubre, Madrid, Spain.

“BIRCH confirms the activity and safety of atezolizumab [formerly known as MPDL3280A] in a large selected cohort of NSCLC [non–small cell lung cancer] patients.”

“Results support previously reported data showing higher response rates with atezolizumab associated with higher intensity expression of PD-L1 staining: 27% vs 17% with less intensity of staining. Survival is good and consistent with prior data with atezolizumab. The survival data are consistent with nivolumab [Opdivo] and pembrolizumab [Keytruda] in first-line ­studies.”

“Safety of atezolizumab was also

confirmed,” he continued, “and is similar to other agents in this class.”

The POPLAR results presented at the 2015 European Cancer Congress have an additional 3 months of

nivolumab,” he said. “Both trials show the same hazard ratio of 0.73, and the survival curves separate at 9 months, so two different agents in the same class are similar in different scenarios.”

Patients with staining in [tumor cells] do better than those with staining in [immune cells] in this trial.

Having the POPLAR database can shed light on outcomes in terms of staining intensity in [tumor cells] and [immune cells].

—Luis Paz-Ares, MD

follow-up since their first presentation at the 2015 ASCO Annual Meeting.

“Overall survival is confirmed, with a 27% improvement for atezolizumab compared with docetaxel. This is similar to the CheckMate 057 trial of

More on PD-L1 Expression The question of PD-L1 expression as a biomarker is complicated because of the many different assays and lack of correspondence between different assay cutoff points. In POP-

LAR, patients who tested negative for PD-L1 did not have a benefit from atezolizumab. Those results are similar to those from the nivolumab Checkmate 057 trial for negative PDL1 expression.

“One trial confirms the other, even though the definition of biomarker differs,” added Dr. Paz-Ares.

“Patients with staining in [tumor cells] do better than those with staining in [immune cells] in this trial.

Having the POPLAR database can shed light on outcomes in terms of staining intensity in [tumor cells] and [immune cells],” he said.

“As with any potential biomarker, this biomarker still needs to be validated in phase III trials,” continued Dr. Paz-Ares.“ A phase III trial of atezolizumab including all-comers is ongoing. In 1 year, we can see if this biomarker is clinically worthy.” n Disclosure: Dr. Paz-Ares reported no potential conflicts of interest.

More From the 2015 European Cancer Congress

To view interviews with experts recorded live during the 2015 European Cancer Congress, visit The ASCO Post Newsreels at http://video.ascopost.com/

The first FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2

AGENTS.

1

THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1-3

Dabrafenib (TAFINLAR) + trametinib (MEKINIST) is recommended by the National Comprehensive Cancer Network® (NCCN®*) as a category 1† first-line treatment option in BRAF V600-mutant unresectable or metastatic melanoma4

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

150 mg twice daily

as a single agent

overall response rate1,2 overall response rate1,2

76 % 54

% (95% CI: 62, 87)

median duration of response1,2

(95% CI: 40, 67)

median duration of response1,2

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

To learn more, visit TAFINLARMEKINISTHCP.com *NCCN Clinical Practice Guidelines in Oncology® for Melanoma Version 3.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. † Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Novartis recently acquired these products from GSK. To ensure a seamless transition, GSK is continuing to provide support for these products and related programs on behalf of Novartis at this time.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1,2 Major efficacy outcome: Investigator-assessed overall response rate1,2 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

60

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible.

Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1,2

50 40 30 20 10 0

9%

4

%

Complete Response

Partial Response

TAFINLAR as a single agent 150 mg twice daily

(N=54)

Complete Response

TAFINLAR

150 mg twice daily

+

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAPkinase signaling and increased cell proliferation in BRAF wildtype cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances.

Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1,2 Efficacy outcome: Investigator-assessed median duration of response1,2

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months

Months

TAFINLAR as a single agent 150 mg twice daily (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1,2 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1,2 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1,2

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level.

Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1.

If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough,

dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent.

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection.

Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.

Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%),

peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).

The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).

Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib.

Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Effects of the Combination of Dabrafenib with Trametinib.

Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. MEKINIST [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 3. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology for Melanoma (Version 3.2015). © 2015 National Comprehensive Cancer Network, Inc. http://www.nccn.org.

Accessed March 17, 2015. All rights reserved. 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.

Novartis recently acquired these products from GSK. To ensure a seamless transition, GSK is continuing to provide support for these products and related programs on behalf of Novartis at this time.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2015 Novartis

4/15

MAF-1113250

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent.

The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749).

RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose.

Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.

In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202).

Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/ iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days).

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations.

Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity.

TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman.

Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.

Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.

In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades a a 3 and 4 Grades Grades Adverse Reactions General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders Rashc 45 0 43 Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

0

8

2

0

2

0

0

9

2

0

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.

Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute.

Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

b

Tests Hematology Leukopenia Lymphopenia Neutropenia Anemia Thrombocytopenia Liver Function Tests Increased AST Increased alkaline phosphatase Increased ALT Hyperbilirubinemia Chemistry Hyperglycemia Increased GGT Hyponatremia Hypoalbuminemia Hypophosphatemia Hypokalemia Increased creatinine Hypomagnesemia Hyperkalemia Hypercalcemia Hypocalcemia

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a

62 55 55 55 31

5 22 13 4 4

46 59 37 46 31

4 19 2 7 2

21 40 9 28 8

0 6 2 0 0

60

5

54

0

15

0

60

2

67

6

26

2

42 15

4 0

35 7

4 4

11 0

0 0

58 56 55 53 47 29 24 18 18 15 13

5 11 11 0 5 2 5 2 0 0 0

67 54 48 43 41 15 20 2 22 19 20

6 17 15 2 11 2 2 0 0 2 0

49 38 36 23 40 23 9 6 15 4 9

2 2 2 0 0 6 0 0 4 0 0

No Grade 4 events were reported in patients receiving TAFINLAR as a single agent.

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.

QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. a

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. 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 Warnings and Precautions (5.11)].

Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].

Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.

In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].

Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.

Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].

Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].

Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].

The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated.

• TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)].

• TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)].

• TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)].

• TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)].

• TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)].

• MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)].

• TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)].

• TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)].

• TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)].

• TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)].

• MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness.

• MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment.

• TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

• Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)].

• Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)].

• TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.

MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved.

Revised: 01/2014 TFR: 4BRS Novartis recently acquired these products from GSK. To ensure a seamless transition, GSK is continuing to provide support for these products and related programs on behalf of Novartis at this time.

ASCOPost.com | OCTOBER 25, 2015

PAGE 15

European Cancer Congress Issues in Oncology

Chemotherapy/Radiotherapy Safe in Second and Third Trimesters of Pregnancy

By Alice Goodman

C

hildren with in utero exposure to chemotherapy and/or radiation therapy during maternal treatment for cancer had no impairment in cognition, cardiac function, and general early childhood development, according to a study reported at the European Cancer Con-

said, “I don’t have to be convinced. We are already convinced that it is good to share these data on how to behave and what to expect [in this setting].” Dr. de Vries is Head of the Department of Medical Oncology at the University Medical Centre Groningen, the ­Netherlands.

EXPERT POINT OF VIEW

I

n an accompanying editorial in The New England Journal of Medicine, Michael F. Greene, MD, Chief of Obstetrics at Massachusetts General Hospital, and Dan L. Longo, MD, Professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute, mentioned the low odds for both oncologists and obstetricians of treating a pregnant patient with cancer.

We hope that with these data, we can convince more oncologists around the world to treat cancer during pregnancy and avoid preterm delivery.

—Frederic Amant, MD

B:14.25 in

T:14 in

S:13 in

gress in Vienna, Austria, and published simultaneously online in The New England Journal of Medicine (see page 63).1,2 Although prematurity generally was correlated with a worse cognitive outcome, this effect was independent of exposure to chemotherapy—which is a novel finding.

“Currently women who develop cancer and require treatment have preterm delivery so that treatment can start. These results show that preterm delivery—but not cancer treatment—is associated with worse outcomes,” said lead author F ­rederic Amant, MD, who is Assistant Professor, Staff Gynecologic Oncologist, and Head of the Scientific Section of Gynecologic Oncology at University Hospitals Leuven in Leuven, Belgium. “This suggests that we should no longer induce preterm delivery and that it is safe to start cancer treatment while a woman is pregnant, except during the first trimester,” he said.

Study Design The multicenter, case-control study enrolled 129 children whose mothers had cancer (prenatal exposure group) and matched them 1:1 to 129 controls from the general population who were born to healthy mothers after uncomplicated pregnancies and deliveries.

Dr. Amant said that 3 years ago, the first interim results were reported with no control group. The main novel finding of current results is that chemotherapy and radiation had no deleterious effects on preterm babies.

A total of 96 women in the exposure group were exposed to chemotherapy alone, 11 to radiation alone, and 13 to surgery alone; 4 of these women had both radiation and surgery, and 7 had chemotherapy and radiation. Fourteen women had no treatment because they were diagnosed late in their pregnancies, so they were treated post delivery.

Birth Data

Elisabeth de Vries, MD, PhD

“We hope that with these data, we can convince more oncologists around the world to treat cancer during pregnancy and avoid preterm delivery,” he told listeners at a press conference held during the Vienna meeting.

The moderator at the press conference, ­Elisabeth de Vries, MD, PhD,

Overall, 61% of births in the study were preterm, defined as before 37 weeks of gestation. This rate is much higher than in the general population (6.8%–8%), Dr. Amant noted. Eleven children were born between 27 and 32 weeks of gestation, 16 between 32 and 33.9 weeks, 52 between 34 and 36.9 weeks, and 50 at 37 weeks (full-term). The numbers and types of congenital malformations were similar between cases and controls.

The main assessments were the health of babies, cognitive outcome, and cardiac morphology and function.

All children were tested at 18 months, continued on page 16

All specialty providers find themselves in unfamiliar territory when cancer is diagnosed in a pregnant woman.

—Michael F. Greene, MD (top), and Dan L. Longo, MD

“All specialty providers find themselves in unfamiliar territory when cancer is diagnosed in a pregnant woman,” they wrote. Available data on outcomes in children exposed to chemotherapy are inconsistent and frequently lack critical information, they noted.

Drs. Greene and Longo concluded: Overall these data [from Amant et al] should be reassuring to women who are facing a new diagnosis of cancer during pregnancies and to their families. Most important, although these women are more likely to deliver prematurely than are women without cancer, the cognitive development of their offspring will be similar to that of children of the same gestational age who were not exposed to maternal cancer and chemotherapy. Prudence continues to suggest avoiding cancer treatment in the first trimester; however, treatment in the second and third trimesters is likely to be best for both mothers and their offspring.

In correspondence with The ASCO Post, Dr. Greene added a cautionary note: “No one would suggest that it is safe for a fetus at any gestational age to be directly in the field of radiation therapy to the maternal pelvis. As little as 50 to 100 cGy direct exposure of a fetus in the second or third trimester will result in microcephaly. No reasonable combination of diagnostic procedures would ever total 50 cGy, but radiation therapy employs a few thousand centigray. Fetal exposures resulting from scatter from modern radiation therapy directed to other regions of the body (not the pelvis) is likely to be trivial and did not result in obvious harm in this study.” n

Disclosure: Dr. Greene is an Associate Editor and Dr. Longo is Deputy Editor at The New England Journal of Medicine.

Reference 1. Greene MF, Longo DL: Cautious optimism for offspring of women with cancer during pregnancy. N Engl J Med. September 28, 2015 (early release online).

The ASCO Post | OCTOBER 25, 2015

PAGE 16

European Cancer Congress Neuroendocrine Tumors

Treatment Options Expanding for Neuroendocrine Tumors

By Caroline Helwick

P

atients with advanced neuroendocrine tumors have two promising new treatment options, according to studies that earned spots in the Presidential Session of the 2015 European Cancer Congress, held recently in Vienna, Austria.

of pancreatic origin, whereas 177LuDOTATATE has been used outside of the United States and has not been formally evaluated. Investigators reported promising results with each of these approaches. In the studies, both treatments significantly prolonged progression-free survival and gave hints that an overall survival benefit could emerge.

“We truly have just heard two practice-changing presentations,” said press briefing moderator Christoph Zielinsky, MD, of the Medical University of Vienna.

The phase III studies evaluated the mTOR inhibitor everolimus (Afinitor) in the RADIANT-4 trial and the radiopharmaceutical agent 177Lu-DOTATATE in the European NETTER-1 trial.1,2 Everolimus was studied in patients with advanced nonfunctional gastrointestinal and lung neuroendocrine tumors, whereas the evaluation of 177 Lu-DOTATATE was limited to midgut neuroendocrine tumors.

Everolimus is approved by the U.S. Food and Drug Administration for locally advanced, metastatic or unresectable progressive neuroendocrine tumors

Cancer During Pregnancy continued from page 15

and 48 children were tested at both 18 months and 36 months.

Birth weight was below the 10th percentile (defined as small for gestational age) in 28 children (22%) in the prenatal exposure group and in 19 control children (15.2%), a difference that was not statistically significant. Looking more closely, the rates of “small for gestational age” were 25% in children exposed to chemotherapy and 36% in children exposed to radiotherapy. Among children whose mothers received chemotherapy and were small for gestational age, 64% had catchup weight at the time of testing, Dr. Amant said.

Other Outcomes For general health (incidence of medical problems, need for surgery and/ or medical care), there was no difference between study children and controls.

Cognitive outcome was assessed at a median age of 22 months using the Bayley Scales of Infant Development. There were no significant differences in cogni-

the 177Lu-DOTATATE arm (hazard ratio [HR] = 0.209; P < .0001), resulting in a median progression-free survival of 8.4 months with octreotide LAR and a me-

While few treatment options were available up to now for patients with advanced midgut gastrointestinal tumors, 177Lu-DOTATATE appears to be a major advance in this population.

—Philippe Ruszniewski, MD

Patients with advanced midgut neuroendocrine tumors have few therapeutic options after progression on first-line somatostatin analog therapy, according to Philippe Ruszniewski, MD, Professor of Gastroenterology at the University of Paris VII, Beaujon Hospital, who presented the results of NETTER-1.1 He explained that 177Lu-DOTATATE belongs to a therapeutic category known as peptide receptor radionuclide therapy. It consists of a lutetium radionuclide chelated to a peptide that targets somatostatin receptors, which are overexpressed in about 80% of neuroendocrine tumors. Upon binding to the receptors, cytotoxic high-energy

differentiated midgut neuroendocrine tumors (functioning or not) that had progressed on octreotide LAR (30 mg). Three-quarters of the patients had the ileum as the primary tumor site, and 84% had liver metastases.

Patients were recruited from 36 sites in Europe and the United States. They received four administrations of 177LuDOTATATE (7.4 GBq) every 8 weeks plus octreotide LAR (30 mg), whereas the control arm received octreotide LAR at 60 mg every 4 weeks. Patients were followed for 5 years.

The primary endpoint, progressionfree survival, was convincingly met by the radiopharmaceutical, according to Dr. Ruszniewski. There were 67 clinical events in the control arm and only 23 in

dian that has not yet been reached with 177 Lu-DOTATATE. “The interim analysis also suggests increased overall survival, but that remains to be confirmed by the final analysis,” said Dr. Ruszniewski.

Thus far, 13 patients in the 177LuDOTATATE arm have died, compared with 22 in the octreotide LAR group (P < .0186). However, the difference did not meet the prespecified level of statistical significance for this analysis.

Response rates were also increased with 177Lu-DOTATATE, from 3% with octreotide LAR alone to 19% with the combination (P < .0004). Serious adverse events were reported for 26% in the experimental arm and 24% in the

tive outcomes between the prenatal exposure group and controls.

“Cognitive results were the same in those exposed to chemotherapy, to radiation, and to surgery alone. This is reassuring,” Dr. Amant stated.

worse outcomes in premature children, he told listeners.

Cardiac function was assessed at 36 months in 50 of 54 children using electrocardiography and echocardiography, and 47 children had sufficient data for evalua-

same for [children exposed to cancer therapy] and controls,” he emphasized.

“If we look at children antenatally, no one can see the difference in cognition and cardiac function between exposed children and other children.”

Most mothers had breast or blood cancers treated with anthracyclines. Dr. Amant said although heart function in the exposed babies was normal, longterm monitoring is advised for those whose mothers received anthracyclines.

Dr. Amant emphasized that these findings apply to treatments used in this study and cannot be extrapolated to newer targeted agents. n

NETTER-1 Trial Christoph Zielinsky, MD

electrons are released into cancer cells.

The NETTER-1 study evaluated 177 Lu-DOTATATE in 229 patients with somatostatin receptor–positive well-

Cancer During Pregnancy ■■ Women who develop cancer during pregnancy can be safely treated with chemotherapy and/or radiation, as long as they are past the first trimester.

■■ More babies exposed to cancer treatment in utero were premature, but any effects of prematurity were independent of exposure to cancer treatment.

■■ This study suggests that it is unnecessary to deliver babies preterm in order to start cancer therapy.

No difference in cognitive function was seen between children exposed to one or two cycles of chemotherapy and those exposed to six or seven cycles of chemotherapy, he added. Additionally, no differences in cognitive function were observed according to the type of chemotherapy.

Previous studies have shown a wide variation in cognitive outcome associated with prematurity, with generally

tion. These children were compared with 47 matched controls for age and sex. No structural abnormalities were seen in any of the children, and no differences in any cardiac parameter assessed were observed between exposed children and controls.

Bottom Line “What is new in this study is that the negative effect of prematurity is the

continued on page 17

Disclosure: The study was funded by the Belgian Cancer Plan. For full disclosures of the study authors, visit www.nejm.org.

References 1. Amant F: Cancer in pregnancy. European Cancer Congress. Special Session. Presented September 28, 2015.

2. Amant F, et al: Pediatric outcome after maternal cancer diagnosed during pregnancy. N Engl J Med. September 28, 2015 (early release online).

ASCOPost.com | OCTOBER 25, 2015

PAGE 17

European Cancer Congress Neuroendocrine Tumors continued from page 16

control arm, with 9% and 1%, respectively, considered related to treatment.

“While few treatment options were available up to now for patients with advanced midgut gastrointestinal tumors, 177Lu-DOTATATE appears to be a major advance in this population,” Dr. Ruszniewski commented.

Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of neuroendocrine tumors, including those arising from the pancreas, lung, and gastrointestinal tract.

—James Yao, MD

RADIANT-4 Trial RADIANT-4 demonstrated a statistically significant 52% reduction in the risk of progression or death with everolimus among patients with a variety of neuroendocrine tumors, after progression on a somatostatin analog, according to James Yao, MD, Chairman in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.

Patients with anatomically diverse neuroendocrine tumors had nearly a threefold increase in median progression-free survival with everolimus: 11.0 vs 3.9 months with placebo (P < .00001).

“Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of neuroendocrine tumors, including those arising from the pancreas, lung, and gastrointestinal tract,” Dr. Yao said.

RADIANT-4 examined everolimus at 10 mg daily vs placebo in 302 pa-

tients with progressive, well-differentiated nonfunctional, advanced neuroendocrine tumors of gastrointestinal or lung origin (about 25% were midgut).

Patients had stopped somatostatin analogs for 4 weeks before enrollment and had no active carcinoid symptoms.

The primary endpoint was progression-free survival, which was reduced by 52% with everolimus (P < .00001) and by 61% according to investigator assessment (P < .00001). “Local radiology review confirmed the significant progression-free survival benefit—a change of 8.5 months. The curves were durable and remained separated for more than 18 months,” he said.

The benefit was observed in all sites of origin. Hazard ratios were most impressive in patients with the worst prognosis—ie, those whose tumors originated in the lung, stomach, rectum, and colon (HR = 0.43) and

among patients with a liver tumor burden > 25% (HR = 0.18). While the response rates were just 2% with everolimus and 1% with placebo, the disease control rates were 82.4% and 64.9%, respectively.

A preliminary analysis of overall survival showed a 36% improvement with everolimus (P = .037), although this did not meet the prespecified statistical criteria for significance at this planned interim analysis. Additional overall survival analyses are planned as the data matures. The safety profile was consistent with the known safety profile for everolimus.

How to Position These Treatments?

Since both agents delayed disease progression, an obvious next step would be to compare them in a randomized trial, said Dr. Zielinsky,

though he and Dr. Yao agreed that a head-to-head comparison would be unlikely.

“Now we have two options that are better than the classical or global standards, but we don’t know which of the two is better,” Dr. Zielinsky said, suggesting they will work as “cascade treatments.” Dr. Yao agreed that in advanced neuroendocrine tumors, most patients should survive long enough to need both treatment options. He also emphasized that the study outcomes in the two populations should not be viewed in comparison. “We should wait for the data to mature,” he said. n

Disclosure: Dr. Ruszniewski has served as an advisor to Advanced Accelerator Applications and has received honoraria and research funding from Advanced Accelerator Applications, Ipsen, and Novartis. Dr. Yao has served in a consulting or advisory role for Advanced Accelerator Applications, Ipsen, Lexicon, and Novartis.

References 1. Strosberg J, Wolin E, Chasen B, et al: 177Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours. 2015 European Cancer Congress. Abstract 6LBA. Presented September 27, 2015.

2. Yao J, Fazio N, Singh S, et al: Everolimus in advanced non-functional neuroendocrine tumours of lung or gastrointestinal origin. 2015 European Cancer Congress.

Abstract 5LBA. Presented September 27, 2015.

EXPERT POINT OF VIEW

E

nrique Grande, MD, Head of the Endocrine and Genitourinary Tumors Section of the Medical Oncology Service at Ramon y Cajal University Hospital, Madrid, discussed the NETTER-1 and RADIANT-4 studies at the Presidential Session of the 2015 European Cancer Congress.

“There is now a stronger rationale behind the use of everolimus (Afinitor) as a single agent after failure on [somatostatin analogs], regardless of the primary tumor origin,” he said, “and 177Lu-DOTATATE plus [a somatostatin analog] might become a standard in progressive midgut [neuroendocrine tumors].”

of other neuroendocrine tumor trials, was actually that impressive.

Acknowledging the danger in cross-trial comparisons and extrapolations, he indicated, “The median progression-free survival of 11 months with everolimus is not better than with [somatostatin analogs] alone,” as was shown in RADIANT-2.

tients with functioning tumors and in patients with a good prognosis, who gained little to nothing from everolimus in RADIANT-4.

‘Impressive Cohort’ Turning to the NETTER-1 trial, Dr. Grande predicted, “Peptide receptor radionuclide therapy is here to

Despite the encouraging activity of everolimus, we don’t have the full picture yet.

—Enrique Grande, MD

Qualifying Remarks Dr. Grande noted that everolimus is the first drug to show, in a randomized trial, significant activity in lung neuroendocrine tumors (hazard ratio [HR] = 0.50), but he questioned whether the primary endpoint, in the context

“Despite the encouraging activity of everolimus, we don’t have the full picture yet,” he continued. Other questions pertain to the benefit in pa-

stay.” The 177Lu-DOTATATE cohort, he said, is “the most impressive cohort we have seen in the [neuroendocrine tumor] field, in terms of hazard ratio

for progression-free survival,” especially since the trial’s comparator arm was an active regimen.

“We have a new mode of action, using an old, classic target in [neuroendocrine tumors],” he concluded.

“NETTER-1 confirms the activity of [peptide receptor radionuclide therapy] found in midgut [neuroendocrine tumor] retrospective series.”

Whether the findings can be extrapolated to nonmidgut neuroendocrine tumors remains unanswered, and its long-term safety profile has not been shown. Furthermore, there may be logistical concerns, he said, including “how to request the compound, how to produce the compound, how to deliver the compound to our institutions, and how to administer it.”

“In spite of its high activity,” he concluded, “I am not sure how available this drug will be for our patients.” n Disclosure: Dr. Grande has been an advisor for IPSEN, Lexicon, Pfizer, and Novartis.

The ASCO Post | OCTOBER 25, 2015

PAGE 18

European Cancer Congress Breast Cancer

TAILORx: Chemotherapy Not Necessary for Women With a Low Recurrence Score

By Caroline Helwick

T

he long-awaited first results are in from the TAILORx study, showing that patients with early breast cancer considered at low risk for recurrence can forgo chemotherapy and be treated with endocrine therapy alone.1 “Women with axillary node-negative, estrogen receptor–positive, HER2-negative breast cancer and a recurrence score less than 11 have a 1% risk of distant recurrence at 5 years with endocrine therapy alone,” according to Joseph A. Sparano, MD, of Albert Einstein College of Medi-

widely used, it does not provide clear guidance on the optimal treatment of the intermediate-risk group. The trial was primarily designed to determine whether adjuvant chemotherapy produced clinical benefit in patients with a midrange recurrence score of 11 to 25. These patients were randomized to chemoendocrine therapy (standard arm), or endocrine therapy alone (experimental arm). Patients with a recurrence score > 25 were assigned to chemoendocrine therapy, based on prior studies showing substantial benefit from chemo-

This prospective clinical trial provides the highest level of evidence supporting the clinical utility of the 21-gene assay in this setting and confirms expert-based clinical guidelines that the recurrence score should be used to risk-stratify and assign adjuvant chemotherapy.

—Joseph A. Sparano, MD

cine in Bronx, New York. “This population may be spared chemotherapy.”

TAILORx (Trial Assigning Individualized Options for Treatment) is the first prospective evaluation of the 21-gene assay (OncotypeDX). Although the assay is

therapy for this subgroup. Patients with a score < 11 were assigned to endocrine therapy alone, since prior studies showed good outcomes for this group when treated with endocrine therapy alone. A score of 11 was set as the cutpoint for random-

The Need for Chemotherapy in Low-Risk Patients ■■ Results were reported for patients deemed to be at low risk for recurrence of breast cancer with the 21-gene assay in the TAILORx trial.

■■ In women with a recurrence score < 11 who received only endocrine therapy (not chemotherapy), the risk of distant recurrence at 5 years was only 1%.

■■ Investigators concluded that this subset of patients with early breast cancer can safely forgo chemotherapy.

ization in this trial because this may be associated with a risk of distant recurrence as high as 10% at 10 years—a threshold above which chemotherapy would typically be recommended.

At the 2015 European Cancer Congress, investigators reported the results for the low-risk subset (recurrence score < 11). Data on the intermediate-risk (recurrence score 11 to 25) and high-risk (recurrence score > 25) groups will be reported in the future. Results were simultaneously published online in The New England Journal of Medicine.2 (See page 48 for more on the published report.)

The recurrence scores used in the TAILORx study are different from those generally applied in the widely used assay, which are recurrence score < 18 for low-risk designation, recurrence score of between 18 and 30 for intermediate-risk designation, and ≥ 31 as high-risk designation. Investigators

wanted to minimize the potential for undertreatment of the participants enrolled in the trial, and so they tightened the definitions of risk.

TAILORx Details The TAILORx study involved 10,253 women with hormone receptor–positive, HER2-negative, lymph node–negative breast cancer. The 16% of women with a recurrence risk score considered low (< 11) received 5 years of treatment with an aromatase inhibitor (59%), tamoxifen (34%), tamoxifen followed by an aromatase inhibitor (1%), ovarian suppression plus other therapy (3%), or other/unknown therapy (3%). Six patients received chemotherapy (one of whom had a recurrence).

Among the 1,626 women deemed at low risk (recurrence score < 11), the following 5-year outcomes (rates) were observed: 93.8% invasive disease-free continued on page 20

EXPERT POINT OF VIEW

C

lifford Hudis, MD, Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York, said the findings suggest there is essentially no meaningful benefit from chemotherapy in the recurrence score low-risk subset.

“It is clinically appropriate to offer endocrine therapy alone to patients with node-negative disease when the recurrence score is below 11,” he said as a discussant of the trials results presented at the Presidential Session of the 2015 European Cancer Congress.

However, in his editorial in The New England Journal of Medicine, he suggested the results are “both reassuring and frustrating” and questioned whether clinicians might be confused by the modification of the risk scoring in the study.1 “For the

many physicians already using the test, the gap between this [low-risk] cutoff point of 10 and the higher ‘standard’ cutoff point of 18 may be a concern,” Dr. Hudis said.

Conflicting Guides to Treatment “There will be two conflicting guides to their treatment that need to be reconciled: the cutoff point used in this trial and the previously available cutoff point that is associated with the commercial test,” he explained.

Dr. Hudis added that risk (ie, prognosis) is related to both biology and anatomic presentation and that risk reductions are related to anatomic presentation, but only within appropriately identified and responsive biologic subsets, according to the results.

It is clinically appropriate to offer endocrine therapy alone to patients with node-negative disease when the recurrence score is below 11.

—Clifford Hudis, MD

“The prediction of the benefit of chemotherapy remains to be validated,” he continued. “The key TAILORx result still pends: Does chemotherapy add for scores of 11–25? But, if it does, was 11 the right cut point? And what do we do about patients in the 11–18 range, given the commercial reports?”

Efforts to answer these questions, he

said, are part of the “many steps needed in the march to precision.” n

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

Reference 1. Hudis CA: Biology before anatomy in early breast cancer: Precisely the point.

Editorial. N Engl J Med. September 28, 2015 (early release online).

IS LONG-TERM TREATMENT A KEY TO SUSTAINING DEEP RESPONSES IN MYELOMA? Hear from myeloma experts and explore critical debates in multiple myeloma today.

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The ASCO Post | OCTOBER 25, 2015

PAGE 20

European Cancer Congress Breast Cancer

Fertility Preservation continued from page 1

lenge, and for young women, the prospect of infertility may be devastating.

“Pharmacologic protection of the ovaries with [luteinizing hormone–releasing hormone analog] during chemotherapy is an attractive option to preserve ovarian function and fertility. The agents are widely available, do not require any invasive procedure, and cause no delay in the initiation of anticancer therapy,” Dr. Lambertini said in a press release.

Women who need chemotherapy for breast cancer have the option of cryopreserving their eggs or embryos for future use prior to starting treatment. Dr. Lambertini said that ovarian suppression could be used in combination with these techniques “to increase the chance of fertility preservation as well as ovarian function after cancer therapies.”

Meta-analysis Details The meta-analysis included 12 randomized trials with a total of 1,231 breast cancer patients treated with chemotherapy with or without luteinizing hormone–releasing hormone analog. Ovarian suppression significantly reduced the number of cases of premature ovarian failure: 18.5% vs 33.5% for no ovarian suppression—a 64% reduction in the risk of developing this side effect (P < .001).

However, these studies used different definitions of premature ovarian failure, and results were in a wide range.

The researchers then restricted the analysis to eight trials that included data on whether menstruation had restarted within 1 year after chemotherapy, which is the

World Health Organization’s definition of menopause. In this restricted analysis, the results were in a similar range, showing a 45% reduction in the risk of developing chemotherapy-induced premature ovarian failure with luteinizing hormone–releasing hormone analog (P < .001). The subanalysis also revealed significantly lower 1-year rates of amenorrhea: 31% vs 42.9%, respectively (P < .001).

Of the original 12 studies, 5 included data on patients achieving pregnancies post treatment. Among 359 patients who received luteinizing hormone–releasing hormone analog during chemotherapy, 33 (9.2%) became pregnant vs 19 (5.5%) of 347 women who did not receive ovarian suppression during chemotherapy (P = .041). Pregnancy rates were similar across all five studies.

Three of the 12 studies looked at disease progression after chemotherapy with or without ovarian suppression and showed no difference in disease-free survival between women treated with luteinizing hormone–releasing hormone analog and those who were not: 19.5% vs 18.8%, respectively.

Current Guidelines In a separate interview, Dr. Lambertini explained that current guidelines in this setting are not in agreement. ASCO guidelines from 2013 consider ovarian suppression “experimental” and state that the strategy should not be used outside of the context of a clinical trial. The POEMS study had positive results with ovarian suppression during chemotherapy in breast cancer patients, which led to its incorporation into the 2015 St. Gallen guidelines,3

Fertility Preservation in Women With Breast Cancer ■■ A meta-analysis found that ovarian suppression with a luteinizing hormone– releasing hormone analog during chemotherapy improves chances of preservation of ovarian function and fertility in women with breast cancer.

■■ Randomized trials suggest that this approach can safely benefit both hormone receptor–negative and hormone receptor–positive patients.

TAILORx Trial continued from page 18

survival; 98.7% recurrence-free interval; 99.3% distant recurrence-free interval (ie, freedom from metastatic disease); and 98.0% overall survival. There were 88 cases of either invasive cancer or death during the 5-year study period, Dr. Sparano reported.

A multivariate analysis found that tumor grade was the only covariate that showed a significant association with any endpoint examined, specifically recurrence-free interval (P = .02).

“Recurrence rates were low, irrespec-

tive of histologic grade,” Dr. Sparano noted. “Recurrence risk was not significantly impacted by age or tumor size….

Second primary cancers exceeded cancer recurrence at 5 years.”

In addition, he noted that clinical characteristics could not reliably distinguish patients with a recurrence score < 11 vs 11 to 25. Interestingly, many of the patients would have been treated with chemotherapy had clinicians considered only their clinical characteristics.

“This prospective clinical trial provides the highest level of evidence sup-

EXPERT POINT OF VIEW

F

rederic Amant, MD, PhD, Assistant Professor, Staff Gynecologic Oncologist, and Head of the Scientific Section of Gynecologic Oncology at University Hospitals Leuven in Leuven, Belgium, stressed that the study by Lambertini et al is a meta-analysis, not a randomized controlled trial. Nevertheless, he was enthusiastic about the results.

“The results are convincing. They suggest that indeed young women should get [luteinizing hormone–releasing hormone analog] to increase the likelihood of ovarian function preservation and fertility. This treatment prolongs time until menopause. Unfortunately, it is not being reimbursed in Belgium,” Dr. Amant noted.

“I would advocate for ovarian suppression during chemotherapy in women with breast cancer, and I think all clinicians and physicians should as well,” he commented. n Disclosure: Dr. Amant reported no potential conflicts of interest.

and National Comprehensive Cancer Network guidelines4 also acknowledge the role of luteinizing hormone–releasing hormone analog in preventing chemotherapyinduced ovarian failure—but for both sets of guidelines, only in hormone receptor– negative breast cancer, as per study inclusion criteria of the POEMS trial.

The updated PROMISE-GIM6 study, including mostly hormone receptor– positive breast cancer patients, reported positive results for ovarian suppression at the 2014 Breast Cancer Symposium, also showing no detrimental effect on prognosis for concurrent administration of luteinizing hormone–releasing hormone analog and chemotherapy.5 Final results have been submitted for publication.

Dr. Lambertini noted that his metaanalysis included both the POEMS and PROMISE-GIM6 data. “Ovarian suppression could be useful and safe not only in hormone receptor–negative breast cancer, but also in those with hormone receptor–positive tumors, who account for two-thirds of new cases of breast cancer in young women,” he said. “Some guidelines favor this approach and others are hesitating to recommend it. To date, the role of this approach in fertility preservation remains controversial.” n Disclosure: Dr. Lambertini reported no potential conflicts of interest.

porting the clinical utility of the 21gene assay in this setting and confirms expert-based clinical guidelines that the recurrence score should be used to riskstratify and assign adjuvant chemotherapy,” Dr. Sparano concluded.

Studies that will be informative include the analysis of the TAILORx population with a recurrence score of between 11 and 25; the RxPONDER and OPTIMA studies of node-positive disease with a recurrence score ≤ 25; and the MINDACT trial, which is testing other gene-expression assays. n

References 1. Lambertini M, Ceppi M, Poggio F, et al: Ovarian suppression with luteinizing hormone-releasing hormone agonists during chemotherapy as a strategy to preserve ovarian function and fertility in breast cancer patients. 2015 European Cancer Congress. Abstract 1957. Presented September 28, 2015.

2. Lambertini M, Ceppi M, Poggio F, et al: Ovarian suppression with luteinizing hormone-releasing hormone agonists during chemotherapy as a strategy to preserve ovarian function and fertility in breast cancer patients. Ann Oncol. September 7, 2015 (early release online).

3. Moore HC, Unger JM, Albain KS: Ovarian protection during adjuvant chemotherapy. N Engl J Med 372:2269-2270, 2015.

4. National Comprehensive Cancer Network: NCCN Guidelines Version 3.2015— Invasive Breast Cancer: Fertility and Birth Control. Available at http://www.nccn.org/ professionals/physician_gls/pdf/breast.pdf.

Accessed October 6, 2015.

5. Lambertini M, Boni L, Michelotti A, et al: Long-term outcome results of the phase III PROMISE-GIM6 study evaluating the role of LHRH analog during chemotherapy as a strategy to reduce ovarian failure in early breast cancer patients. 2014 Breast Cancer Symposium. Abstract 105.

Presented September 4, 2014.

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

References 1. Sparano J, Gray R, Zujewski JA, et al: Prospective trial of endocrine therapy alone in patients with estrogen-receptor positive, HER2-negative, node-negative breast cancer. 2015 European Cancer Congress. Abstract 5BA. Presented September 28, 2015.

2. Sparano JA, Gray RJ, Makower DF, et al: Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. September 27, 2015 (early release online).

Biologics, Biosimilars and the United States: An Overview BIOSIMILARS VERSUS BIOLOGICS: WHAT’S THE DIFFERENCE? The first biosimilar has been approved in the United States, paving the way for many others that are certain to follow.

According to the US Food and Drug Administration (FDA), biosimilars are defined as biological products that are highly similar to an FDA-approved biological product (also called the reference product), with no clinically meaningful differences in safety and effectiveness. Only minor differences in clinically inactive components are permitted.1 This definition is closely aligned with that of the European Medicines Agency (EMA) and the World Health Organization (WHO).2,3 Biological products, or biologics, vary widely and can comprise a complex combination of proteins, nucleic acids and posttranslational elements such as sugars, or they may be living entities such as cells and tissues. For the purposes of this discussion, we are focused on recombinant therapeutic proteins. Biologics are isolated from a variety of natural sources—human, animal or microorganism—and are produced using biotechnology and/or other innovative technologies.4

DEVELOPMENT AND GROWTH OF BIOSIMILARS IN THE UNITED STATES Biologics have been revolutionary in the treatment of many diseases, including cancer, multiple sclerosis and chronic kidney disease. However, relative to the number of patients treated, biologics account for a disproportionate amount of healthcare resources and continue to outpace overall pharmaceutical spending growth. In 2002, biologics had global sales of $46 billion in US dollars, and this figure is expected to reach $221 billion by 2017.5 In 2010, eight of the 10 highest-expenditure drugs were biologics, accounting for $8 billion in Medicare Part B spending.6 Conversely, biosimilars have been predicted to lead to a $250 billion reduction in US spending on biologic drugs for the years 2014 to 2024.7 Global Biologics Sales, 2002-20175

$169 $106 $46

$221 billion

billion

billion

billion 2002

2007

2012

2017 (projected)

Biologics continue to outpace overall spending growth and are expected to represent 19% to 20% of global market value by 2017.5

Drug Development Comparison8 Smallmolecule Generic

$1-5 million

Originator Biologic

$375 million ($1.33 billion*)

Biosimilar

$100-200 million

Time in years: 0

2

4

6

8

10

12

14

*If discovery and development costs of failed products are included.

PATHWAYS FOR DRUG APPROVAL: BIOSIMILARS BREAKING NEW GROUND Generics and small-molecule drugs Small-molecule drugs, such as aspirin, and their accompanying generics are approved via the Food, Drug, and Cosmetic Act (FDCA). For decades, new small-molecule drugs have been regulated and controlled with the New Drug Application (NDA) process.9 FDA approval is based on demonstration of safety and efficacy. Generics must demonstrate bioequivalence for FDA approval and are approved via an abbreviated new drug application (ANDA) process established by the Hatch-Waxman Amendments enacted in 1984.10 Biologics Although biologics must also prove safety and efficacy to obtain FDA approval, the pathway is regulated differently through the biologics license application (BLA), or Section 351(a) of the Public Health Service Act, rather than an NDA. Both the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) are responsible for regulation of therapeutic biological products. A biologics license is issued if the biological product, the manufacturing process and the manufacturing facilities meet the requirements to ensure the continued safety, purity and potency of the biological product.11 Biosimilars The abbreviated, or tailored, licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product became possible when the Biologics Price Competition and Innovation (BPCI) Act was signed into law as part of the Affordable Care Act in 2010.1 Proposed biosimilars must scientifically demonstrate that there are no clinically meaningful differences from the reference biological product in terms of safety, purity and potency.12 Final FDA guidance on the requirements for interchangeability has not yet been defined.

Standard and Abbreviated Pathways for Drug Approval in the United States9-12 Small molecules

Biologics

Approved via Food, Drug, and Cosmetic Act (FDCA)

Approved via Public Health Service Act (PHSA)

Generics

Biosimilars

New drug application (NDA)

Abbreviated new drug application (ANDA),“Hatch-Waxman”

Biologics license application (BLA)

Biosimilar biologics license application (BPCI Act)

Safety and efficacy must be demonstrated

Bioequivalence must be demonstrated

Safety and efficacy must be demonstrated

Must demonstrate high similarity to reference / No clinically meaningful differences

ADDITIONAL SOURCES In addition to already-gained experience with abbreviated applications for protein products regulated as drugs, the FDA is following guidance from several other key sources in regulating biosimilar products. One source is the FDA’s previous experience with manufacturing changes proposed for currently marketed biologic products. Comprised of living cells, variability is inherent in the manufacture of biological products, both batch-to-batch and after a manufacturing change.13 Since the mid-1990s, the FDA has required physicochemical and functional assays to characterize the effects of manufacturing changes in biologics. Any remaining uncertainties about the comparability of pre- and postchange products are then addressed by conducting animal or clinical studies to provide the FDA with sufficient confidence that safety and efficacy are not diminished as a result of the manufacturing process change.14 Through comparative testing, the FDA also may be able to ascertain when additional clinical testing is unnecessary, allowing the drug to be brought to market more quickly.15 Another source of FDA guidance in regulating biosimilars comes from European regulation, which has been in place since 2005. Available guidelines include those that define principles (Guideline on Similar Biological Medicinal Products);

general comparability guidelines (immunogenicity assessment, quality issues and nonclinical/clinical issues); and productspecific comparability guidelines. More than 7 years of experience with biosimilars in Europe have not shown any unusual or unexpected effects with their use compared with their reference biologics.16,17 Leveraging this European experience with biosimilars, along with its own extensive experience in regulating biological products, has left the FDA well-positioned to oversee the introduction and utilization of these much-anticipated biosimilar products in the United States. Both the European experience and expert FDA oversight should give providers a high level of confidence to prescribe biosimilar products.

The approval of the first biosimilar is a milestone for the agency [FDA] and a significant positive development as patients and their physicians will have more treatment options. 18 — Alliance for Safe Biologic Medicines

References: 1. U.S. Food and Drug Administration (FDA). Biosimilars. FDA [website]. April 28, 2015. Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm. Accessed April 24, 2015. 2. European Medicines Agency (EMA). Questions and answers on biosimilar medicines (similar biological medicinal products). EMA [website]. September 27, 2012. Available at http://www.ema. europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf. Accessed April 24, 2015. 3. WHO: Definitions of biosimilars. Generics and biosimilars initiative (GaBi); 2012. GaBi [website]. Available at http://gabionline.net/Biosimilars/General/WHO-definitions-of-biosimilars. Accessed July 23, 2015. 4. U.S. Food and Drug Administration (FDA). Drug approvals and databases. February 2, 2012. FDA [website]. Available at http://www.fda.gov/drugs/informationondrugs/ucm079436. htm. Accessed April 24, 2015. 5. Institute for Healthcare Informatics. The global use of medicines: Outlook through 2017. November 2013. Parsippany, NJ: IMS Institute for Healthcare Informatics. 6. US Government Accountability Office. Medicare: Information on the Highest-Expenditure Part B Drugs. GAO-13-739T. June 28, 2013. 7. Miller S. The $250 billion potential of biosimilars. April 23, 2013. Express Scripts [website]. Available at http://lab.express-scripts.com/insights/industry-updates/the-$250-billionpotential-of-biosimilars. Accessed July 7, 2015. 8. Federal Trade Commission Report. Emerging health care issues: Follow-on biologic drug competition. Washington, DC: Federal Trade Commission; June 2009. 9. U.S. Food and Drug Administration (FDA). New drug application (NDA). February 3, 2015. FDA [website]. Available at http://www. fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/. Accessed April 28, 2015. 10. U.S. Food and Drug Administration (FDA). Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Amendments) [FDA testimony before the Senate Committee on the Judiciary]. August 1, 2003. FDA [website]. Available at http://www.fda.gov/newsevents/testimony/ucm115033.htm. Accessed April 29, 2015. 11. U.S. Food and Drug Administration (FDA). Frequently asked questions about therapeutic biological products. May 22, 2015. FDA [website]. Available at http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/%20HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm113522.htm. Accessed April 30, 2015.

12. U.S. Food and Drug Administration (FDA). Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference product. April 2015. 13. Shiestl M, Stangler T, Torella C, et al. Acceptable changes in quality attributes of glycosylated biopharmaceuticals [letter]. Nature Biotechnol. 2011;29(4):310-312. 14. Kozlowski S, Woodcock J, Midthun K, et al. Developing the nation’s biosimilars program. N Engl J Med. 2011;365(5):385-388. 15. U.S. Food and Drug Administration (FDA). Guidance for industry: Q5E comparability of biotechnological/biological products subject to changes in their manufacturing process. June 2005. 16. Ebbers HC, Crow SA, Vulto AG, et al.

Interchangeability, immunogenicity and biosimilars. Nature Biotechnol. 2012;30(12):1186-1190. 17. Ahmed I, Kaspar B, Sharma U. Biosimilars: Impact of biologic product life cycle and European experience on the regulatory trajectory in the United States. Clin Ther. 2012;34(2):400-419.

18. Alliance for Safe Biologic Medicines. ASBM commends FDA for approval, clear naming of first biosimilar. March 6, 2015. ASBM [website].

Available at http://safebiologics.org/press-releases.php. Accessed June 24, 2015.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

P15-0740-2-Jul., 15.

ASCOPost.com | OCTOBER 25, 2015

PAGE 23

Breast Cancer Symposium Breast Cancer

Aromatase Inhibitors May Decrease Risk of Contralateral Breast Cancer in BRCA Mutation–Positive Patients

By Chase Doyle

G

iven that BRCA1 and BRCA2 mutation carriers have an estimated 40% to 85% lifetime risk of breast cancer and an increased risk of developing contralateral breast cancer, risk reduction in this population remains essential. According to a study presented at the 2015 Breast Cancer Symposium, use of aromatase inhibitors may help accomplish this aim.1

Study Background In BRCA1/2 mutation carriers, the risk of contralateral breast cancer is approximately 2.5% per year, and the incidence of contralateral breast cancer is six times greater than in noncarriers.

Current options for reducing risk of contralateral breast cancer in mutation carriers with a personal history of breast cancer, however, remain limited—ei-

Use of aromatase inhibitors in the adjuvant setting after diagnosis of hormone receptor–positive breast cancer seems to delay the development of contralateral breast cancer in all individuals … especially in BRCA1/2 mutation–positive patients.”

—Maryam Nemati Shafaee, MD

“Use of aromatase inhibitors in the adjuvant setting after diagnosis of hormone receptor–positive breast cancer seems to delay the development of contralateral breast cancer in all individuals,” said Maryam Nemati Shafaee, MD, Hematology/Oncology Fellow at The University of Texas MD Anderson Cancer Center in Houston. “This effect was especially seen in BRCA1/2 mutation–positive patients. This gives patients an alternative option besides considering preventive mastectomy.”

ther prophylactic contralateral mastectomy (rates between 20% and 80% have been reported) or surveillance.

“The role of chemoprevention remains relatively unknown at this time,” said Dr. Shafaee, “but there are data suggesting that endocrine therapy, especially tamoxifen in the adjuvant setting for estrogen receptor–positive breast cancer, may reduce the risk of [contralateral breast cancer] in this high-risk population.”

Although several studies have examined adjuvant tamoxifen use in

EXPERT POINT OF VIEW

D

iscussant William J. Gradishar, MD, the Betsy Bramsen Professor of Breast Oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, endorsed Dr. Shafaee’s conclusions, while highlighting caution in interpreting the results.

“At first blush, it certainly is impressive,” said Dr. Gradishar, “but as Dr. Shafaee observed, the number of subjects is simply too small to make any sweeping recommendations based on these data. Another issue to consider—the cohort is largely an estrogen receptor–positive population. Is this necessarily a population that reflects all BRCA mutation carriers? Also, as

William J. Gradishar, MD,

pointed out, the follow-up is short.”

“I think the conclusions from these data are intriguing and warrant further evaluation,” he added, “but I would caution the use of this broadly in this group of individuals.” n Disclosure: Dr. Gradishar reported no potential conflicts of interest.

Aromatase Inhibitors and Contralateral Breast Cancer ■■ Patients who are BRCA1 and BRCA2 mutation carriers have an increased risk of contralateral breast cancer or shorter time to its development (P = .04).

■■ Use of aromatase inhibitors in this high-risk population was associated with a smaller risk of developing contralateral breast cancer (P = .04).

BRCA1/2 mutation carriers, data remain inconclusive regarding its role in preventing contralateral breast cancer. Furthermore, Dr. Shafaee added, there are no data on the use of adjuvant aromatase inhibitors and contralateral breast cancer risk-reduction in this population.

Study Design Dr. Shafaee and colleagues sought to identify predictors of contralateral breast cancer in a cohort of patients with known BRCA status and personal history of breast cancer by reviewing a prospectively maintained research database of patients who underwent BRCA testing at MD Anderson Cancer Center between 2004 and 2014.

The following variables were included in the study: age at diagnosis, bilateral salpingo-oophorectomy, BRCA1/2 mutation status, HER2/neu amplification, TNM stage, nuclear grade, tamoxifen use, aromatase inhibitor use, or combined use of tamoxifen plus an aromatase inhibitor.

Investigators excluded male patients and those who had undergone contralateral prophylactic mastectomy, as well as those with the following features: noninvasive disease (ie, ductal carcinoma in situ), hormone receptor–negative tumors, synchronous breast cancer, variant BRCA mutation, metastatic disease at time of diagnosis or within 1 year from diagnosis, and development of gynecologic cancer during follow-up.

Of the 486 patients included for final analysis, the majority were diagnosed with primary breast cancer before age 50, were premenopausal at diagnosis, and had not undergone prophylactic bilateral salpingooophorectomy. BRCA1/2 mutation carriers formed 9% of the total population.

“In terms of adjuvant therapy,” said Dr. Shafaee, “the majority of our patients received tamoxifen only (60%). This was followed by a combination of aromatase inhibitor plus tamoxifen (21%). Patients receiving an aromatase inhibitor only represented 16% of the population, and 3% of the population did not receive any adjuvant endocrine therapy.”

The median follow-up of 8.6 years,

although shorter than desired, was significant for identification of 43 contralateral breast cancers, Dr. Shafaee noted.

BRCA Mutation and Aromatase Inhibitors The hazard ratio for developing contralateral breast cancer for BRCA1/2 mutation carriers vs noncarriers was 2.3 (P = .04) in both univariate and multivariate analyses.

Other factors, including age at diagnosis, prophylactic bilateral salpingo-oophorectomy, HER2/neu status, nuclear grade, and use of tamoxifen, were not significantly associated with increased risk of contralateral breast cancer.

“Interestingly,” said Dr. Shafaee, “aromatase inhibitor use in all patients was suggestive of decreased risk of contralateral breast cancer, but this was not statistically significant (P = .08). Among patients with BRCA1/2 mutations, however, aromatase-inhibitor use was significantly associated with a smaller hazard of developing [contralateral breast cancer] (P = .04).”

The hazard ratio for aromatase inhibitor use vs no use in the overall population was 0.54 (P = .08), a 46% reduction in risk that indicated a trend.

Of the 23 patients with BRCA1/2 mutations who did not receive aromatase inhibitors, 7 developed contralateral breast cancer. However, of the 18 patients with BRCA1/2 mutations who received aromatase inhibitors, none developed the disease.

“For future directions,” she concluded, “validation of our findings based on a larger cohort and longer follow-up of BRCA mutation carriers who have received endocrine therapy in the adjuvant setting are recommended.” n

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

Reference 1. Shafaee M, Gutierrez-Barrera A, Lin H, et al: Aromatase inhibitors and the risk of contralateral breast cancer in BRCA mutation carriers. 2015 Breast Cancer Symposium. Abstract 3. Presented September 25, 2015.

The ASCO Post | OCTOBER 25, 2015

PAGE 24

Breast Cancer Symposium Breast Cancer

MRI Improves Breast Cancer Detection in Women at Average Risk

By Chase Doyle

M

agnetic resonance imaging (MRI) screening of women at average risk for breast cancer achieved a mean additional cancer yield of 15.8 cases per 1,000 women, greatly surpassing yields for supplemental digital breast tomosynthesis (1.25 per 1,000) or supplemental ultrasound (4.1 per 1,000). The study, presented at the 2015 Breast Cancer Symposium, also showed that in average-risk women, the contribution of mammography to early diagnosis will be limited.1 “Breast MRI improves the detection of small, node-negative, highgrade cancers in women at average risk to an extent that the interval cancer rate is zero,” said Christiane K. Kuhl, MD, Department of Diagnostic and Interventional Radiology at RWTH Aachen University in Germany. “In average-risk women, breast MRI–screening alone every 3 years may therefore be sufficient.”

Study Design To explore this issue, researchers recruited 2,120 women who underwent a prospective, two-center, comparative, diagnostic-accuracy study.

Participants (age 40 to 70) had normal screening mammograms and, in dense breasts, normal screening ultrasound at the time of study inclusion. “Prior MRI screening studies had included highly selected women at elevated or high risk of breast cancer. In this study, we looked at the much larger group of regular women without specific risk factors other than possibly dense breast tissue,” Dr. Kuhl explained.

Breast MRI improves the detection of small, high-grade cancers in women at average risk to an extent that the interval cancer rate is zero. In averagerisk women, breast MRI–screening alone every 3 years may therefore be sufficient.

Over- and Underdiagnosis “Between 30% and 50% of breast cancers that are diagnosed in women who participate in mammography screening programs will not be diagnosed by mammography, but as socalled ‘interval cancers’ in between screening rounds,” said Dr. Kuhl. “In other words, mammography fails to detect up to half of all breast ­cancers.”

At the same time, she noted, because detection of cancer in mammography is based on pathophysiologic processes that reflect regressive changes, overdiagnosis may be an unavoidable effect of the procedure.

Dynamic contrast-enhanced MRI, on the other hand, is a biomarker; detection of breast cancer in dynamic contrast-enhanced MRI is based on tissue alterations that directly correlate with carcinogenesis, cell proliferation, and even metastatic potential.

“MRI will preferably detect cancers that are biologically active and prognostically relevant, whereas it is relatively ‘blind’ for inactive disease or ‘dormant’ DCIS [ductal carcinoma in situ],” said Dr. Kuhl.” And yet, MRI screening has only been used so far in high-risk women—there’s no existing evidence for its use in women with average risk of breast cancer.

found by both mammography and MRI, and 60 were only MRI-detected, giving a supplemental cancer yield of 15.8 per 1,000 screening rounds. This compares to an average supplemental yield of 1.25 per 1,000 for tomosynthesis, or 4.1 per 1,000 for ultrasound screening.

Most cancers (22.6 per 1,000) were found in the initial screening round, substantially less (2.7 per 1,000 women-years) during the 4,887 subsequent screening rounds No interval cancers were observed, not even in women undergoing MRI screening only every 3 years.

Dr. Kuhl also noted that, in accordance with dynamic contrast-enhanced

—Christiane K. Kuhl, MD

The women were randomly assigned to undergo dynamic contrast-enhanced breast MRI and mammography every 12, 24, or 36 months, plus follow-up of 2 years. A total of 3,861 MRI studies covering 7,007 women-years were conducted over the course of the study.

Key Results The vast majority of MRIs (91.0%) were read as normal or benign. Women with suspicious findings (4.4%) underwent biopsy. From this group, 35.7% of lesions were ultimately found to be malignant, 24.6% revealed high-risk changes, and 39.8% revealed benign changes.

“This translates into a positive predictive value of 35.7% for cancer, which compares favorably to the respective value for digital breast tomosynthesis (29.3%) or ultrasound screening (8.0%–16.0%).” said Dr. Kuhl.

Ultimately, 61 cancers were identified in 2,120 women for an overall detection rate of 28.8 per 1,000 women.

Of these 61 cancers, none was only mammography-detected, one was

MRI being a biomarker, the added cancers diagnosed by MRI had pathologic features of biologic ­importance.

“The cancers detected skewed toward a higher-than-normal rate of high-grade and estrogen receptor/ progesterone receptor–negative cancers,” said Dr. Kuhl. “Thus, cancers detected by MRI had similar biologic profiles as the usual interval cancers—interval cancers that were not observed in our study but that would have been expected to be seen in this cohort if women had undergone mammographic screening alone.”

Clinical Trial Needed Discussant A. Marilyn Leitch, MD, Professor of Surgery at The University of Texas Southwestern Medical Center at Dallas, emphasized that this was a highly selected population with negative mammograms.

“One of the concerns we hear about MRIs,” said Dr. Leitch, “is that falsepositive rates are higher than were reported in this study. MRI detects le-

sions that might drive patients to avoid breast-conserving surgery, and there can be unreasonable costs of screening and workup of false-positives.… Even the most liberal screening guidelines in the United States reserve MRI for highrisk patients.”

A. Marilyn Leitch, MD

What is needed, said Dr. Leitch, is a clinical trial. “It would be useful to compare screening MRI at 3-year intervals to an annual tomosynthesis mammogram in all average-risk women,” she concluded.

While agreeing with the need for further clinical trials, Dr. Kuhl replied that the population was everything but highly selected. “These were regular women without specific risk ­factors.”

She also took exception to the notion of high false-positive rates. “The positive predictive value for MRI in our study was higher than that of digital breast tomosynthesis in the screening situation,” said Dr. Kuhl. “A high positive predictive value and an interval cancer rate of zero make up a perfect screening test.”

She concluded: “As long as breast cancer continues to represent one of the main causes of cancer death in women, the search for improved screening methods should continue. Such methods should combine a maximum sensitivity for cancers that have the potential to kill, with a desirable lack of sensitivity for disease that is prognostically unimportant. This is what MRI screening may achieve.” n

Disclosure: Drs. Kuhl and Leitch reported no potential conflicts of interest.

Reference 1. Kuhl C, Strobel K, Bieling H: Breast MRI screening of women at average risk of breast cancer: An observational cohort study. 2015 Breast Cancer Symposium. Abstract 1. Presented September 25, 2015.

ASCOPost.com | OCTOBER 25, 2015

PAGE 25

World Conference on Lung Cancer Thoracic Oncology

Smoking Cessation Reduces Mortality in Lung Cancer Screening Population

By Caroline Helwick

D

ata from an analysis of lung cancer screening programs in Italy add further evidence that smoking cessation reduces mortality. Heavy smokers screened by low-dose computed tomography (CT) who stopped smoking before or during the screening period had a three- to fivefold reduction in mortality compared with current smokers. The data were presented at the 16th World Conference on Lung Cancer.1

Ugo Pastorino, MD

“Stopping smoking is associated with a significant reduction of the overall mortality of heavy smokers enrolled in [low-dose CT] screening programs.

The benefit of stopping smoking appears to be three- to fivefold greater than the one achieved by earlier detection in the National Lung Screening Trial (NLST),” said lead researcher Ugo Pastorino, MD, Director Thoracic Surgery, IRCCS Istituto Nazionale dei Tumori Foundation, Milan, Italy. The NLST had previously found a 7% reduction in all-cause mortality with lowdose CT screening, he indicated.

In the current study, the Italian investigators analyzed 3,381 heavy smokers enrolled in two low-dose CT screening programs. They divided patients according to whether they were current smokers (also including those who quit smoking less than 1 year before the end of follow-up or death) or former smokers; former smokers could be ex-smokers at the time of baseline screening or smokers who stopped smoking during the screening period, at least a year before the end of follow-up or death (ie, quitters).

“The difference between the mortality curves was consistent throughout the period of observation. The two curves diverged nicely,” he added.

Deaths Reduced

Lung cancer deaths accounted for about one-third of all deaths and numbered 45 of 17,846 person-years among current smokers, 11 of 7,809 personyears among ex-smokers, and 17 of 7,202 person-years among quitters.

The analysis also identified other risk factors for mortality. These risk factors and their associated risk ratios included male sex (1.6); age older than 62 years (3.2); forced expiratory volume, first second (FEV1) < 80% (2.5); packs/year ≥ 40 (1.5); and total cigarettes ≥ 292,200 (1.5).

Investigators also evaluated the benefit of pharmaceutical support in a smoking cessation program that involved a sample of 187 persons screened over 5 years. In this government-funded pilot observational study, the drug varenicline (Chantrix) plus behavioral intervention resulted in a quitting rate of 49% after 3 months, which declined but remained at

The population included 1,801 current smokers, 872 ex-smokers, and 708 quitters. The percentage of baseline smokers who quit during the low-dose CT screening period was 28%.

After almost 9 years of follow-up, there were 151 deaths among the smoking group and 109 deaths among enrollees who stopped smoking during the screening period (50 among ex-smokers and 59 among quitters). The all-cause mortality for current smokers was 846 per 100,000 pack-years and for former smokers was 726 per 100,000 packyears. Multivariate analysis, adjusted for age, gender, lung function, and pack/ years, revealed a relative risk of death of 0.75 to 0.57 for ex-smokers and quitters.

This finding amounted to a relative risk reduction of 26% for former smokers vs current smokers and 43% for quitters vs current smokers, Dr. Pastorino said.

20% at 12 months, he reported.

“This tells us that pharmaceutical support is effective as part of an intervention and that quitting is difficult, but

Smoking and Lung Cancer Screening ■■ An analysis of two screening programs in Italy found that enrollees who stopped smoking during the course of the screening period had a threefold to fivefold reduction in mortality, compared with current smokers.

■■ The relative risk reduction was 26% for former smokers vs current smokers and 43% for quitters vs current smokers.

if you do it systematically, with repeated interventions, you can achieve more,” commented Dr. Pastorino. “You have to do it more than once if you want to maintain the effect.”

“The take-home message is that stopping smoking is the most effective and feasible strategy to reduce mortality in current smokers,” Dr. Pastorino said. He added that the next step along this path is to combine preventive efforts with screening to further reduce mortality among smokers. n

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

Reference 1. Pastorino U, Boffi R, Marchiano A, et al: Stopping smoking reduces mortality in low-dose computed tomography screening volunteers. 16th World Conference on Lung Cancer. Abstract PLEN04.07. Presented September 9, 2015.

Drug Development

Delays in Drug Approval Are Deadly, Highlighting the Need for Improved Regulatory Efficiency

By Caroline Helwick

R

esearchers have determined just how many lives are lost when effective investigational drugs are not approved in a timely manner. These delays in the process of anticancer drug approvals result in thousands of premature deaths each year, according to an analysis presented at the 16th World Conference on Lung Cancer.1 David Stewart, MD, Head of Medical Oncology at the University of Ottawa/The Ottawa Hospital, Canada, looked at 21 drugs as illustrative examples. For these 21 drugs combined, there were 29 life-years lost in North

David Stewart, MD

America and 260 life-years lost worldwide per hour of delay in drug approval.

Dr. Stewart indicated that the current regulatory process for approving new drugs increases drug development

costs and hinders drug approval. Despite relatively modest gains in survival afforded by new anticancer agents, delays in their approval still result in many life-years lost, he said.

Worldwide, steadily increasing regulatory complexity has driven up the cost of drug development much faster than the rate of inflation, and this contributes directly to high health-care costs. There has been a minimal demonstrable impact on clinical trials safety, and the slowed progress leads to increased suffering and premature death, according to Dr. Stewart.

“There would be a large negative impact associated with approval delays, even if factors such as comorbidities, performance status, and ability to pay limit the number of patients treated to a fraction of the total dying from a specific malignancy,” he said.

Accelerated approval and breakthrough drug designation have not solved the problem. These changes may have cut the time to drug approval substantially, but predominantly they have just removed the requirement for phase III trials, Dr. Stewart pointed out.

“They have not fixed the escalatcontinued on page 30

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials FOR NEWLY DIAGNOSED MULTIPLE MYELOMA

SHAPE PROGRESSION-FREE SURVIVAL WITH CONTINUOUS TREATMENT Continuous REVLIMID + dex until progression showed a PFS and OS benefit in patients with newly diagnosed multiple myeloma vs MPT

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM See full prescribing information for complete boxed warning.

EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death.

• Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception.

REVLIMID is available only through a restricted distribution program called the REVLIMID REMS® program (formerly known as the “RevAssist® program”).

HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia.

• For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter.

VENOUS AND ARTERIAL THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving REVLIMID with dexamethasone.

Anti-thrombotic prophylaxis is recommended.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNINGS, on the following pages.

Learn more at www.REVLIMID.com

Median Progression-Free Survival (PFS) Rd Continuous (n=535) 25.5 mo (95% CI 20.7, 29.4) Rd18 (n=541) 20.7 mo (95% CI 19.4, 22.0) MPT (n=547) 21.2 mo (95% CI 19.3, 23.2)

100

Survival Probability (%)

80 Rd Continuous vs MPT Rd Continuous vs Rd18 Rd18 vs MPT

60

Logrank P value (2-sided) HR (95% CI) 0.72 (0.61, 0.85) P<0.0001 0.70 (0.60, 0.82) 1.03 (0.89, 1.20)

Planned duration of treatment in the Rd18 40 and MPT arms was 18 months 20

0

0

1

2

3

4

5

Progression-Free Survival (Years) •535 PFS Rd Continuous Rd18 541 MPT MM-020 547 Study design: The

Events: (52.0%), (64.3%), MPT=334/547 400Rd Continuous=278/535 319 265 218 Rd18=348/541 168 105 55 19 (61.1%)2 391 380 (FIRST)

319 265 167 304 244 compared REVLIMID170+

108 116 low-dose

56 30 58 28 (Rd) dexamethasone

7 2 6 1 Continuous until

0 0 0 progression,

trial fixed-cycle MPT, and fixed-cycle Rd18. MM-020 was a Phase 3, randomized, multicenter, open-label, 3-arm study enrolling 1623 newly diagnosed Number of Subjects at mg Risk patients who did not receive a stem cell transplant (SCT).

REVLIMID was given 25 once daily orally on Days 1 to 21 of 28-day cycles, PFS Events: Rd Continuous=278/535 (52.0%), Rd18=348/541 (64.3%), MPT=334/547 (61.1%) ≤75 years and 20 mg for patients and dex was dosed once daily orally on Days 1, 8, 15, and 22 of each 28-day cycle (40 mg for patients >75 years). The primary endpoint in the trial was progression-free survival (PFS), as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms.

58.9 months median overall survival (OS) with Rd Continuous until progression in an interim analysis, compared with 48.5 months with MPT (HR 0.75 [95% CI 0.62, 0.90]) and 56.7 months with Rd18 (HR 0.91 [95% CI 0.75, 1.09]) • At median follow-up of 45.5 months, only 78% of prespecified events had occurred (697/896 of the final OS events) • OS is defined as the time from randomization to death from any cause ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75% Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female 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 the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, StevensJohnson syndrome, toxic epidermal necrolysis) to lenalidomide

Treatment is a science. Patient care is your art.

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM) REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS® program (formerly known as the “RevAssist®” program).

Information about the REVLIMID REMS® program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female 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 the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in offspring of female monkeys who received drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug.

Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID REVLIMID REMS® Program Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS® program (formerly known as the “RevAssist®” program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS®

program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436 Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter.

Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM after at least one prior therapy, treated with REVLIMID/dex compared to placebo/dex (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In NDMM study, in which nearly all patients received antithrombotic prophylaxis, DVT (3.6%) and PE (3.8%) were reported in the Rd continuous arm. Myocardial infarction (MI, 1.7%) and stroke (CVA, 2.3%) are increased in patients with MM after at least 1 prior therapy who were treated with REVLIMID/dex therapy compared with placebo/dex (0.6%, and 0.9%) in clinical trials. In NDMM study, MI (including acute) was reported (2.3%) in the Rd Continuous arm. Frequency of serious adverse reactions of CVA was (0.8%) in the Rd Continuous arm. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID/dex compared to 8.3% thrombosis in the placebo/dex group. Median time to first thrombosis event was 2.8 months. In NDMM study, which nearly all patients received antithrombotic prophylaxis, overall frequency of thrombotic events was 17.4% in combined Rd Continuous and Rd18 arms. Median time to first thrombosis event was 4.37 months.

Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41] consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID

WARNINGS AND PRECAUTIONS (continued) treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials Second Primary Malignancies: In clinical trials in patients with MM receiving REVLIMID, an increase of invasive second primary malignancies (SPM) notably AML and MDS have been observed. The increase of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (5.3%) or immediately following high dose intravenous melphalan and ASCT (up to 5.2%). The frequency of AML and MDS cases in the REVLIMID/dex arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received REVLIMID in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and risk of second primary malignancies when considering treatment Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID in combination with dex. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash.

REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken Tumor Flare Reaction: Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash.

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are autologous stem cell transplant (ASCT) candidates, referral to a transplant center should occur early in treatment to optimize timing of the stem cell collection ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75%

Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous • After at least one prior therapy most adverse reactions and Grade 3 or 4 adverse reactions were more frequent in MM patients who received the combination of REVLIMID/dex compared to placebo/dex. Grade 3 or 4 adverse reactions included neutropenia 33.4% vs 3.4%, febrile neutropenia 2.3% vs 0%, DVT 8.2% vs 3.4% and PE 4% vs 0.9% respectively Adverse reactions reported in ≥15% of MM patients (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%) DRUG INTERACTIONS Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436 Nursing Mothers: It is not known whether REVLIMID is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother Pediatric Use: Safety and effectiveness in patients below the age of 18 have not been established Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the following pages.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

REVLIMID® and REVLIMID REMS® are registered trademarks of Celgene Corporation. © 2015 Celgene Corporation 07/15 US-REV140068a(1)

The ASCO Post | OCTOBER 25, 2015

PAGE 30

World Conference on Lung Cancer Delays in Drug Approval

Assessing Life-Years Lost

continued from page 25

Between 2001 and 2015, Dr. Stewart and colleagues assessed drugs shown in phase III trials to significantly improve overall survival, excluding adjuvant trials and trials in rare malignancies. They then multiplied the improvements in median survival (years) by the estimated number of patients who died annu-

ing burden of clinical research bureaucracy,” he said, adding that although there may be a “shorter distance to the goal posts, the mud on the way to these closer goal posts keeps getting deeper.”

Dr. Stewart commented, “We need to fix this problem.”

There would be a large negative impact associated with approval delays, even if factors such as comorbidities, performance status, and ability to pay limit the number of patients treated to a fraction of the total dying from a specific malignancy.

—David Stewart, MD

T:7”

REVLIMID [lenalidomide] capsules, for oral use

Table 1: Dose Adjustments for Hematologic Toxicities for MM

The following is a Brief Summary; refer to full Prescribing Information for complete product information.

Platelet counts

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study.

Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2).

Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia.

Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study.

Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM).

1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)].

2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed.

2.1 Multiple Myeloma Multiple Myeloma The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone.

Refer to Section 14.1 for specific dexamethasone dosing. For patients > 75 years old, the starting dose of dexamethasone may be reduced.

Treatment should be continued until disease progression or unacceptable toxicity.

In patients who are not eligible for autologous stem cell transplantation (ASCT), treatment should continue until disease progression or unacceptable toxicity. For patients who are ASCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy [see Warnings and Precautions (5.11)].

Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.

When Platelets

Recommended Course

Fall to <30,000/mcL

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at next lower dose.

Do not dose below 2.5 mg daily

Return to ≥30,000/mcL For each subsequent drop <30,000/mcL Return to ≥30,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose.

Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils

Recommended Course

Fall to <1000/mcL Return to ≥1,000/mcL and neutropenia is the only toxicity

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at 25 mg daily or initial starting dose

Return to ≥1,000/mcL and if other toxicity

Resume REVLIMID at next lower dose.

Do not dose below 2.5 mg daily

For each subsequent drop <1,000/mcL Return to ≥1,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose.

Do not dose below 2.5 mg daily

Other Toxicities in MM For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.

Starting Dose Adjustment for Renal Impairment in MM: [See Dosage and Administration (2.4)].

2.4 Starting Dose for Renal Impairment in MM Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min.

The recommendations for initial starting doses for patients with MM are as follows: Table 3: Starting Dose Adjustments for Patients with Renal Impairment in MM Category

Renal Function (Cockcroft-Gault)

Dose in MM

Moderate Renal Impairment

CLcr 30-50 mL/min

10 mg Every 24 hours

Severe Renal Impairment

CLcr < 30 mL/min (not requiring dialysis)

15 mg Every 48 hours

End Stage Renal Disease

CLcr < 30 mL/min (requiring dialysis)

5 mg Once daily. On dialysis days, administer the dose following dialysis.

Moderate renal impairment for MM: Consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity.

After initiation of REVLIMID therapy, subsequent REVLIMID dose increase or decrease is based on individual patient treatment tolerance, as described elsewhere [See Dosage and Administration (2.1-2.3)].

4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female.

Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)].

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Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism.

Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.

Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.4)].

Thrombocytopenia in MM

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World Conference on Lung Cancer Impact of Delays in Drug Approval ■■ Each hour that is lost to regulatory delays in approving new cancer drugs costs up to 29 life-years in the United States and 260 life-years worldwide.

■■ For the approval of 21 agents in 11 malignancies, 1 life-year was lost in North America for every 2.2 minutes of delay in drug approval.

■■ Accelerated drug approval and breakthrough designation have not solved the problem of delays in drug approval.

T:7”

4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)].

5.2 REVLIMID REMS™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program).

Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements.

Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.

5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia.

Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)].

Patients taking REVLIMID in combination with dexamethasone for MM should have their complete blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every

He broke the analysis down for individual drugs and demonstrated that cumulatively, to achieve drug approval, more than 250,000 life-years are lost per year in North America.

Their calculations did not take into account the impact of drugs that were considered nonevaluable due to crosscontinued on page 32

28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)].

Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter.

Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days).

In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days) [see Boxed Warning and Dosage and Administration (2.2)].

Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.

5.4 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)].

Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)]. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking).

In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months.

In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.37 months in the combined Rd Continuous and Rd18 Arms. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events.

ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID [see Drug Interactions (7.2)].

5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013.

Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

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5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.

REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)].

Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.

Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy.

Two negative pregnancy tests must be obtained prior to initiating therapy.

The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].

Males Lenalidomide is present in the semen of patients receiving the drug.

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)].

Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID.

ally from the malignancy in both North America and worldwide.

Dr. Stewart presented data on the approval for 21 agents in 11 malignancies.

For all drugs and tumor sites combined, 1 life-year was lost in North America for every 2.2 minutes of delay in drug approval. Worldwide, 1 life-year was lost for every 12 seconds of delay.

The ASCO Post | OCTOBER 25, 2015

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World Conference on Lung Cancer Delays in Drug Approval continued from page 31

over or missing survival data, drugs that were prematurely abandoned, and drugs still under investigation.

By emphasizing that these lives are “unnecessarily lost,” Dr. Stewart concluded, “even if only 1% to 10% of patients had drug access, the losses are still enormous.”

Accelerated drug approval and breakthrough designation are helpful, “but we must do much more,” he maintained.

“We all share the blame,” including investigators, research staff, institutions, internal review boards, sponsors, clinical research organizations, regulators, the tort system, and the press. “We all share responsibility, therefore, to solve this,”

stated Dr. Stewart. “It’s time to act.” n Disclosure: Dr. Stewart is a consultant and on the advisory boards of Roche Canada, Pfizer Canada, Boehringer Ingelheim Canada, Amgen, Amgen Canada, and Novartis Canada; receives clinical trial support from Boehringer Ingelheim, AstraZeneca, Novartis, BristolMyers Squibb, and Celgene; and scientific T:7” writing support from Boehring Ingelheim.

5.6 Second Primary Malignancies In clinical trials in patients with multiple myeloma receiving REVLIMID an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of cases of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (frequency of 5.3%) or immediately following high dose intravenous melphalan and ASCT (frequency of up to 5.2%). The frequency of AML and MDS cases in the REVLIMID / dexamethasone arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received lenalidomide in the post-ASCT setting.

Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically.

Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.

5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1.

Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 5.11 Impaired Stem Cell Mobilization A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are ASCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other sections of the prescribing information: • Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Venous and arterial thromboembolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.9)] • Tumor Flare Reactions [see Warnings and Precautions (5.10)] • Impaired Stem Cell Mobilization [see Warnings and Precautions (5.11)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience Specific Populations Newly Diagnosed Multiple Myeloma: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541) General disorders and administration site conditions Fatigue%

173 (32.5) 177 (32.8) 154 (28.5) 39 (7.3)

46 (8.5)

31 (5.7)

Asthenia

150 (28.2) 123 (22.8) 124 (22.9) 41 (7.7)

33 (6.1)

32 (5.9)

Pyrexiac

114 (21.4) 102 (18.9) 76 (14.0) 13 (2.4)

7 (1.3)

7 (1.3)

< 1%

< 1%

18 (3.3)

8 (1.5)

Non-cardiac chest pain f

29 (5.5)

31 (5.7)

18 (3.3)

<1%

Gastrointestinal disorders Diarrhea

242 (45.5) 208 (38.5) 89 (16.5) 21 (3.9)

Abdominal pain%f 109 (20.5) 78 (14.4) 60 (11.1) Dyspepsia f

57 (10.7)

28 (5.2)

7 (1.3)

9 (1.7)

< 1%

<1%

< 1%

0 (0.0)

36 (6.7)

(continued)

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REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.

Reference 1. Stewart DJ, Stewart AA, Wheatley-Price P, et al: Impact of time to drug approval on potential years of life lost: The compelling need for improved trial and regulatory efficiency. 16th World Conference on Lung Cancer. Abstract ORAL12.05. Presented September 7, 2015.

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PAGE 33

Palliative Care in Oncology Important Research in the Palliative Care of Patients With Cancer

By Jo Cavallo

T

he emphasis at this year’s Palliative Care in Oncology Symposium, held earlier this month in Boston, was on patient-centered care throughout the cancer continuum. The meeting

attracted more than 650 attendees and included six general sessions featuring best practices in communication, nonpharmacologic interventions for pain, and systemsT:7” integration; two oral

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* All Adverse Reactionsa

sessions; and two poster sessions. The symposium attracted an international audience with attendees participating from the United States, Canada, United Kingdom, France, Italy, and China,

Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)

Musculoskeletal and connective tissue disorders

Psychiatric disorders

170 ( 32) 145 (26.9) 116 (21.4)

37 (7)

34 (6.3)

28 (5.2)

Muscle spasms f

109 (20.5) 102 (18.9) 61 (11.3)

< 1%

< 1%

< 1%

Arthralgia f

101 (19.0) 71 (13.1) 66 (12.2)

9 (1.7)

8 (1.5)

8 (1.5)

Bone pain f

87 (16.4) 77 (14.3) 62 (11.5) 16 (3.0)

15 (2.8)

14 (2.6)

Pain in extremity f 79 (14.8) 66 (12.2) 61 (11.3)

8 (1.5)

8 (1.5)

7 (1.3)

Musculoskeletal pain f

67 (12.6) 59 (10.9)

36 (6.7)

< 1%

< 1%

< 1%

Musculoskeletal chest pain f

60 (11.3)

51 (9.4)

39 (7.2)

6 (1.1)

< 1%

< 1%

Muscular weakness f

43 (8.1)

35 (6.5)

29 (5.4)

< 1%

8 (1.5)

< 1%

40 (7.5)

19 (3.5)

10 (1.8)

< 1%

< 1%

< 1%

90 (16.9) 59 (10.9)

43 (7.9)

9 (1.7)

6 (1.1)

3 (0.6)

33 (6.1)

0 (0.0)

0 (0.0)

0 (0.0)

Neck pain

f

Infections and infestations Bronchitisc Nasopharyngitis f Urinary tract infection f

80 (15)

54 (10)

76 (14.3) 63 (11.7)

41 (7.6)

8 (1.5)

8 (1.5)

< 1%

Upper respiratory tract infectionc% f

69 (13.0)

Pneumoniac@

93 (17.5) 87 (16.1) 56 (10.4) 60 (11.3) 57 (10.5) 41 (7.6)

53 (9.8)

31 (5.7)

< 1%

8 (1.5)

< 1%

Respiratory tract infection%

35 (6.6)

25 (4.6)

21 ( 3.9)

7 ( 1.3)

4 ( 0.7)

1 ( 0.2)

Influenza f

33 (6.2)

23 (4.3)

15 (2.8)

< 1%

< 1%

0 (0.0)

Gastroenteritis f

32 (6.0)

17 (3.1)

13 (2.4)

0 (0.0)

< 1%

< 1%

29 (5.5)

14 (2.6)

16 (3.0)

10 (1.9)

3 (0.6)

3 (0.6)

Rhinitis f

29 ( 5.5)

24 ( 4.4) 14 ( 2.6)

0 (0.0)

0 (0.0)

0 (0.0)

Cellulitisc

< 5%

< 5%

< 5%

8 (1.5)

3 ( 0.6)

2 ( 0.4)

Sepsisc@

33 (6.2)

26-(4.8)

18 (3.3)

26 (4.9)

20 (3.7)

13 (2.4)

Nervous system disorders Headache f

75 (14.1)

52 (9.6)

56 (10.4)

< 1%

< 1%

< 1%

Dysgeusia f

39 (7.3)

45 (8.3)

22 (4.1)

< 1%

0 (0.0)

< 1%

Blood and lymphatic system disordersd Anemia

233 (43.8) 193 (35.7) 229 (42.3) 97 (18.2) 85 (15.7) 102 (18.9)

Neutropenia

186 (35.0) 178 (33) 328 (60.6) 148 (27.8) 143 (26.5) 243 (44.9)

Thrombocytopenia 104 (19.5) 100 (18.5) 135 (25.0) 44 (8.3)

43 (8.0)

60 (11.1)

Febrile neutropenia

7 (1.3)

17 (3.1)

15 (2.8)

6 (1.1)

16 (3.0)

14 (2.6)

Pancytopenia

5 (0.9)

6 (1.1)

7 (1.3)

1 (0.2)

3 (0.6)

5 (0.9)

Respiratory, thoracic and mediastinal disorders Cough f

121 (22.7) 94 (17.4) 68 (12.6)

Dyspneac,e

117 (22.0) 89 (16.5) 113 (20.9) 30 (5.6)

< 1%

< 1%

< 1%

22 (4.1)

18 (3.3)

Epistaxis f

32 (6.0)

31 (5.7)

17 (3.1)

< 1%

< 1%

0 (0.0)

Oropharyngeal pain f

30 (5.6)

22 (4.1)

14 (2.6)

0 (0.0)

0 (0.0)

0 (0.0)

Dyspnea exertional e

27 (5.1)

29 (5.4)

< 5%

6 (1.1)

2 (0.4)

0 (0.0)

Metabolism and nutrition disorders Decreased appetite

123 (23.1) 115 (21.3) 72 (13.3) 14 (2.6)

7 (1.3)

5 (0.9)

Hypokalemia%

91 ( 17.1) 62 (11.5)

20 (3.7)

11 (2.0)

38 ( 7)

35 (6.6)

Hyperglycemia

62 (11.7)

52 (9.6)

19 (3.5)

28 (5.3)

23 (4.3)

9 (1.7)

Hypocalcemia

57 (10.7) 56 (10.4)

31 (5.7)

23 (4.3)

19 (3.5)

8 (1.5)

Dehydration%

25 ( 4.7)

29 ( 5.4)

17 ( 3.1)

8 (1.5)

13 (2.4)

9 (1.7)

Gout e

< 5%

< 5%

< 5%

8 (1.5)

0 (0.0)

0 (0.0)

Diabetes mellitus% e

< 5%

< 5%

< 5%

8 (1.5)

4 (0.7)

2 (0.4)

Hypophosphatemia e

< 5%

< 5%

< 5%

7 (1.3)

3 (0.6)

1 (0.2)

Hyponatremia% e

< 5%

< 5%

< 5%

7 (1.3)

13 (2.4)

6 (1.1)

139 (26.1) 151 (28.0) 105 (19.4) 39 (7.3)

38 (7.0)

33 (6.1)

Skin and subcutaneous tissue disorders Rash Pruritus f

47 (8.8)

49 (9.1)

24 (4.4)

< 1%

< 1%

< 1% (continued)

Insomnia

147 (27.6) 127 (23.5) 53 (9.8)

4 (0.8)

6 (1.1)

0 (0.0)

Depression

58 (10.9)

46 (8.5)

30 (5.5)

10 (1.9)

4 (0.7)

1 (0.2)

Deep vein thrombosisc%

55 (10.3)

39 (7.2)

22 (4.1)

30 (5.6)

20 (3.7)

15 (2.8)

Hypotensionc%

51 (9.6)

35 (6.5)

36 (6.7)

11 (2.1)

8 (1.5)

6 (1.1)

Vascular disorders

Injury, Poisoning, and Procedural Complications Fall f

43 (8.1)

25 (4.6)

25 (4.6)

< 1%

6 (1.1)

6 (1.1)

Contusion f

33 (6.2)

24 (4.4)

15 (2.8)

< 1%

< 1%

0 (0.0)

73 (13.7)

31 (5.7)

5 (0.9)

31 (5.8)

14 (2.6)

3 (0.6)

< 5%

< 5%

< 5%

7 (1.3)

0 (0.0)

0 (0.0)

48 (8.9)

11 (2.1)

4 (0.7)

4 (0.7)

Eye disorders Cataract Cataract subcapsular e Investigations Weight decreased 72 (13.5) 78 (14.4) Cardiac disorders Atrial fibrillationc Myocardial infarction (including acute)c ,e

37 (7.0)

25 (4.6)

25 (4.6)

13 (2.4)

9 (1.7)

6 (1.1)

< 5%

< 5%

< 5%

10 (1.9)

3 (0.6)

5 (0.9)

54 (10.0)

37 (6.8)

28 (5.3)

33 (6.1)

29 (5.4)

Renal and Urinary disorders Renal failure (including acute)c@,f 49 (9.2)

Neoplasms benign, malignant and unspecified (Incl cysts and polyps) Squamous cell carcinomac e

< 5%

< 5%

< 5%

8 (1.5)

4 (0.7)

0 (0.0)

Basal cell carcinomac e,f

< 5%

< 5%

< 5%

< 1%

< 1%

0 (0.0)

Note: System organ classes (SOC) and preferred terms (PTs) reflect coding of adverse reactions using MedDRA. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable SOC/PT. a All treatment-emergent adverse reactions in at least 5.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 2.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders SOC were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) *PTs for combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalised, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

After At Least One Prior Therapy for MM Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).

In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or Cosmos Communications

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Lower respiratory tract infection

continued on page 34

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

Grade 3/4 Adverse Reactionsb

Back painc

among other countries.

Sponsored by ASCO, the American Academy of Hospice and Palliative Medicine (AAHPM), the American

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Palliative Care in Oncology Palliative Care in Oncology Symposium continued from page 33

Society for Radiation Oncology (ASTRO), and the Multinational ­ Association of Supportive Care in Cancer (MASCC), this year’s symposium included about 250 abstracts.

Watch future issues of The ASCO Post for more from the Palliative Care in Oncology Symposium, and be sure to visit http://video.ascopost.com (The ASCO Post Newsreels) to view interviews with experts recorded live during the meeting.

ABSTRACT 108:

Identifying Patients With Cancer Who Are Most at Risk of Death Determining the answer to a simple question, “Would you be surprised if this patient died within the next year?” may be an important tool to help predict which patients with cancer may T:7” of life, according be in their final year

to the findings from the study by Vick et al.1 The tool, known as the “Surprise Question,” was found to be more accurate in predicting the risk of cancer death within 1 year than other factors such as cancer type, stage, the age of the patient, or time from diagnosis.

Study Details

without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Table 5: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (N=353) (N=350) n (%) n (%)

Tables 5, 6, and 7 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Metabolism and nutrition disorders Anorexia Hypokalemia Hypocalcemia Appetite Decreased Dehydration Hypomagnesemia Investigations Weight Decreased Eye disorders Blurred vision Vascular disorders Deep vein thrombosis% Hypertension Hypotension

55 (15.6) 48 (13.6) 31 (8.8) 24 (6.8) 23 (6.5) 24 (6.8)

34 (9.7) 21 (6.0) 10 (2.9) 14 (4.0) 15 (4.3) 10 (2.9)

69 (19.5)

52 (14.9)

61 (17.3)

40 (11.4)

33 (9.3) 28 (7.9) 25 (7.1)

15 (4.3) 20 (5.7) 15 (4.3)

Table 6: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia% 118 (33.4) 12 (3.4) Thrombocytopenia@ 43 (12.2) 22 (6.3) Anemia@ 35 (9.9) 20 (5.7) Leukopenia 14 (4.0) 1 (0.3) Lymphopenia 10 (2.8) 4 (1.1) Febrile Neutropenia% 8 (2.3) 0 (0.0) General disorders and administration site conditions Fatigue 23 (6.5) 17 (4.9) Vascular disorders Deep vein thrombosis% 29 (8.2) 12 (3.4) Infections and infestations Pneumonia@ 30 (8.5) 19 (5.4) Urinary Tract Infection 5 (1.4) 1 (0.3) Metabolism and nutrition disorders Hypokalemia 17 (4.8) 5 (1.4) Hypocalcemia 13 (3.7) 6 (1.7) Hypophosphatemia 9 (2.5) 0 (0.0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism@ 14 (4.0) 3 (0.9) Respiratory Distress@ 4 (1.1) 0 (0.0) Musculoskeletal and connective tissue disorders Muscle weakness 20 (5.7) 10 (2.9) Gastrointestinal disorders Diarrhea@ 11 (3.1) 4 (1.1) Constipation 7 (2.0) 1 (0.3) Nausea@ 6 (1.7) 2 (0.6) Cardiac disorders Atrial fibrillation@ 13 (3.7) 4 (1.1) Tachycardia 6 (1.7) 1 (0.3) Cardiac Failure Congestive@ 5 (1.4) 1 (0.3) Nervous System disorders Syncope 10 (2.8) 3 (0.9) Dizziness 7 (2.0) 3 (0.9) (continued)

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Table 5: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia % 149 (42.2) 22 (6.3) Anemia@ 111 (31.4) 83 (23.7) Thrombocytopenia@ 76 (21.5) 37 (10.6) Leukopenia 28 (7.9) 4 (1.1) Lymphopenia 19 (5.4) 5 (1.4) General disorders and administration site conditions Fatigue 155 (43.9) 146 (41.7) Pyrexia 97 (27.5) 82 (23.4) Peripheral edema 93 (26.3) 74 (21.1) Chest Pain 29 ( 8.2) 20 (5.7) Lethargy 24 ( 6.8) 8 (2.3) Gastrointestinal disorders Constipation 143 (40.5) 74 (21.1) Diarrhea@ 136 (38.5) 96 (27.4) Nausea@ 92 (26.1) 75 (21.4) Vomiting@ 43 (12.2) 33 (9.4) Abdominal Pain@ 35 (9.9) 22 (6.3) Dry Mouth 25 (7.1) 13 (3.7) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33.4) 74 (21.1) Back pain 91 (25.8) 65 (18.6) Bone Pain 48 (13.6) 39 (11.1) Pain in Limb 42 (11.9) 32 (9.1) Nervous system disorders Dizziness 82 (23.2) 59 (16.9) Tremor 75 (21.2) 26 (7.4) Dysgeusia 54 (15.3) 34 (9.7) Hypoaesthesia 36 (10.2) 25 (7.1) Neuropathyª 23 (6.5) 13 (3.7) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 83 (23.5) 60 (17.1) Nasopharyngitis 62 (17.6) 31 (8.9) Pharyngitis 48 (13.6) 33 (9.4) Bronchitis 40 (11.3) 30 (8.6) Infectionsb and infestations Upper respiratory tract infection 87 (24.6) 55 (15.7) Pneumonia@ 48 (13.6) 29 (8.3) Urinary Tract Infection 30 (8.5) 19 (5.4) Sinusitis 26 (7.4) 16 (4.6) Skin and subcutaneous system disorders Rashc 75 (21.2) 33 (9.4) Sweating Increased 35 (9.9) 25 (7.1) Dry Skin 33 (9.3) 14 (4.0) Pruritus 27 (7.6) 18 (5.1) (continued)

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Palliative Care in Oncology From July 2012 to October 2014, researchers at Ariadne Labs enrolled 81 oncology clinicians, including oncologists (59), nurse practitioners (18), and physician assistants (4), from Dana-Farber Cancer Institute in Boston, into a randomized trial. The trial investigated the impact of a structured intervention to improve conversations

about end-of-life goals among patients with cancer.

The clinicians answered the Surprise Question—“Would you be surprised if this patient died within the next year?”—regarding nearly 5,000 patients, aged 19 to 95 with all types and stages of cancer, as the first step in T:7” Ariadne Labs’ patient-centered Serious

Table 6: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (N=353) (N=350) n (%) n (%) Eye Disorders Cataract 6 (1.7) 1 (0.3) Cataract Unilateral 5 (1.4) 0 (0.0) Psychiatric Disorder Depression 10 (2.8) 6 (1.7)

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)] Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms.

Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious

“No” patients (P < .0001).

The Surprise Question was more predictive of patient death than other factors, including type of cancer, age of the patient, cancer stage, or time since diagnosis.

A Simple, Effective Tool continued on page 36

adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/ dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.

Other Adverse Reactions: After At Least One Prior Therapy for MM In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/ cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.7 to 5.10)].

Cases of hypothyroidism and hyperthyroidism have also been reported.

Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.

7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions.

7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4)].

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Table 7: Serious Adverse Reactions Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex& Placebo/Dex& (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Febrile Neutropenia% 6 (1.7) 0 (0.0) Vascular disorders Deep vein thrombosis% 26 (7.4) 11 (3.1) Infections and infestations Pneumonia@ 33 (9.3) 21 (6.0) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism@ 13 (3.7) 3 (0.9) Cardiac disorders Atrial fibrillation@ 11 (3.1) 2 (0.6) Cardiac Failure Congestive@ 5 (1.4) 0 (0.0) Nervous system disorders Cerebrovascular accident@ 7 (2.0) 3 (0.9) Gastrointestinal disorders Diarrhea @ 6 (1.7) 2 (0.6) Musculoskeletal and connective tissue disorders Bone Pain 4 (1.1) 0 (0.0) For Tables 5, 6 and 7 above: @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.

Illness Care Program. Of the 4,617 patients for whom the researchers had complete data, 3,821 (83%) answered “Yes” to the Surprise Question and 796 (17%) answered “No.” The propensityadjusted 1-year survival rate for “Yes” patients was 93% (95% confidence interval [CI] = 91%–96%) compared to 53% (95% CI = 46%–60%) for the

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Palliative Care in Oncology Palliative Care in Oncology Symposium continued from page 35

“There is no generally accepted tool to identify seriously ill patients who would benefit from conversations about their values, goals, and priorities,” said Judith Vick, a medical student at the Johns Hopkins University School of

Medicine in Baltimore, and lead author of this study, during a press briefing about the study results.

“The Surprise Question is a simple tool that allows clinicians to identify those patients,” she continued. “It is a simple, affordable, and available tool that is easily implemented. Our results show that oncology clinicians’ own

judgment using the Surprise Question identified about 60% of patients with a short life expectancy. However, given that 40% of these patients were not identified by the Surprise Question, more research is needed to understand why.”

T:7”Into Context Putting the Data

7.3 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1).]

NDMM: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the AE categories (eg, all AEs, grade 3/4 AEs, serious AEs) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 AEs in the General Disorders and Administration Site Conditions SOC were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade 3 or 4 TEAEs in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) SOCs were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other SOCs (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 AEs in older vs younger subjects across all treatment arms Serious AEs were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms.

REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%).

The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.

8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy.

Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.

Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.

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Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue.

Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.

Lenalidomide caused thalidomide-type limb defects in monkey offspring.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis.

Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg.

Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.

In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.

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

8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established.

8.5 Geriatric Use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 91 years of age.

After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.

Commenting on the study results, ASCO expert and moderator of the press briefing, Don S. Dizon, MD, Clinical Co-Director of Gynecologic Oncology at Massachusetts General Hospital, Boston, said, “This important work shows that one question that clinicians actually ask themselves may be more effective than the usual clinical

ASCOPost.com | OCTOBER 25, 2015

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Palliative Care in Oncology and laboratory parameters to identify patients who have a risk of dying within a year. I think this is important, especially in an era where we are looking at values and preferences regarding current and future cancer care and I look forward to future results of this multipronged intervention.”

Don S. Dizon, MD

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)].

8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment.

The elimination of unchanged lenalidomide is predominantly by the renal route.

10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients with MM, MDS, or MCL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with lenalidomide have not been conducted.

Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindications (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

• Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy.

• Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test.

• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy.

Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.

• Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.

• Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy.

• Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

An innovative service model that partners radiation oncology with palliative care leads to better results for patients, according to a new analysis.

The model of care, established at Mount

• All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)].

• Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)].

• REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product.

Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)].

Venous and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warnings and Warning and Precautions (5.4)].

Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)].

Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID [see Warnings and Precautions (5.6)].

Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)].

Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens-Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.8)].

Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.9)].

Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10)].

Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water.

Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.

Manufactured for:

GUEST EDITOR

Celgene Corporation Summit, NJ 07901

REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation.

REVLIMID REMS™ is a trademark of Celgene Corporation.

Pat. www.celgene.com/therapies ©2005-2015 Celgene Corporation, All Rights Reserved.

REV_MM_HCP_BS_v020 02_2015

Jamie H. Von Roenn, MD

A

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

Sinai Medical Center, New York, is one of only a handful in the country. The study was presented at the Palliative Care in Oncology Symposium in Boston.2 Since its implementation in 2013, the service has led to shorter durations of radiation treatment, fewer unfinished radiation treatments, shorter hospital stays, and increased use of palliative care services. Based on these preliminary findings, the authors suggest that better integration of palliative medicine into the care of patients with advanced cancer undergoing radiation therapy improves outcomes for patients, their families, and hospital systems.

T:10”

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

T:7”

ABSTRACT 110: Collaboration Improves Care for Patients With Advanced Cancer

The Model Whole-patient assessments and family meetings are critical parts of the new multidisciplinary service model. During these encounters, a careful evaluation of patients’ physical symptoms as well as psychosocial, spiritual, lifestyle, and logistical concerns is performed. Overall goals of care are discussed in an open and compassionate way.

In addition to radiation oncologists, medical oncologists, and palliative care specialists, family meetings may include representatives from social work, nursing, chaplaincy, and family members, all of whom play vital roles in a patient’s decision-making.

“Our study validates the importance of cohesive collaboration in cancer care.

As a palliative radiation oncologist, tackling pain is only a small part of what I do. My role extends to engage patients and families in conversations that help continued on page 38

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Palliative Care in Oncology Palliative Care in Oncology Symposium continued from page 37

distill their priorities and set realistic expectations of treatment. Partnering with palliative care helps us incorporate goals and preferences into our care plans,” said ­ Kavita Dharmarajan, MD, Assistant Professor of Radiation Oncology and Palliative Medicine at Mount Sinai Medical Center. “When we work together, patients receive a higher quality of care that focuses on the whole person, not just a tumor.”

The service model is available to all patients with any type of cancer receiving radiation for palliative purposes, whether it is for metastases in the bone, brain, lungs, pelvis, or any other organ system in the body. The current study focused on patients with painful bone metastases.

Study Findings Researchers examined charts of patients with advanced cancer who received palliative radiation therapy for painful bone metastases. The study included 175 patients treated before the

new service started and 161 treated after the new service was established.

This study showed that judicious use of shorter and more efficient radiation treatments within the new service model led to patients spending fewer days hospitalized. The new service decreased the median length of hospital stay from 18 to 12 days and halved the proportion of ra-

Kavita Dharmarajan, MD

diation treatments that went unfinished (15% vs 8%). Under the new service model, more patients received palliative care services within a month of finishing their treatment (49% vs 34%).

Benefits of the New Model According to the authors, these find-

ings are important because the great majority of patients appreciate being able to spend more time outside of the hospital, particularly as they near the end of life.

The support from palliative care services allowed patients and families to manage symptoms at home.

The new service more than doubled the use of single-fraction radiotherapy and short-course radiotherapy from 26% to 61%. Patients were also more likely to complete their radiation ­treatment.

Before the new model was established, many patients received radiation treatments lasting 2 weeks or longer. At times, patients who are very sick do not survive long enough after completion of therapy to see its benefits. This occurred more frequently when patients underwent longer radiation treatments before the new service model was established.

Importantly, increasing the use of shorter palliative radiation treatments did not compromise the pain relief provided by the treatment. In fact, there was a slight increase in the per-

centage of patients who reported pain improvement (80% vs 74%) within the new service model, although the difference was not statistically significant.

“This study reinforces the importance of integrating palliative care throughout treatment,” said Dr. ­Dizon.

“The results serve as welcome evidence that we can achieve better care for patients through cooperation across ­disciplines.” n

Disclosure: Drs. Dharmarajan and Dizon and Ms. Vick reported no potential conflicts of interest.

References 1. Vick JB, Pertsch N, Hutchings M, et al: The utility of the surprise question in identifying patients most at risk of death.

Palliative Care in Oncology Symposium.

Abstract 108. Presented O ­ ctober 9, 2015.

2. Chang S, Smith CB, ­Dharmarajan KV, et al: A palliative radiation oncology consult service’s impact on care of advanced cancer patients with symptomatic bone metastases. Palliative Care in Oncology Symposium. Abstract 110. Presented October 9, 2015.

Philip A. Salem, MD, Awarded the FOEDUS Supreme Medal of Excellence

F

OEDUS, the Italian Foundation of Culture and Science, awarded the Supreme Medal of Excellence to oncologist Philip A. Salem, MD, Director Emeritus of Cancer Research at Baylor St. Luke’s Medical Center in Houston and President of the Salem Oncology Center at the Texas Medical Center.

The Foundation Chairman, Mario Baccini, bestowed this highest award from the Foundation upon Dr. Salem in a ceremony in Rome, Italy. In his presentation of the award, Mr. Baccini

pointed out not only Dr. Salem’s great skills as a physician and scientist, but also his championing of a world movement to humanize medicine.

Dr. Salem, who has been a doctor for 50 years, has worked with the Italian Consulate General in Houston to help treat more than 500 patients from Italy as well as many other patients from around the world. In his acceptance speech, Dr. Salem said, “I have come to believe that all mankind is my family, that my church is my clinic, and that my prayer is my work.” n

Photo Credit: Gus Salinas

The ASCO Post Wants to Hear From You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

www.ASCOPost.com

Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

ASCOPost.com | OCTOBER 25, 2015

PAGE 39

Direct From ASCO

Journal of Clinical Oncology’s Fall Special Series, Journal of Global Oncology’s Inaugural Issue

T

his fall, the Journal of Clinical Oncology (JCO) presented two special series: “Pediatric Cancer— Progress Through Collaboration” and “Head and Neck Cancer: Recent Advances, Changing Epidemiology, and Future Directions.”

The Pediatric Special Series highlighted collaborative efforts that have contributed to the remarkable progress achieved in advancing survival for patients with pediatric cancers.

The pediatric cancer experience is unique in that it has a high level of clinical trial participation—making it instrumental in establishing effective therapies, characterizing toxici-

Volume 29, Issue 15

May 20, 2011

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

ties of therapy, refining treatment approaches, and modifying therapy to prevent adverse treatment-related effects. This Special Series also featured articles on innovative and genomic discoveries that have guided riskadapted stratification of therapy and the use of targeted therapy in providing real prospects for precision medicine. The Pediatric Special Series was particularly appealing to pediatric, surgical, and radiation oncologists; hospitalists; family physicians; pharmacists; and many others.

The Head and Neck Cancer Special Series aimed to deliver the latest evidence and recommendations for

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

What’s Hot in

JCO

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

JCO.org Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group

by Antonio Palumbo, et al

Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian Cancer

by Alexi A. Wright, et al

Relative Effectiveness of Letrozole Compared With Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial

by Otto Metzger Filho, et al

Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

by John G. Gribben, et al

Oncolytic Virus-Mediated Immunotherapy: A Combinatorial Approach for Cancer Treatment

by Sean E. Lawler, et al

management of mucosal head and neck, nasopharyngeal, and nonmelanoma cutaneous carcinomas. In addition, this series provided timely reviews on varied topics, such as the rapidly evolving data on human papillomavirus-associated oropharyngeal cancer; the significant technologic advances in surgery and radiotherapy; improved understanding of the genomics of head and neck cancers; the exciting prospects of the new immunotherapeutic agents; insights into the management of late toxicities; and survivorship and quality-of-life issues. The goal of the Head and Neck Cancer Special Series was to enhance the understanding of the advances in biology and treatment of head and neck cancer, with a focus on the areas of greatest relevance to practicing clinicians. This Special Series was of particular interest to medical, surgical, and radiation oncology doctors and nurses; radiation therapists; scientists; speech therapists; dietitians; dentists; industry leaders; and epidemiologists.

Volume 33, Issue 29

October 10, 2015

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

SPECIAL SERIES Head and Neck Cancer: Recent Advances, Changing Epidemiology, and Future Directions

Overview of Advances in Head and Neck Cancer D. Rischin et al Genetic Landscape of Human Papillomavirus– Associated Head and Neck Cancer and Comparison to Tobacco-Related Tumors. D.N. Hayes et al Epidemiology of Human Papillomavirus–Positive Head and Neck Squamous Cell Carcinoma. M.L. Gillison et al Human Papillomavirus–Associated Oropharyngeal Cancer: Defining Risk Groups and Clinical Trials A. Bhatia et al Organ Preservation for Advanced Larynx Cancer: Issues and Outcomes. A.A. Forastiere et al Immunology and Immunotherapy of Head and Neck Cancer. R.L. Ferris Advances in Supportive Care for Late Effects of Head and Neck Cancer. B.A. Murphy et al Survivorship and Quality of Life in Head and Neck Cancer. J. Ringash Management of Nasopharyngeal Carcinoma: Current Practice and Future Perspective. A.W.M. Lee et al

Highlights From the Journal of Global Oncology’s First Issue The Journal of Global Oncology (JGO) published its first issue this September.

ASCO President Julie Vose, MD, MBA, FASCO, and Immediate Past President Peter Paul Yu, MD, FACP, FASCO, wrote the inaugural editorial, “Building Bridges for Collective Wisdom,” welcoming readers to this online-only open-access journal.

Highlights of this first issue include: • A review by Daniela Stefan, MD: “Cancer Care in Africa: An Overview of Resources” • A special article by Pat GarciaGonzalez et al: “A Novel Humanitarian Aid Program, the Glivec International Patient Assistance Program (GIPAP): Lessons Learned from Providing Access to Breakthrough Targeted Oncology Treatment in Low- and MiddleIncome Countries (LMICs)”

• An original report by Kenneth Cornetta, MD, et al: “Integration of Palliative Care Into Comprehensive Cancer Treatment at Moi Teaching and Referral Hospital in Western Kenya” • An editorial by Shahin Sayed, PhD, et al: “Providing Pathology Support in Low-Income Countries”

Stayed Tuned—New Journal!

ASCO’s board has approved a new journal focusing on clinical cancer informatics. n © 2015. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | OCTOBER 25, 2015

PAGE 40

Direct From ASCO

Community Research Forum Holds 2015 Annual Meeting, Explores Developments and Strategies in Conducting Clinical Research

A

SCO’s Community Research Forum (CRF) held its 2015 Annual Meeting September 20–21 at ASCO Headquarters in Alexandria, Virginia.

Over 75 physician investigators, program directors, and research staff attended the meeting, representing a wide range of community-based practices and research sites across the country.

The CRF was established in 2010 as part of ASCO’s efforts to support clinical investigators and community-based research sites. Each year, the Forum holds its Annual Meeting to give physician investigators and their research

staff the unique opportunity to network and collaborate to propose solutions to common challenges community-based practices face in conducting research.

Following opening remarks by ASCO President Julie M. Vose, MD, MBA, FASCO, and CRF Council Chair Howard “Skip” A. Burris III, MD, FACP, FASCO, the meeting began with a keynote address by Edward S. Kim, MD, Chair of Solid Tumor Oncology and Investigational Therapeutics at the Levine Cancer Institute Carolinas HealthCare System, highlighting the importance of community-based re-

Howard A. Burris III, MD, FACP, FASCO, provides opening remarks at the 2015 ASCO CRF Annual Meeting.

search as oncology research evolves.

Presentations and panels covered a range of topics, including best practices, precision medicine, coverage analysis, patient engagement, and resources for community-based research programs.

James L. Wade III, MD, FACP, FASCO, of Cancer Care Specialists of Central Illinois, and Kathy Wilkinson, RN, BSN, OCN, of Billings Clinic— recipients of ASCO’s Clinical Trials Participation Award (CTPA), which recognizes high-quality clinical research sites—shared insights and perspectives from their practice in a panel led by Stephen S. Grubbs, MD, Senior Director of ASCO’s new Clinical Affairs Department.

Additionally, Chair-Elect of the CRF Council, Michael A. ­Thompson, MD, PhD, led a panel on precision medicine and implementing personalized care in community oncology, which ASCO’s Chief Medical Officer Richard L. Schilsky, MD, FASCO, participated on as well. The panel looked at the shift toward precision medicine in clinical trials, discussing trial designs and profiling patients for trials, as well as new clinical trial opportunities, such as ­ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) Study, the Society’s first-ever clinical trial.

The meeting also included break-

out sessions, during which participants engaged with one another to discuss strategies for effectively managing difficult aspects of conducting research in a community setting. Attendees shared ideas and experiences on topics such as building clinical trial menus, education and awareness, contract negotiations, financial concerns, and assessing the quality of research programs.

Nearly 20 attendees at this year’s meeting received a travel stipend award from the ASCO’s Conquer Cancer Foundation Mission Endowment Fund.

In addition to holding its Annual Meeting each year, the CRF has also released several online tools and resources to help community-based cancer research sites conduct and manage their research programs efficiently and effectively. These tools include the ASCO Research Program Quality Assessment Tool, the ASCO Clinical Trial Workload Assessment Tool, and an online repository of resources. Visit the CRF website at www.asco.org/communityresearchforum for more information about these resources, other CRF initiatives, and updates and registration information for the next CRF Annual Meeting, which will be held in the fall of 2016. n © 2015. American Society of Clinical Oncology. All rights reserved.

Conquer Cancer Foundation Grants and Awards: Funding Opportunities Now Available

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he Conquer Cancer Foundation (CCF) of the American Society of Clinical Oncology (CCF) is fueling cancer research and pursuing dramatic advances in the diagnosis, prevention, treatment, and cure of all types of cancer. CCF’s Grants and Awards program supports clinical and translational cancer research conducted by gifted physicianscientists at every stage of their careers, from the best and brightest among young investigators to senior researchers providing mentorship opportunities for the next generation of cancer researchers. More than $90 million in funding has been awarded through 1,457 grants and awards to individuals in 65 countries.

Four funding opportunities for 2016

are still available. Visit ConquerCancerFoundation.org/grants-awards to learn more, view eligibility criteria, and apply.

Long-Term International Fellowship: Apply by November 3, 2015 The Long-term International Fellowship provides early-career oncologists in low- to middle-income countries the support and resources needed to advance their training by deepening their relationship with a mentor in the United States, Canada, or the European Union.

During the 1-year fellowship, recipients receive valuable training and experience, which they use to effect change in cancer care in their home countries. The Long-

Term International Fellowship is a grant to pay for personnel, research, and travel expenses, including travel to attend the CCF Grants and Awards Ceremony at the ASCO Annual Meeting.

Application Deadlines

Medical Student Rotation for Underrepresented Populations: Apply by December 7, 2015

Medical Student Rotation for Underrepresented Populations (MSR): December 7, 2015

The Medical Student Rotation provides financial support for American medical students from populations underrepresented in medicine who are interested in oncology as a career to experience an 8- to 12-week clinical or clinical research rotation. Each participant will

Resident Travel Award for Underrepresented Populations (RTA): December 7, 2015

continued on page 41

Long-Term International Fellowship (LIFe): November 3, 2015

International Development & Education Award (IDEA) and IDEA in Palliative Care: January 6, 2016

ASCOPost.com | OCTOBER 25, 2015

PAGE 41

Direct From ASCO CCF Grants and Awards continued from page 40

be paired with a mentor to oversee the student in his or her rotation, as well as to provide ongoing academic and career guidance following the rotation experience. The Medical Student Rotation award includes a stipend for the rotation as well as for travel to the ASCO Annual Meeting. An additional stipend will be provided to support the student’s mentor.

Meeting, participate in a post-Meeting visit to the Mentor’s institution, and develop long-term relationships to improve cancer care in their countries. In addition, IDEA recipients also receive three years of complementary ASCO membership, including a subscription to the Journal of Clinical Oncology.

The IDEA in Palliative Care (IDEA-

PC) provides medical education in palliative care, assists with career development, and helps establish strong relationships with leading ASCO members in the field of palliative care who serve as scientific mentors to each recipient. IDEA-PC recipients are expected to share the knowledge and training they receive through the

program with colleagues in their home countries once they return. n Excerpts have been reprinted, with permission, from the Grants and Awards page on the Conquer Cancer Foundation website. © 2015. American Society of Clinical Oncology. All rights reserved.

ASCO POST

Resident Travel Award for Underrepresented Populations: Apply by December 7, 2015 The Resident Travel Award provides financial support for residents from underrepresented populations to attend the ASCO Annual Meeting. This award allows residents interested in a career in oncology to travel to the ASCO Annual Meeting, where they will have the opportunity to meet oncologists and to learn more about career options in the field of oncology. The Resident Travel Award includes a travel advance and complementary ASCO Annual Meeting registration.

International Development and Education Award and IDEA in Palliative Care: Apply by January 6, 2016

95

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The International Development and Education Award (IDEA) provides support for early-career oncologists in low- and middle-income countries and facilitates the sharing of knowledge between these oncologists and ASCO members. The program pairs IDEA recipients with a leading ASCO member “mentor” and enables recipients to attend the ASCO Annual

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heck out the latest ASCO Answers fact sheet on understanding blood test results. This one-page guide has information on complete blood count, white blood cell count, white blood cell differential, red blood cell count, platelet count, terms to know, and questions to ask the doctor. Download a printable PDF at www.cancer.net/factsheets, or visit cancer.net/estore to order today.

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Direct From ASCO

Be a Voice in The Campaign to Conquer Cancer

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

million to fund patient and caregiver education, boost the careers of young oncologists, and support clinical research around the world. Let the people who turn to you for advice on medicine and health know CCF resources are at the core of cancer treatment and discoveries. To learn more, sign up at conquer.org/asco, and we’ll share some ways you can help us connect others to The Campaign to Conquer Cancer. n © 2015. American Society of Clinical Oncology. All rights reserved.

EXERCISE AND CANCER EXERCISE BENEFITS IN PATIENTS WITH CANCER Observational data show an ASSOCIATION between physical activity and CANCER-SPECIFIC AND OVERALL

majority provided direct, causal evidence of the

SURVIVAL, primarily in breast and colorectal cancers.

interventions.

The American Cancer Society,6 American College of Sports Medicine,7 and National Comprehensive Cancer Network Survivorship Guidelines8 provide oncologists with guidance on how to help patients incorporate exercise into their treatment programs.

PRESCRIBE EXERCISE

2

START SLOWLY Patients with significant fatigue should start slowly and increase exercise in a gradual way.1

Suggest moderate-intensity exercise:

During treatment, the majority of physical activity interventions had a positive and significant effect on

SELF-ESTEEM.

after cancer treatment. Evidence not only suggests that exercise is safe during cancer treatment, but it may improve quality of life and exercise capacity, as well as reduce cancer-related symptoms such as fatigue, anxiety, and depression.1

EXERCISE GUIDELINES FOR CANCER SURVIVORS

In a systematic, quantitative review of 82 interventional studies that examined the effects of exercise, the

POSITIVE AND SIGNIFICANT EFFECTS of exercise

Although it is widely accepted that exercise is good for one’s health, an increasing number of studies are examining the therapeutic value of exercise during and

2

A systematic review showed that there was evidence from

27

observational studies that regular exercise (e.g., 150 minutes of moderate-intensity exercise per week) is associated with

30 MIN

ADULTS AGES 18–65

5 DAYS / WK

PERSONALIZE RECOMMENDATIONS

BUILD INCREMENTALLY REDUCED ALL-CAUSE, BREAST CANCERAND COLON CANCER-SPECIFIC MORTALITY,

Exercise can be broken down into shorter increments throughout the day while working toward a goal of 30 minutes per day.8

compared with being inactive.3

+

Regular exercise is associated with a

10 –50 %

Post-treatment, the majority of physical activity interventions had a positive and significant effect on overall quality of life, vigor/vitality,

FATIGUE, AND FITNESS MEASURES.

10 MIN

%

=

+ 10 MIN

30 MIN / DAY

10 MIN

Use caution when recommending exercise to certain patients. For example, survivors with significant peripheral neuropathies or ataxia may experience weakness or loss of balance. Suggest a stationary reclining bicycle rather than a treadmill for these patients.1,6

REDUCTI ON 2

in the risk of recurrence, as well as cancer-specific death.4,5

PATIENT RESOURCES FROM ASCO “MANAGING YOUR WEIGHT AFTER A CANCER DIAGNOSIS,” an ASCO booklet, provides patients with advice on weight management and making healthy lifestyle choices following a cancer diagnosis and is available at cancer.net/obesity.9

DIRECT PATIENTS TO CANCER.NET Although there are currently no completed randomized controlled trials examining whether exercise reduces the risk of recurrence or improves survival, THE CHALENGE TRIAL is examining this in colon cancer.

The hope is for other studies to follow suit in the years to come.

for additional physical activity recommendations: cancer.net/physicalactivity.

REFERENCES: 1. Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin. 2012;62:242-274.

2. Speck RM, Courneya KS, Mâsse LC, Duval S, Schmitz KH. An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. J Cancer Surviv.

2010;4:87-100.

3. Ballard-Barbash R, Friedenreich CM, Courneya KS, Siddiqi SM, McTiernan A, Alfano CM. Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review.

J Natl Cancer Inst. 2012;104:815-840.

4. Betof AS, Dewhirst MW, Jones LW. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective. Brain Behav Immun. 2013;30 Suppl:S75-87.

5. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al. Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review. J Natl Cancer Inst. 2012;104:815-840.

6. Physical Activity and the Cancer Patient. American Cancer Society website. cancer.org/treatment/survivorshipduringandaftertreatment/stayingactive/physical-activity-and-t he-cancer-patient. Accessed February 9, 2015.

Save the Date

7. Courneya K, McNeely M. Exercising During Cancer Treatment. The American College of Sports Medicine website. acsm.org/access-public-information/articles/2012/01/12/exercise-duringcancer-treatment. Accessed February 9, 2015.

8. Exercising During Cancer Treatment. The National Comprehensive Cancer Network website. nccn.org/patients/resources/life_with_cancer/exercise.aspx. Accessed February 9, 2015.

9. Managing Your Weight After a Cancer Diagnosis: A Guide for Patients and Families.

American Society of Clinical Oncology website. cancer.net/sites/cancer.net/files/weight_ after_cancer_diagnosis.pdf. Accessed February 9, 2015.

10. LIVESTRONG at the YMCA. LIVESTRONG website. livestrong.org/what-we-do/our-actions/ programs-partnerships/livestrong-at-the-ymca/. Accessed February 9, 2015.

11. ACSM/ACS Certified Cancer Exercise Trainer. American College of Sports Medicine website. certification.acsm.org/acsm-cancer-exercise-trainer. Accessed February 9, 2015.

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The ASCO Post | OCTOBER 25, 2015

PAGE 44

Integrative Oncology Alternative Therapies: Knowledge Is Power, but Consider the Source

By Barrie R. Cassileth, MS, PhD

T

he use of dietary supplements and other complementary and “alternative” therapies by patients with cancer has increased significantly over the past 20 years despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about complementary therapies can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information.

The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidencebased information on integrative and complementary therapies commonly used by patients with cancer. With this installment, we present an overview of alternative treatments that your patients may be using.

Compiled by Barrie R. Cassileth, MS, PhD, and Jyothirmai Gubili, MS, Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, Memorial Sloan Kettering Cancer Center.

A

n enormous amount of information about integrative medicine can be found in printed sources and online. But, a word of caution—some of this information is high quality and scientifically validated, and some is not. Some is downright ugly, as there are many scam artists promoting bogus remedies and cures.

At present, a simple Google search for “alternative cancer” produces over 65 million hits. Two examples of sites that rank highly in that search and should be avoided—CancerTutor.com and Alternative-Cancer.net—are representative examples of the numerous sites that provide and/or sell “advice” on a range of therapies purported to cure cancer without mainstream treatment.

On the other hand, there are useful sites that debunk false information, such as the National Cancer Institute’s Cancer and Alternative Medicine site (http:// www.cancer.gov/about-cancer/treatment/cam) and QuackWatch.org, and others that provide good information on the complementary treatments, their risks, and their benefits.

Scam Alert: Disproved Alternative Therapies The problem of quackery has been recorded since the 17th century. Some quacks are true charlatans with purely financial motives, while others are believers in what they preach. Both, however, promote unproven or disproved alternative therapies as cures for disease. And unfortunately there is no shortage of patients willing to embark on these questionable and often very expensive treatment plans. The truth is that unproven approaches are dangerous. Even when the therapy itself does not cause harm, people too often choose to shun conventional treatment entirely and replace it with an alternative treatment that does nothing to diminish their disease.

Public education can help minimize

GUEST EDITOR

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 and growing number of entries offers health-care professional and patient versions, and entries are regularly updated with the latest research findings. this problem, along with knowledgeable doctors who are familiar enough with alternative approaches to successfully guide patients away from them. Several of the alternative approaches promoted to cancer patients that lack evidence to support their usage are discussed herein.

Caution: All treatments listed here should be avoided.

Electrical Devices These are devices used to neutralize unhealthy energy of cancer cells; this may also be referred to as bioresonance therapy. The concept is based on a belief that diseased tissues emit “electromagnetic oscillations” that are distinct from those of healthy cells. Devices promise to diagnose and treat cancer and other diseases with the use of electromagnetic fields and currents. Such a claim is unsupported by science.

Recommended: NO

Energy Therapies “Therapeutic touch” and application of electromagnetic energy are treatments applied in the belief that energy fields exist around the body and that those fields can be manipulated to treat disease and restore health. Neither the existence of such energy fields nor the ability to manipulate them for greater health is supported by scientific evidence.

Recommended: NO

Entelev A liquid formulation, also called CanCell, Cantron, Protocel, and others, entelev is a brown liquid composed of several chemical compounds. It was created in 1936 by chemist James Sheridan. Over the years, it has been touted to treat a variety of chronic diseases in addition to cancer, including HIV/AIDS, epilepsy, and Alzheimer’s disease. Animal studies have shown

Learn More About

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

www.mskcc.org/aboutherbs

ASCOPost.com | OCTOBER 25, 2015

PAGE 45

Integrative Oncology no evidence of anticancer activity, and the U.S. Food and Drug Administration made it illegal to distribute entelev across state lines in 1989.

Recommended: NO

Essiac Essiac is an herbal product that is available in a tea, pill, or liquid. It is also called Flor-Essence. This herb was originally popularized in the 1920s by a Canadian nurse named Rene Caisse.

(In fact, the herb got its name from a reverse spelling of her name.) It started as a blend of four herbs, but other herbs have been added over the intervening years. While it is readily available online and in health food stores, there is lack of data on its safety and efficacy. No clinical evidence supports its use.

Recommended: NO

Mind-Body Techniques Meditation or biofeedback is based on the theory that patients can harness the power of their mind to heal their physical ills. Techniques, such as meditation and biofeedback have been shown to reduce stress and promote relaxation, and they can be used as effective complementary therapies.

However, claims that stress and other emotional issues can cause diseases such as cancer and that correcting those issues alone can effectively treat those diseases have no support in scientific evidence.

Recommended: NO (can be used as complementary therapy with traditional treatment).

Oxygen Therapy Oxygen therapy is available in pills or via intravenous oxygen, oral and intravenous hydrogen peroxide, and infusion of ozone-treated blood. There is no scientific evidence to support a tumor’s need for an oxygen-poor environment, that oxygen is absorbed during digestion, or continued on page 46

Healers Healers will promote “Touch,” which is also called biofield therapy, healing touch, and energy therapy. Therapeutic touch is practiced by passing hands above a patient’s body to sweep away blockages in the patient’s energy. Neither the existence of such energy fields nor the ability to manipulate them for greater health is supported by scientific evidence.

Recommended: NO

Homeopathic Medicine A liquid formulation, the practice of homeopathy was begun in 1796 by Samuel Hahnemann. This is based on the theory that “like cures like.” A substance that causes disease in a person can be used diluted to cure the same disease. Homeopathy has been the object of many clinical studies. At best, the homeopathic “medicines” had no better results than placebos, and at worst, homeopathy can be actively harmful.

Recommended: NO

Hyperbaric Oxygen Treatments In hyperbaric oxygen treatments, the patient is placed in an oxygen-rich chamber. Although hyperbaric oxygen therapy is used to treat decompression sickness, carbon monoxide poisoning, and some types of burns, no scientific evidence supports its use in treating cancer.

Recommended: NO (has medical uses but not in cancer treatment)

Laetrile Laetrile is available in oral or intravenous formulations and is also called amygdalin and vitamin B17. Years of study found no anticancer activity.

Recommended: NO

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The ASCO Post | OCTOBER 25, 2015

PAGE 46

American College of Surgeons Clinical Congress Gastrointestinal Oncology

Many Patients Do Not Accurately Recall Important Colonoscopy Details as Time Lapses

A

s time lapses, many patients who have undergone a colonoscopy become less and less likely to recall when and where they last had the procedure performed, who the doctor was who performed it, whether polyps were found, and, if so, the number and size of those polyps, according to new study results presented at the 2015 Clinical Congress of the American College of Surgeons, held recently in Chicago.1 Study coauthor Amer Alame, MD, a colorectal surgeon at St. John Hospital and Medical Center, Detroit, said he wanted to conduct the study after noticing during his fellowship training at the University of Miami that patients had a wide range of answers when asked what he thought was a simple question: Have you had a colonoscopy before?

“Some patients don’t recall, some know they’ve had one but then start guessing as to how long ago it was, some don’t know who did it, or what was found, or what was done,” Dr. ­Alame said. When he and his team decided to measure these recollections with a study, “I truly had no idea what we were going to find,” he said.

Study Findings Study authors randomly selected 200 patients and split them into four groups of 50, based on the time

Alternative Therapies continued from page 45

that any form of oxygen therapy has any efficacy. Even more concerning, serious adverse effects have been reported.

Recommended: NO

Prayer Although prayer may be helpful when used in conjunction with appropriate mainstream treatment, some pa-

Patients’ personal recollections of endoscopy results can be misleading.

—Amer Alame, MD

lapsed from their last colonoscopy: 2 months, 1 year, 2 years, and 4 years.

The patients were then surveyed by telephone and asked to recall the date of their last exam and the findings, including whether there were polyps present, how many, and the recommended follow-up interval. Their answers were compared to electronic health records.

When asked how long it had been since their last colonoscopy, 94%, 42%, 30%, and 28% of patients in the 2-month, 1-year, 2-year, and 4-year groups, respectively, remembered the date of their last scope to within 1 month. The number of patients who knew about the presence of polyps on their endoscopy was 65.2%, 31.6%, 35.7%, and 37.5%, respectively. The number of patients who accurately recalled the number of polyps on their exam was 39.1%, 10.5%, 7.1%, and 6.25%, respectively. tients elect to forgo care in the hope that prayer alone will heal them. A recent research review found that, although certain individual studies suggest some benefit from intercessory prayer, there is no clear evidence that it has any impact on clinical outcomes. Prayer may be useful, but not as an alternative to mainstream cancer treatment.

Recommended: Not as an alternative treatment (can be used as com-

“Patients’ personal recollections of endoscopy results can be misleading,” Dr. Alame said.

Ways to Increase Recall However, Dr. Alame said these results show that everyone involved in this procedure may contribute to the breaks in communication that can occur. After seeing these results, Dr. Alame said he now makes a point to reintroduce himself every time he sees a patient in the endoscopy suite and advises other endoscopists to do the same. Dr. Alame said it’s important for doctors to repeat crucial information to patients, such as what was done, what was found, and what the recommended plan is for follow-up care. A document for the patient to take home and keep in their files is also helpful if the doctor can provide it.

For patients, Dr. Alame stressed that knowing who the endoscopist is and plementary therapy with traditional treatment).

Shark Cartilage Shark cartilage is available in powder and liquid formulations. In the 1950s, surgeon John Prudden began testing the use of animal cartilage. It is purported to reduce the size of tumors by preventing blood vessel growth to the tumor. A few early animal studies sup-

where the procedure was done are the most important things to remember.

That way, if a patient comes to him but can’t remember specific details about the test, he knows what doctor and institution to request the report from and the test won’t need to be repeated.

In the Detroit metropolitan area, Dr. Alame said that many health systems are combined, making it easier for administrators and doctors to retrieve electronic health records across hospitals.

“I think that [arrangement] may help to fix the problem right at its root,” Dr. ­Alame said, but added that it’s a stretch for all hospital records across the country to combine with each other.

Another possible solution is to have the endoscopist send the results directly to the patient’s primary care doctor, since most patients remember who that is. Typically, Dr. Alame said, “they won’t send it until the primary care doctor requests it, but I know of centers that are being proactive about it and already doing this.” n Disclosure: For full disclosures of the study authors, visit www.journalacs.org.

Reference 1. Tarakji M, Al-Raishouni M, Alame A, et al: Patients’ recollection of colonoscopy results: Are they reliable? 2015 American College of Surgeons Clinical Congress. J Am Coll Surg 221(4 suppl 1):S34, 2015.

ported an antitumor effect, but results from clinical studies since then have not been promising. n Recommended: NO Adapted with permission from: Cassileth B: Survivorship: Living Well During and After Cancer. Spry Publishing, Ann Arbor, Michigan. Copyright 2014 by Barrie Cassileth, PhD. Available at Amazon and other booksellers.

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ASCOPost.com | OCTOBER 25, 2015

PAGE 47

National Academies of Sciences, Engineering, and Medicine Health-Care Policy

Inconsistent Federal Regulations Undercut U.S. Research Productivity, National Academies’ Report Finds

By Kirsten Boyd Goldberg

A

sk any U.S. academic investigator whether research is hindered by duplicative or confusing federal regulations, and the answer is usually a resounding “Yes.” Now comes a report written by representatives of research administrators, former federal government officials, and principal investigators—including three prominent academic oncologists—making the case for a “course correction” in what they argue has been a continual expansion of requirements.

gests that principal investigators spend 42% of their time on administrative work. “That’s an enormous amount of time to spend on administrative issues and not on science and improving the health of the nation,” Dr. Bierer said.

Academic institutions often receive research funding from multiple federal agencies, but each agency has different formats for commonly required documents, such as an investigator’s biographical information.

The Congressionally mandated re-

We’re not asking that regulations go away. We’re asking for them to be harmonized and simplified to improve compliance and oversight.

—Barbara E. Bierer, MD

Regulations address important issues of scientific integrity, use of federal funds, and protections for people and animals involved in research, but these well-intended efforts often needlessly encumber investigators with administrative work, according to a report by the National Academies of Sciences, Engineering, and Medicine.

“We’re not asking that regulations go away. We’re asking for them to be harmonized and simplified to improve compliance and oversight,” said committee member and oncologist Barbara E. Bierer, MD, Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, and Faculty Co-Director, MultiRegional Clinical Trials Center of Harvard and the Brigham and Women’s Hospital.

The release of the report, “Optimizing the Nation’s Investment in Academic Research: A New Regulatory Framework for the 21st Century,” completes the first phase of the study. Another report is expected to be issued in the spring of 2016.

Scope of the Problem Although research on the administrative burden is sparse, one study sug-

port also placed some blame on academic institutions for adding to the administrative burden by imposing additional requirements in their attempts to deal with confusing regulations.

The report calls on Congress to create a research policy board to establish a new regulatory framework to govern government-academic research partnerships and to harmonize requirements across funding agencies. This board should be formally connected to government through a new associate director position at the White House Office of Science and Technology Policy and through the Office of Information and Regulatory Affairs at the White House Office of Management and Budget, the report said.

Key Recommendations The report offered several key recommendations for Congress, the White House Office of Management and Budget, federal agencies, and universities.

Congress • Work with the White House Office of Management and Budget to develop a uniform format for research

grant proposals to be used by all funding agencies; • Work with the White House Office of Science and Technology Policy and research institutions to develop a single financial conflict-of-interest policy to be used by all research funding agencies; • Task a single agency with overseeing and unifying efforts to develop a central database of investigators and their professional output; • Direct agencies to align and harmonize their regulations and definitions concerning the protection of human subjects; • Instruct the White House Office of Science and Technology Policy to convene representatives from federal agencies that fund animal research and from the research community to assess and report to Congress on the feasibility and usefulness of a unified federal approach to policies and regulations pertaining to the care and use of research animals.

White House Office of Management and Budget • Require that research funding agencies use a uniform format for research progress reporting; • Amend the new Uniform Guidance to improve the efficiency and consistency of procurement standards, financial reporting, and cost accounting.

Federal Agencies • Limit research proposals to the minimum information necessary to permit peer evaluation of the merit of the scientific questions being asked, the feasibility of answering those questions, and the ability of the investigator to carry out that research. Any supplementary information— Institutional Review Board approval, conflictof-interest disclosures, detailed budgets, etc.—should be provided “just in time,” after the research proposal is deemed likely to be funded;

• With regard to animal research, reduce and streamline reporting, assurances, and verifications. Agencies should also develop a central repository to house assurances.

Universities • Conduct a review of institutional policies developed to comply with federal regulations of research to determine whether the institution itself has created excessive or unnecessary self-imposed burden; and • Revise self-imposed burdensome institutional policies that go beyond those necessary and sufficient to comply with federal, state, and local requirements.

Lee M. Ellis, MD

David Korn, MD

In addition to Dr. Bierer, the 18-member committee included two other academic oncologists: Lee M. Ellis, MD, Professor of Surgical Oncology and Molecular and Cellular Oncology, and the William C. Liedtke Jr. Chair in Cancer Research at MD Anderson Cancer Center; and David Korn, MD, Professor of Pathology, Massachusetts General Hospital, Harvard Medical School and former Chairman of the National Cancer Institute’s National Cancer Advisory Board. n Disclosure: Dr. Bierer reported no potential conflicts of interest.

The ASCO Post | OCTOBER 25, 2015

PAGE 48

Journal Spotlight Breast Cancer

Endocrine Therapy Alone Linked to Low Risk of Breast Cancer Recurrence in Women With a Low-Risk Score on 21-Gene Assay

By Matthew Stenger

A

prospective validation study of a 21-gene expression assay showed that treatment with endocrine therapy alone in women with hormone receptor–positive, HER2-negative breast cancer who had a low recurrence risk score resulted in low risk of recurrence.

All patients included in the study were eligible for adjuvant chemotherapy on the basis of current guidelines, as reported in The New England Journal of Medicine by Joseph A. Sparano, MD, of Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, and colleagues.1

Study Details Between April 2006 and October 2010, the trial enrolled 10,253 women with hormone receptor–positive, HER2-negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6– 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for receiving adjuvant chemotherapy.

A 21-gene reverse-transcriptase polymerase chain reaction assay was performed on paraffin-embedded tumor tissue, with results being used to calculate a score of 0 to 100, indicating lower to higher risk of recurrence. Patients with a score of 0 to 10, indicating very low risk, were assigned to receive endocrine therapy without chemotherapy.

Patient Characteristics In total, 1,626 women (15.9%) had a recurrence score of 0 to 10 and were assigned to receive endocrine therapy alone. Totals of 6,897 (67.3%) and 1,730 (16.9%) had midrange-risk (11–25) and high-risk scores (≥ 26).

Compared with the subgroup with midrange-risk scores, women with low-risk scores had a similar tumor size (median, 1.5 cm in both), and a similar proportion had intermediate-grade tumors (59% vs 57%).

In the low-risk group, endocrine therapy consisted of an aromatase inhibitor in 59%, tamoxifen in 34%, sequential tamoxifen and aromatase inhibitor in 1%, ovarian-function suppression in 3%, and other therapy in 3%. Six patients re-

Among patients with hormonereceptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable geneexpression profile had very low rates of recurrence at 5 years with endocrine therapy alone.

—Joseph A. Sparano, MD, and colleagues

Significant differences (all P < .001) included proportions with low-grade (34% vs 29%) and high-grade tumors (7% vs 14%), age (median, 58 vs 55 years), menopausal status (70% vs 64% postmenopausal), progesterone receptor expression (positive for 98% vs 92%; > 99% estrogen receptor positive in both), and primary surgery (lumpectomy for 68% vs 72%, mastectomy for 32% and 28%). The age distribution in the low-risk group was ≤ 40 years for 4%, 41 to 50 years for 23%, 51 to 60 years for 35%, 61 to 70 years for 32%, and > 70 years for 7%. Distribution of tumor size was < 1.0 cm in 8%, 1.0 to 1.9 cm in 61%, 2.0 to 2.9 cm in 23%, 3.0 to 3.9 cm in 6%, and ≥ 4.0 cm in 2%.

Endocrine Therapy and Breast Cancer Recurrence Risk ■■ Endocrine therapy alone was associated with a low risk of recurrence in women with a low-risk score on the 21-gene assay.

■■ At 5 years, the rate of freedom from any recurrence was 98.7%, and overall survival was 98.0%

ceived adjuvant chemotherapy against protocol, with one having recurrence despite such treatment.

Recurrence and Survival Within 5 years, there were 88 events of either invasive cancer or death and 30 deaths in the low-risk group. The initial event was local or regional recurrence in 8 patients, distant recurrence in 10, invasive contralateral breast cancer in 15, other invasive new primary cancer in 43, and death without another event in 12.

Five-year rates were 93.8% (95% confidence interval [CI] = 92.4%– 94.9%) for invasive disease–free survival, 99.3% (95% CI = 98.7%–99.6%) for freedom from distant recurrence, 98.7% (95% CI = 97.9%–99.2%) for freedom from any recurrence, and 98.0% (95% CI = 97.1%–98.6%) for overall survival.

Risk Factor Analysis In a multivariate analysis in the low-risk group that included age, tu-

mor size, histologic grade, and surgery type, no factors were associated with a significantly increased risk of the composite endpoint of recurrence, second primary breast cancer, second primary nonbreast invasive cancer, or death without recurrence of cancer.

Borderline associations were noted for age (hazard ratios [HRs] = 0.87 for 51–60 vs ≤ 50 years and 1.53 for 61–75 vs ≤ 50 years; P = .07) and lumpectomy vs mastectomy (HR = 0.63, P = .07). No factors were associated with a significantly increased risk of recurrence at a distant site. Tumor grade was associated with risk of any recurrence (HRs = 8.07 for intermediate- vs low-grade and 4.73 for highvs low-grade, P = .02).

Five-year rates for invasive disease– free survival, freedom from distant recurrence, freedom from any recurrence, and overall survival were 95.8%, 99.8%, 99.8%, and 98.7% among patients with low-grade tumors, 93.6%, 99.0%, 98.2%, and 97.9% among those with intermediate-grade tumors, and 91.3%, 100%, 98.7%, and 97.3% among those with high-grade tumors.

The investigators concluded: “Among patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone.” n

Disclosure: The study was funded by the National Cancer Institute, Canadian Cancer Society Research Institute, National Institutes of Health, Breast Cancer Research Foundation, and Susan G. Komen. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Sparano JA, Gray RJ, Makower DF, et al: Prospective validation of a 21gene expression assay in breast cancer. N Engl J Med. September 28, 2015 (early release online).

More on TAILORx Study See page 18 for a report on the TAILORx data as presented at the 2015 European Cancer Congress in Vienna.

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The ASCO Post | OCTOBER 25, 2015

PAGE 50

Journal Spotlight Genitourinary Oncology

Nivolumab and Cabozantinib Improve Outcomes vs Everolimus in Previously Treated Advanced Renal Cell Carcinoma

By Matthew Stenger

T

he CheckMate 025 trial, reported in The New England Journal of Medicine by Robert J. Motzer, MD, and colleagues, showed that treatment with the programmed cell death protein (PD-1) checkpoint inhibitor nivolumab (Opdivo) increased overall survival vs the mTOR inhibitor everolimus (Afinitor) in patients with advanced clear cell renal cell carcinoma who had received one or two prior regimens of antiangiogenic therapy.1 The METEOR trial, reported in The New England Journal of Medicine by Toni K. Choueiri, MD, and colleagues, showed that the multikinase inhibitor cabozantinib (Cometriq) improved progression-free survival vs everolimus in patients with advanced clear cell renal cell carcinoma progressing after vascular endothelial growth factor receptor (VEGFR)-targeted therapy.2 Cabozantinib targets ­VEGFR, MET, and AXL, the latter two of which are implicated in the development of resistance to ­VEGFR inhibitors.

Dr. Motzer is Professor of Medicine at Weill Cornell Medical College and Attending Physician at Memorial Sloan Kettering Cancer Center, New York. Dr.

of an independent data monitoring committee assessment concluding that the study had met its endpoint with regard to significant results for overall survival.

The minimum follow-up was 14 months.

Survival and Subsequent Therapy Median overall survival was 25.0 months (95% confidence interval [CI] = 21.8 to not estimable) in the nivolumab group and 19.6 months (95% CI = 17.6–23.1 months) in the everolimus group (hazard ratio [HR] = 0.73, P = .002, meeting the prespecified criterion for superiority of P ≤ .0148). Hazard ratios consistently favored nivolumab in subgroup analyses, including subgroups for region, Memorial Sloan Kettering Cancer Center risk group, and number of previous antiangiogenic regimens.

Analysis by PD-1 ligand (PD-L1) expression level showed a median overall survival of 21.8 vs 18.8 months (HR = 0.79, 95% CI = 0.53–1.17) in patients with ≥ 1% and 27.4 vs 21.2 months (HR = 0.77, 95% CI = 0.60–0.97) in those with < 1%. Similar results were observed among patients with ≥ 5% and < 5% expression.

New Findings in Renal Cell Carcinoma ■■ Nivolumab improved overall survival vs everolimus in patients who had received one or two prior regimens of antiangiogenic therapy.

■■ Cabozantinib improved progression-free survival vs everolimus in patients with disease progression after VEGFR-targeted therapy.

Choueiri is Associate Professor of Medicine at Harvard Medical School and Attending Physician at Dana-Farber Cancer Institute, Boston.

CheckMate 025 Trial In the open-label CheckMate 025 study,1 821 patients from 146 sites in 24 countries in North America, Europe, Australia, South America, and Asia were randomly assigned between October 2012 and March 2014 to receive intravenous nivolumab at 3 mg/kg every 2 weeks (n = 410) or oral everolimus at 10 mg once daily (n = 411). The primary endpoint was overall survival.

The nivolumab and everolimus groups were generally balanced for all baseline characteristics assessed.

After a preplanned interim analysis, the study was stopped early on the basis

Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus.

After progression, subsequent systemic therapy was given to 55% of the nivolumab group (including everolimus in 26%, axitinib [Inlyta] in 24%, and pazopanib [Votrient] in 9%) and 63% of the everolimus group (including axitinib in 36%, pazopanib in 16%, sorafenib [Nexavar] in 9%, and anti– PD-1 therapy in 2%). Study treatment was continued beyond progression in 44% of the nivolumab group and 46% of the everolimus group on the basis of investigator observation of continued clinical benefit.

Response Rate and Progression-Free Survival The objective response rate was 25% (complete response in four patients) in the nivolumab group vs 5% (complete response in two patients) in the everoli-

—Robert J. Motzer, MD, and colleagues

Progression-free survival was longer with cabozantinib than with everolimus among patients with renalcell carcinoma that had progressed after VEGFR-targeted therapy.

—Toni K. Choueiri, MD, and colleagues

mus group (P < .001). Median progression-free survival was 4.6 vs 4.4 months (HR = 0.88, P = 0.11).

In light of a delayed separation of Kaplan-Meier survival curves, an ad hoc sensitivity analysis was performed including 145 nivolumab patients and 129 everolimus patients who had not died or had disease progression at 6 months.

This analysis showed a median progression-free survival of 15.6 vs 11.7 months (HR = 0.64, 95% CI = 0.47–0.88).

Adverse Events The most common treatment-related adverse events were fatigue (33%), nausea (14%), and pruritus (14%) in the nivolumab group and fatigue (34%), stomatitis (29%), and anemia (24%) in the everolimus group. Grade 3 or 4 treatment-related adverse events occurred in 19% vs 37%, with the most common being fatigue (2%) with nivolumab and anemia (8%) with everolimus.

Dose reductions occurred in 26% of everolimus patients. No reductions in nivolumab dose were permitted. Treatment-related adverse events led to treatment discontinuation in 8% vs 13% in the everolimus and nivolumab groups, respectively. Death considered related to treatment occurred in zero and two patients (due to septic shock and acute bowel ischemia).

The investigators concluded: “Among patients with previously treat-

ed advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus.”

METEOR Trial In the open-label METEOR trial,2 658 patients from 173 sites in 26 countries with disease progression after VEGFR-targeted therapy were randomly assigned between August 2013 and November 2014 to receive oral cabozantinib at 60 mg/d (n = 330) or oral everolimus at 10 mg/d (n = 328).

The primary endpoint was progressionfree survival.

The first 375 randomized patients (187 assigned to cabozantinib and 188 assigned to everolimus) constituted the progression-free survival population for the primary endpoint analysis.

An interim analysis of overall survival, a secondary endpoint, was performed among the entire study population. The progression-free survival population cabozantinib and everolimus groups were generally balanced for all baseline characteristics assessed.

Progression-Free Survival Minimum follow-up was 11 months in the progression-free survival population. Median progression-free survival on independent review was 7.4 months (95% CI = 5.6–9.1 months) in the cabocontinued on page 56

If she has ovarian cancer

TEST FOR BRCA

If indicated* TREAT WITH LYNPARZA

Help her continue the fight with the first approved PARP inhibitor1

* INDICATION LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

SELECT SAFETY INFORMATION Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue LYNPARZA.

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

LYNPARZA demonstrated an objective response rate of 34% in patients with BRCA-mutated advanced ovarian cancer who had been treated with 3 or more lines of chemotherapy1 The efficacy of LYNPARZA was investigated in a single-arm study of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancer. A total of 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. Efficacy was based on objective response rate and duration of response.1 Objective response rate was defined as a ≥30% reduction in target lesion size, according to RECIST criteria, as measured by CT or MRI and confirmed at least 4 weeks later.2

34

%

OBJECTIVE RESPONSE RATE (95% CI: 26, 42)

0

10

20

30

PERCENTAGE OF PATIENTS WHO RESPONDED TO THERAPY

• The rate of partial response was 32% and the rate of complete response was 2%1

7.9

MEDIAN DURATION OF RESPONSE

MONTHS (95% CI: 5.6, 9.6)

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

Warnings and Precautions Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of LYNPARZA monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with LYNPARZA. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with LYNPARZA. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with LYNPARZA in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue LYNPARZA. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation.

If pneumonitis is confirmed, discontinue LYNPARZA. Embryo-Fetal Toxicity LYNPARZA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Advise females of reproductive potential to avoid becoming pregnant while taking LYNPARZA. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of LYNPARZA.

Use in Nursing Mothers Nursing Mothers It is not known whether olaparib 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 olaparib, 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.

Safety and tolerability of LYNPARZA • LYNPARZA 400 mg twice daily was evaluated as monotherapy in 223 patients with BRCA-mutated advanced ovarian cancer who had 3 or more prior lines of chemotherapy in 6 clinical trials1

Adverse Reactions Reported in ≥20% of Patients1

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

34

18

Abdominal pain/discomfort

43

8

Decreased appetite

22

1

Nausea

64

3

Vomiting

43

4

Diarrhea

31

1

Dyspepsia

25

0

66

8

26

0

Arthralgia/musculoskeletal pain

21

0

Myalgia

22

0

BLOOD AND LYMPHATIC DISORDERS

Anemia GASTROINTESTINAL DISORDERS

GENERAL DISORDERS

Fatigue/asthenia INFECTIONS AND INFESTATIONS

Nasopharyngitis/URI MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Please see accompanying Brief Summary of Full Prescribing Information.

References: 1. LYNPARZA [package insert]. Wilmington, DE: AstraZeneca; 2014. 2. 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.

LYNPARZA is a trademark of the AstraZeneca group of companies. ©2015 AstraZeneca. All rights reserved. 3118712 Last Updated 4/15

1

Laboratory Abnormalities

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Decrease in hemoglobin (anemia)

90

15

Decrease in absolute neutrophil count (neutropenia)

25

7

Decrease in platelets (thrombocytopenia)

30

3

Decrease in lymphocytes (lymphopenia)

56

17

Mean corpuscular volume elevation

57

-

Increase in creatininea

30

2

a

Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The safety and tolerability of LYNPARZA were also evaluated in a randomized, placebo-controlled study1 â&#x20AC;˘ LYNPARZA 400 mg twice daily was evaluated as maintenance monotherapy in a randomized, placebo-controlled clinical trial of 96 patients with germline BRCA-mutated platinum-sensitive ovarian cancer who had received 2 or more lines of platinum-containing chemotherapy 1 â&#x20AC;˘ Frequently occurring adverse reactions and lab abnormalities were consistent with those seen in the 6 clinical trials, with the addition of back pain, headache, cough, rash, and dysgeusia 1

To learn more, including how to order LYNPARZA, please visit www.lynparza.com

The ASCO Post | OCTOBER 25, 2015

PAGE 56

Journal Spotlight Nivolumab and Cabozantinib continued from page 50

zantinib group vs 3.8 months (95% CI = 3.7–5.4 months) in the everolimus group (HR = 0.58, P < .001).

A consistent benefit of cabozantinib was observed across subgroups defined by the number of prior VEGFR inhibitors and Memorial Sloan Kettering risk category. A

post hoc analysis among 153 patients who received only sunitinib as VEGFR-targeted therapy showed a median progression-free survival of 9.1 vs 3.7 months (HR = 0.41).

Response Rate and Overall Survival The objective response rate in the progression-free survival population

was 21% with cabozantinib vs 5% with everolimus (all partial responses, P < .001). Objective response was observed in 22% (17/76) of cabozantinib recipients and 3% (2/77) of everolimus recipients who had received sunitinib as their only VEGFR inhibitor.

An interim analysis of overall survival in the entire population, with a minimum

Trim: 7.625 x 10.5

LYNPARZA™ (olaparib) capsules, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGE Treatment of gBRCA-mutated advanced ovarian cancer Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in the full Prescribing Information].

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION Patient Selection Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information].

Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.

Recommended Dosing The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.

If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.

Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2) in the full Prescribing Information].

Dose Adjustments for Adverse Reactions To manage adverse reactions, consider dose interruption of treatment or dose reduction.

The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.

If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.

Dose Modifications for Use with CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2) in the full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy ( CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.

Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza.

Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) in the full Prescribing Information].

Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza.

If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations (8.6) in the full Prescribing Information].

ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) in the full Prescribing Information] • Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]

follow-up of 6 months, showed a benefit of cabozantinib (HR = 0.67, P = .005), but the difference did not cross the significance boundary for the interim analysis (P ≤ .0019). Follow-up continues for the final analysis of overall survival.

After progression, subsequent anticancer therapy was used in 38% of the cabozantinib group and 47% of the

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.

Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.

In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in 20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days.

Table 1 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction Blood and Lymphatic disorders Anemia Gastrointestinal disorders Abdominal pain/discomfort Decreased appetite Nausea Vomiting Diarrhea Dyspepsia General disorders Fatigue/asthenia Infections and infestations Nasopharyngitis/URI Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain Myalgia

3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % 34

18

43 22 64 43 31 25

8 1 3 4 1 0

66

8

26

0

21 22

0 0

Table 2 presents the frequency of abnormal laboratory findings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily.

Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Laboratory Parameter* 3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % Decrease in hemoglobin (anemia) 90 15 Decrease in absolute neutrophil count 25 7 (neutropenia) Decrease in platelets (thrombocytopenia) 30 3 Decrease in lymphocytes (lymphopenia) 56 17 Mean corpuscular volume elevation 57 Increase in creatinine* 30 2 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The following adverse reactions and laboratory abnormalities have been identified in 10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in 1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.

Table 3 presents adverse reactions reported in 20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCAmutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.

Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

ASCOPost.com | OCTOBER 25, 2015

PAGE 57

Journal Spotlight

everolimus group. The most common subsequent treatments were everolimus (23%) in the cabozantinib group and axitinib (23%) in the everolimus group.

Adverse Events The most common adverse events of any grade, irrespective of causal relationship to study drug, were diarrhea (74%),

fatigue (56%), nausea (50%), decreased appetite (46%), and palmar-plantar erythrodysesthesia syndrome (42%) in the cabozantinib group and fatigue (46%), anemia (38%), and decreased appetite (34%) in the everolimus group.

Grade 3 or 4 adverse events occurred in 68% vs 58%; the most common in the cabozantinib group were hyperten-

Trim: 7.625 x 10.5

LYNPARZATM (olaparib) capsules Table 3 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and Lymphatic disorders Anemia 25 4 7 2 Gastrointestinal disorders Abdominal pain/discomfort 47 0 58 2 Decreased appetite 25 0 14 0 Nausea 75 2 37 0 Vomiting 32 4 9 0 Diarrhea 28 4 21 2 Dyspepsia 25 0 14 0 Dysgeusia 21 0 9 0 General disorders Fatigue (including asthenia, lethargy) 68 6 53 2 Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0 Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Decrease in hemoglobin 85 8 58 2 Decrease in absolute neutrophil count 32 8 23 0 Decrease in platelets 26 6 19 0 Mean corpuscular volume elevation 85 44 Increase in creatinine* 26 0 5 0 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

DRUG INTERACTIONS Olaparib is primarily metabolized by CYP3A. Anticancer Agents Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Drugs that may Increase Olaparib Plasma Concentrations In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.

Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4) in the full Prescribing Information].

Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information].

Drugs that may Decrease Olaparib Plasma Concentrations In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.

Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3) in the full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.3) in the full Prescribing Information] Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.

Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which

sion (15%), diarrhea (11%), and fatigue (9%), and the most common in the everolimus group were anemia (16%), fatigue (7%), and hyperglycemia (5%).

Dose reductions occurred in 60% and 25% of patients, with the most common causes being diarrhea (16%), palmar-plantar erythrodysesthesia syndrome (11%), and fatigue (10%)

2 resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).

In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery.

Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.

Nursing Mothers It is not known whether olaparib 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 olaparib, 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 Lynparza has not been established in pediatric patients.

Geriatric Use In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged 65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE 3 which were reported more frequently in patients aged 65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.

Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza.

Hepatic Impairment The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT 2.5 X ULN ( 5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Renal Impairment Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in the full Prescribing Information].

OVERDOSAGE There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.

17 PATIENT COUNSELING INFORMATION SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE) • Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and Administration (2.1) in the full Prescribing Information]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges.

• MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1) in the full Prescribing Information].

• Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2) in the full Prescribing Information].

• Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6) in the full Prescribing Information].

• Nursing Mothers: Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations (8.3) in the full Prescribing Information].

• Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options.

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 3079901 12/14 Issued: 12/2014

in the cabozantinib group and pneumonitis (4%), fatigue (3%), and stomatitis (3%) in the everolimus group.

Adverse events led to treatment discontinuation in 9% vs 10%. Death considered related to study treatment occurred in one patient in the cabozantinib group (death not otherwise specified) and in two patients in the everolimus group (aspergillosis and aspiration pneumonia).

The investigators concluded: “Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFRtargeted therapy.” n

Disclosure: The CheckMate 025 trial was funded by Bristol-Myers Squibb. The METEOR trial was funded by Exelixis. For full disclosures of the study authors, visit www.nejm.org.

References 1. Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. September 25, 2015 (early release online).

2. Choueiri TK, Escudier B, Powles T, et al: Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. September 25, 2015 (early release online).

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

The ASCO Post | OCTOBER 25, 2015

PAGE 58

Announcements

UNC-Chapel Hill Researchers Awarded $11.3 Million for Four Cancer Nanotechnology Projects

U

niversity of North Carolina (UNC) at Chapel Hill researchers received an $11.3 million, 5-year grant to conduct multiple studies exploring the use of tiny nanoparticles to create cancer vaccines and improve cancer drug delivery and responses.

The grant is the third in a series of awards that the university has won from the National Cancer Institute (NCI) for cancer nanotechnology research. It will fund work by researchers with the Carolina Center of Cancer Nanotechnology Excellence (CCCNE), an NCIfunded collaboration between UNCChapel Hill and the UNC Lineberger Comprehensive Cancer Center.

“UNC-Chapel Hill has emerged as a leader in nanotechnology in the last 10 years,” said Leaf Huang, PhD, a UNC Lineberger member, Fred Eshelman Distinguished Professor, and Interim Chair of the UNC Eshelman School of Pharmacy Division of Molecular Therapeutics, and Coleader of the CCCNE. “This grant is a testament to the quality

Leaf Huang, PhD

of our research in using nanotechnology to continue to find innovative ways to fight cancer.”

Study Specifics The grant will fund four different studies into the use of nanotechnology to fight cancer.

The first project will be a study of nanoparticles to create a vaccine that would train the body’s immune system to recognize and fight drug-resistant melanoma. The project is led by Dr. Huang; William Kim, MD, a UNC Lineberger member and Associate Professor of Medicine and Genetics in the

UNC School of Medicine; and Jenny Ting, PhD, a UNC Lineberger member and the UNC William R. Kenan Jr. Distinguished Professor in the UNC School of Medicine.

The second project will involve using nanoparticles to develop a vaccine for advanced melanoma. The concept is to use nanoparticles to deliver drugs targeting molecules in the tumor’s microenvironment. Specifically, the nanoparticles would target molecules that would help immune cells destroy cancerous cells. The project is led by Joseph DeSimone, PhD, Chancellor’s Eminent Professor of Chemistry; Jon Serody, MD, Associate Director of Translational Science at UNC Lineberger and a medical oncologist in the UNC Lineberger Leukemia and Lymphoma Program; and Dr. Ting.

The third project will involve using nanotechnology and radiation therapy to try to improve patient responses to certain cancer drugs. Specifically, the

study will aim to improve responses to cancer immunotherapy checkpoint blockade agents in melanoma. It is being led by Andrew Wang, MD, a UNC Lineberger member and Associate Professor in the UNC School of Medicine Department of Radiation Oncology and UNC Eshelman School of Pharmacy; Joel Tepper, MD, Hector MacLean Distinguished Professor of Cancer Research in Radiation Oncology and Coleader of CCCNE; and Dr. Serody.

In the final project, researchers will use a capsule made using nanoparticles to more effectively load and deliver cancer drugs. The project is led by Alexander ­K abanov, PhD, DSc, Mescal Swain Ferguson Distinguished Professor in the UNC Eshelman School of Pharmacy and Director of the UNC Center for Nanotechnology in Drug Delivery; Chad Pecot, MD, a UNC Lineberger member and Assistant Professor in the UNC School of Medicine, and Dr. Wang. n

UPCI Wins $10.9 Million Grant Renewal for Head and Neck Cancer Research

U

niversity of Pittsburgh Cancer Institute (UPCI) researchers have received renewal of their head and neck cancer research through the National Cancer Institute’s competitive Specialized Program of Research Excellence (SPORE) program. The 5-year, $10.9 million grant includes a new project to study differentiated thyroid cancer.

Translational Research and Coleader of the UPCI’s Cancer Immunology Program—and a collaborator at the University of California at San Francisco.

Three of the four projects focus on head and neck squamous cell carcinoma, a frequently lethal cancer with few U.S. Food and Drug Administration-approved drugs available for treatment.

“Building on our past research, we are excited to continue our work into

novel treatments to attack cancerpromoting proteins that have been resistant to drug intervention, and an exciting immunotherapy strategy to counteract inhibitory immune cells in head and neck squamous cell carcinoma,” said Dr. Ferris, who also is Vice Chair and Chief of the Division of Head and Neck Surgery for the Departments of Otolaryngology, Immunology, and Radiation Oncology.

“We’ve also added a new project looking at chemoprevention to reverse oral cancer development, which is a promising area of study.”

The thyroid cancer project will focus on using next-generation sequencing to reduce unnecessary surgeries for those with less aggressive tumors, while identifying individuals with more aggressive disease who need additional therapy. n

UCSF Receives $5 Million NCI Grant to Integrate Data From Cancer Research Models Robert L. Ferris, MD, PhD

The award is one of four grants awarded to the UPCI through the prestigious SPORE program, which requires a team of scientists and clinicians to collaborate to translate findings from the laboratory to the clinic and the community. The other UPCI SPORE grants are in melanoma, lung, and ovarian cancers.

The head and neck SPORE consists of four study projects, headed by coprincipal investigator Robert L. F ­ erris, MD, PhD—Associate Director for

T

he University of California, San Francisco (UCSF) has received a National Cancer Institute grant of $5 million over the next 5 years to lead a massive effort to integrate the data from all experimental models across all types of cancer.

The Web-based repository is an important step in moving the fight against cancer toward precision medicine.

The goal is to accelerate cancer research to improve the way we diagnose, treat, and conduct further research on the disease. The resulting database, called the Oncology Models Forum, will be accessible to researchers through the Na-

tional Institutes of Health, to encourage scientists to use existing validated cancer models, rather than creating new ones.

Harnessing Data “There are incredible new discoveries happening in cancer research today, such as detecting cancer cells and DNA in the bloodstream, and even harnessing the immune system to fight cancers,” said Atul Butte, MD, PhD, Director of the Institute for Computational Health Sciences at UCSF and principal investigator for the grant. “These research methodologies generate enormous

amounts of data that can and should be harnessed by researchers and engineers to yield new drugs and diagnostics.”

The project aims to create an online cache of molecular data that oncologists and cancer researchers could use to validate the current models that best translate to humans, make predictions about the disease, and move toward a collaborative, precision medicine approach to cancer. Ultimately, Dr. Butte said, the effort also has the potential to create computer-based cancer models that greatly reduce the need for using animals in research. n

Image not intended to depict total daily dose. Number of tablets may vary depending on prescribed dose. Tablets shown are not actual size.

Introducing

NOW APPROVED Please see Important Safety Information and brief summary of Prescribing Information on the following pages.

The ASCO Post | OCTOBER 25, 2015

PAGE 60

Announcements LARGE TRIM: 8.125” BLEED:8.5”

Children’s Healthcare, Emory Name Douglas Graham, MD, PhD, Director of Aflac Cancer and Blood Disorders Center SMALL TRIM:7.875” SAFETY:6.875”

C

hildren’s Healthcare of Atlanta and Emory University has announced that William G. Woods, MD, has stepped down as Director of the Aflac Cancer and Blood Disorders Center of

Children’s Healthcare of Atlanta and Chief of Hematology/Oncology/BMT in the Department of Pediatrics at Emory University. Dr. Woods held this position for 15 years; he will remain on fac-

ulty with the title of Director Emeritus.

Douglas Graham, MD, PhD, has been named as the successor to this role following a nationwide search; Dr. Graham joined Children’s in August.

“Dr. Graham brings to Children’s a vision for the Aflac Cancer Center to enhance innovation and discovery across our core missions of clinical care, research, and teaching,” said Dr. Woods.

NOW APPROVED Indication LONSURF® (trifluridine and tipiracil) is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild type, an anti-EGFR therapy.

Important Safety Information WARNINGS AND PRECAUTIONS Severe Myelosuppression: In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%), and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF-treated patients received granulocyte-colony stimulating factors.

Obtain complete blood counts prior to and on day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery, resume LONSURF at a reduced dose.

Embryo-Fetal Toxicity: LONSURF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. USE IN SPECIFIC POPULATIONS Lactation: It is not known whether LONSURF or its metabolites are present in human milk. There are no data to assess the effects of LONSURF or its metabolites on the breast-fed infant or the effects on milk production. Because of the potential for serious adverse reactions in breast-fed infants, advise women not to breast-feed during treatment with LONSURF and for 1 day following the final dose.

Male Contraception: Advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose.

Geriatric Use: Grade 3 or 4 neutropenia and thrombocytopenia and Grade 3 anemia occurred more commonly in patients 65 years or older who received LONSURF. Renal Impairment: Patients with moderate renal impairment may require dose modifications for increased toxicity. No patients with severe renal impairment were enrolled in Study 1.

Hepatic Impairment: Patients with moderate or severe hepatic impairment were not enrolled in Study 1.

ADVERSE REACTIONS Most Common Adverse Drug Reactions in Patients Treated With LONSURF (≥5%): The most common adverse drug reactions in LONSURF-treated patients vs placebo-treated patients with refractory mCRC, respectively, were asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), abdominal pain (21% vs 18%), pyrexia (19% vs 14%), stomatitis (8% vs 6%), dysgeusia (7% vs 2%), and alopecia (7% vs 1%).

Additional Important Adverse Drug Reactions: The following occurred more frequently in LONSURF-treated patients compared to placebo: infections (27% vs 15%) and pulmonary emboli (2% vs 0%).

Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia.

Laboratory Test Abnormalities in Patients Treated With LONSURF: Laboratory test abnormalities in LONSURF-treated patients vs placebo-treated patients with refractory mCRC, respectively, were anemia (77% vs 33%), neutropenia (67% vs 1%), and thrombocytopenia (42% vs 8%).

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

Learn more at LONSURFhcp.com/new

© TAIHO ONCOLOGY, INC.

09/2015

All rights reserved.

LON-PM-US-0035

ASCOPost.com | OCTOBER 25, 2015

PAGE 61

Announcements LARGE TRIM: 8.125” BLEED:8.5” TRIM:7.875” of isSMALL a member

William G. Woods, MD

Dr. Graham the Senior SAFETY:6.875” Leadership Council of Winship Cancer Institute of Emory University. He will play a key role in helping to jointly recruit new oncology faculty with Winship.

Dr. Graham previously served as Professor of Pediatrics and Immunology at the University of Colorado, with clinical practice at Children’s

LONSURF (trifluridine and tipiracil) tablets, for oral use Initial U.S. Approval: 2015 Brief Summary of Prescribing Information For complete Prescribing Information, consult official package insert.

Douglas Graham, MD, PhD

Table 1 Per Patient Incidence of Adverse Drug Reactions (≥5%) in Study 1 Occurring More Commonly (>2%) than in Patients Receiving Placebo.

LONSURF (N=533)

Adverse Reactions

All Grades

Placebo (N=265)

Grades 3-4* All Grades

1 INDICATIONS AND USAGE LONSURF is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

Gastrointestinal disorders

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Severe Myelosuppression In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF-treated patients received granulocyte-colony stimulating factors.

General disorders and administration site conditions

Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery resume LONSURF at a reduced dose. [see Dosage and Administration (2.2) in the full Prescribing Information] 5.2 Embryo-Fetal Toxicity Based on animal studies and its mechanism of action, LONSURF can cause fetal harm when administered to a pregnant woman. Trifluridine/tipiracil caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at dose levels resulting in exposures lower than those achieved at the recommended dose of 35 mg/m2 twice daily.

In Study 1, 3.6% of patients discontinued LONSURF for an adverse event and 13.7% of patients required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.

2%

24%

1%

32%

3%

12%

<1%

Vomiting

28%

2%

14%

<1%

Abdominal pain

21%

2%

18%

4%

Stomatitis

8%

<1%

6%

0%

Asthenia/fatigue

52%

7%

35%

9%

Pyrexia

19%

1%

14%

<1%

4%

29%

5%

0%

2%

0%

1%

0%

Metabolism and nutrition disorders Decreased appetite

39%

Nervous system disorders Dysgeusia

7%

Skin and subcutaneous tissue disorders Alopecia

7%

0%

*No Grade 4 definition for nausea, abdominal pain, or fatigue in National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

Table 2 Laboratory Test Abnormalities LONSURF (N=533*) Laboratory Parameter

Placebo (N=265*)

Grade† All %

3 %

Grade† 4 %

All %

3 %

4 % N/A

Blood and lymphatic system disorders Anemia‡

77

18

N/A#

33

3

Neutropenia

67

27

11

1

0

0

Thrombocytopenia

42

5

1

8

<1

<1

*% based on number of patients with post-baseline samples, which may be less than 533 (LONSURF) or 265 (placebo) Terminology Criteria for Adverse Events (CTCAE), v4.03 ‡ Anemia: No Grade 4 definition for these laboratory parameters in CTCAE, v4.03 # One Grade 4 anemia adverse reaction based on clinical criteria was reported † Common

In Study 1, infections occurred more frequently in LONSURF-treated patients (27%) compared to those receiving placebo (15%). The most commonly reported infections which occurred more frequently in LONSURF-treated patients were nasopharyngitis (4% versus 2%), and urinary tract infections (4% versus 2%).

In Study 1, pulmonary emboli occurred more frequently in LONSURFtreatment patients (2%) compared to no patients on placebo.

Additional Clinical Experience Interstitial lung disease was reported in fifteen (0.2%) patients, three of which were fatal, among approximately 7,000 patients exposed to LONSURF in clinical studies and clinical practice settings in Asia.

7 DRUG INTERACTIONS No pharmacokinetic drug-drug interaction studies have been conducted with LONSURF. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, LONSURF can cause fetal harm. LONSURF caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when given during gestation at doses resulting in exposures lower than or similar to exposures at the recommended dose in humans. [see Data] There are no available data on LONSURF exposure in pregnant women. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

LARGE TRIM: 10.875”

The most common adverse drug reactions or laboratory abnormalities (all Grades and greater than or equal to 10% in incidence) in patients treated with LONSURF at a rate that exceeds the rate in patients receiving placebo were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

48%

Diarrhea

BLEED:11.25”

The data described below are from Study 1, a randomized (2:1), doubleblind, placebo-controlled trial in which 533 patients (median age 63 years; 61% men; 57% White, 35% Asian, 1% Black) with previously treated metastatic colorectal cancer received LONSURF as a single agent at a dose of 35 mg/m2/dose administered twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. The mean duration of LONSURF therapy was 12.7 weeks.

Nausea

SAFETY:9.5”

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

Grades 3-4*

SMALL TRIM:10.5”

LARGE TRIM: 10.875”

BLEED:11.25”

SAFETY:9.5”

SMALL TRIM:10.5”

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1) in the full Prescribing Information]

Hospital Colorado. While there, Dr. Graham led the Biology and Treatment of Childhood Cancer Research Emphasis Area.

Dr. Graham is a National Institutes of Health–funded investigator with an active laboratory focusing on developing novel therapeutics for pediatric cancer. n

The ASCO Post | OCTOBER 25, 2015

PAGE 62

Announcements LARGE TRIM: 8.125” BLEED:8.5”

CancerCare® Welcomes Christine Verini, RPh, as Chief Business Development Officer SMALL TRIM:7.875” SAFETY:6.875”

C

ancerCare®, a national nonprofit organization providing free, professional support services to anyone affected by cancer, is pleased to welcome Chief Business Development

Officer Christine Verini, RPh. In her role, Ms. Verini will serve as a key member of CancerCare’s Executive Leadership Team, with a primary focus on expanding existing and future

for support of patients emotionally, financially, and with everyday, practical needs,” shared Ms. Verini. “I am excited to be a part of the CancerCare team to help the organization to continue to grow and support the needs of patients and their families.”

8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of LONSURF. In Study 1, patients with moderate renal impairment (CLcr = 30 to 59 mL/min, n= 47) had a higher incidence (difference of at least 5%) of ≥ Grade 3 adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr ≥ 90 mL/min, n= 306) or patients with mild renal impairment (CLcr = 60 to 89 mL/min, n= 178).

No dose adjustment to the starting dose of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min); however patients with moderate renal impairment may require dose modification for increased toxicity. No patients with severe renal impairment (CLcr < 30 mL/min) were enrolled in Study 1. [ see Clinical Pharmacology (12.3) in the full Prescribing Information] 8.8 Ethnicity There were no clinically meaningful differences in Study 1 between Western and Asian subgroups with respect to overall incidence of adverse events or ≥ Grade 3 adverse events in either the LONSURF or placebo groups.

10 OVERDOSAGE The highest dose of LONSURF administered in clinical studies was 180 mg/m2 per day.

There is no known antidote for LONSURF overdosage.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Severe Myelosuppression: Advise the patient to immediately contact their healthcare provider if they experience signs or symptoms of infection and advise patients to keep all appointments for blood tests. [see Warnings and Precautions (5.1)]

Advise the patient that anyone else who handles their medication should wear gloves. [see References (15) in the full Prescribing Information] Embryo-Fetal Toxicity: Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)] Lactation: Advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. [see Use in Specific Populations (8.2)] © TAIHO ONCOLOGY, INC. 09/2015

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

LARGE TRIM: 10.875”

Advise the patient to take LONSURF within 1 hour after eating their morning and evening meals. [see Dosage and Administration (2.1) in the full Prescribing Information]

BLEED:11.25”

Administration Instructions: Advise the patient that LONSURF is available in two strengths and they may receive both strength tablets to provide the prescribed dose. Advise the patient of the importance of reading prescription labels carefully and taking the appropriate number of tablets.

Ms. Verini brings a wealth of advocacy and strategic planning expertise to her new role, most recently serving as Vice President of Corporate Communications and Advocacy at Eisai. Prior to joining Eisai, Ms. Verini spent 8 years at Sanofi-Aventis United States. A registered pharmacist by training, she began her career at Sanofi as a medical liaison in oncology before serving in a number of marketing roles for the company’s oncology business.

Ms. Verini was also instrumental in creating Magnolia™, an Eisai women’s oncology program, which is designed to give women living with cancer a way to address their challenges. The program’s Magnolia Meals at Home™ initiative, which was launched in May 2012, provides meals at no cost to eligible patients and families living with breast and thyroid cancers.

Ms. Verini formerly served on the Board of Directors of CancerCare New Jersey and currently serves on the board of HealthyWomen, an independent health information organization that seeks to educate, inform, and empower women to make smart health choices for themselves and their families. n SAFETY:9.5”

Gastrointestinal toxicity: Advise patients to contact their healthcare provider for severe or persistent nausea, vomiting, diarrhea, or abdominal pain. [see Adverse Reactions (6.1)]

Christine Verini, RPh

SMALL TRIM:10.5”

Data Animal Data Trifluridine/tipiracil was administered orally once daily to female rats during organogenesis at dose levels of 15, 50, and 150 mg/kg [trifluridine (FTD) equivalent]. Decreased fetal weight was observed at FTD doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily). At the FTD dose of 150 mg/kg (approximately 0.92 times the FTD exposure at the clinical dose of 35 mg/m2 twice daily) embryolethality and structural anomalies (kinked tail, cleft palate, ectrodactyly, anasarca, alterations in great vessels, and skeletal anomalies) were observed.

8.2 Lactation Risk Summary It is not known whether LONSURF or its metabolites are present in human milk. In nursing rats, trifluridine and tipiracil or their metabolites were present in breast milk. There are no data to assess the effects of LONSURF or its metabolites on the breastfed infant or the effects on milk production.

Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LONSURF and for one day following the final dose.

Data Radioactivity was excreted in the milk of nursing rats dosed with trifluridine/ tipiracil containing 14C-FTD or 14C-tipiracil (TPI). Levels of FTD-derived radioactivity were as high as approximately 50% of the exposure in maternal plasma an hour after dosing with trifluridine/tipiracil and were approximately the same as those in maternal plasma for up to 12 hours following dosing. Exposure to TPI-derived radioactivity was higher in milk than in maternal plasma beginning 2 hours after dosing and continuing for at least 12 hours following administration of trifuridine/tipiracil.

8.3 Females and Males of Reproductive Potential Contraception Females LONSURF can cause fetal harm when administered to a pregnant woman. [see Use in Specific Populations (8.1)] Advise females of reproductive potential to use effective contraception during treatment.

Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose. [see Nonclinical Toxicology (13.1) in the full Prescribing Information] 8.4 Pediatric Use Safety and effectiveness of LONSURF in pediatric patients have not been established.

Animal Data Dental toxicity including whitening, breakage, and malocclusion (degeneration and disarrangement in the ameloblasts, papillary layer cells and odontoblasts) were observed in rats treated with trifluridine/tipiracil at doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily).

8.5 Geriatric Use In Study 1, 533 patients received LONSURF; 44% were 65 years of age or over, while 7% were 75 and over. No overall differences in effectiveness were observed in patients 65 or older versus younger patients, and no adjustment is recommended for the starting dose of LONSURF based on age.

Patients 65 years of age or older who received LONSURF had a higher incidence of the following compared to patients younger than 65 years: Grade 3 or 4 neutropenia (48% vs 30%), Grade 3 anemia (26% vs 12%), and Grade 3 or 4 thrombocytopenia (9% vs 2%).

8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of LONSURF. No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (TB) less than or equal to the upper limit of normal (ULN) and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST). Patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment were not enrolled in Study 1. [see Clinical Pharmacology (12.3) in the full Prescribing Information]

mission-based programs and enhancing and building organizational support and collaborations.

“CancerCare is a great organization that has always been a strong advocate

ASCOPost.com | OCTOBER 25, 2015

PAGE 63

Journal Spotlight Issues in Oncology

Maternal Cancer During Pregnancy Does Not Appear to Affect Cognitive or General Development in Early Childhood

By Matthew Stenger

I

n a study reported in The New England Journal of Medicine, Frederic Amant, MD, PhD, of University Hospitals Leuven, Belgium, and colleagues in the International Network on Cancer, Infertility, and Pregnancy found that cancer diagnosed during pregnancy did not appear to affect cognitive, cardiac, or general development in offspring during early childhood irrespective of whether the mothers received cancer treatment.1 The study was published concurrently with its presentation by Dr. Amant at the European Cancer Congress in Vienna, Austria (see page 15).

Study Details This multicenter case-control study included 129 children whose mothers received a diagnosis of cancer during pregnancy (see sidebar) and 129 matched children of women without a cancer diagnosis who had uncomplicated pregnancy and delivery. Cases were recruited from referral centers in Belgium, the Netherlands, Italy, and the Czech Republic, and controls were recruited from the general population of each country.

A health questionnaire and medical files were used to obtain data on neonatal and general health. All children were assessed by neurologic examination and the Bayley Scales of Infant Development at 18 months, 36 months, or both. Cardiac assessment was performed at 36 months.

In addition to being matched for age at the time of cognitive assessment, children in the control group were also matched with those in the prenatal-ex-

posure group for gestational age at birth, country, and edition of the Bayley scale used in assessment. Children in the prenatal-exposure group had a median age of 22 months (range = 12–42 months).

During pregnancy, 96 children in the prenatal-exposure group (74.4%) were exposed to chemotherapy alone or in combination with other treatments, 11 (8.5%) to radiotherapy alone or in combination, 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment.

Birth and Growth Median gestational age at birth was 36 weeks in the prenatal-exposure group; 61.2% (79 children) were born preterm, compared with a general percentage of 6.8% to 8.0% in the countries of birth (control children were matched for gestational age at birth). Median birth weight was 2,705 g. Birth weight was below the 10th percentile (small for gestational age) in 28 (22.0%) of 127 children in the prenatal-exposure group and in 19 (15.2%) of 125 children in the control group (P = .16). Among children with available data, the status of small for gestational age was reported for 24 (25%) of 95 exposed to chemotherapy and 4 (36%) of 11 exposed to radiotherapy.

The frequencies of medical problems and need for surgery or medical care were similar in the two groups.

Biometric data showed similar results in the two groups for weight, height, and head circumference during growth.

In 22 children of mothers who received

Maternal Malignancy Treated During Pregnancy (125 Mothers)

T

he majority of women with cancer treated during pregnancy had a diagnosis of breast cancer (69 mothers, including 2 twin pregnancies [55%]) or a hematologic malignancy (20 mothers [16%], including 1 mother with acute lymphoid leukemia, 4 with acute myeloid leukemia, 1 with chronic myeloid leukemia, 8 with Hodgkin lymphoma, and 6 with nonHodgkin lymphoma).

Other tumor types treated during pregnancy and included in the study were cervical (8%), ovarian (7%), brain (2%), colon (2%), thyroid (2%), and renal cell carcinomas, lung, melanoma, Ewing sarcoma, or soft-tissue sarcoma (1%). n

Source: Amant F, Vandenbroucke T, Verheecke M, et al: Pediatric outcomes after maternal cancer diagnosed during pregnancy. Supplementary appendix. N Engl J Med. September 28, 2015 (early release online)

chemotherapy and were small for gestational age, catch-up weight was observed at the time of testing (18 months for 17) in 14 (63.3%).

Cognitive Development Control group parents were more highly educated than prenatal-exposure group parents and parental education levels were significantly related to cognitive outcome testing in children.

findings. No significant differences between groups were observed for heart rate, blood pressure, ejection fraction, fractional shortening, values for global longitudinal strain and circumferential strain, or echocardiographic measurement of diastolic function.

No structural abnormalities were detected by echocardiography in any children, and all measures of cardiacchamber dimensions and wall thickness

Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood.

—Frederic Amant, MD, PhD, and colleagues

Thus, analyses comparing the two groups included parental education level as a covariate.

There were no significant differences between groups in cognitive development according to children’s country of origin. Most children in both groups had normal cognitive development based on Bayley score; no significant difference between groups was observed (P = .08) including after adjustment for parental education level (P = .52). Cognitive outcome also did not differ significantly between children exposed to chemotherapy and the control group (P = .43).

Univariate linear regression analysis including 238 children from both groups with available data showed that average cognitive score increased by 2.9 points for each additional week in gestational age at birth (P < .001). In a regression model including gestational age, study group, and the interaction between gestational age and study group, the interaction term was not significant (P = .68; P = .05 for gestational age, P = .62 for study group). After adjustment for sex, test age, country, parental education level, and race, the average increase was 2.2 points for each additional week of gestational age (P < .001).

Cardiac Development Cardiologic evaluation of 47 prenatal-exposure children and 47 sexmatched control children at 36 months of age showed generally normal cardiac

were within normal ranges. Small but significant differences were observed in tissue Doppler imaging measurements of the basal segment of the interventricular septum, with higher mean peak systolic and early diastolic velocities in the control group (P = .003 for both); no differences were observed in the leftventricular lateral wall. The differences were not observed in the 26 children exposed to anthracyclines compared with the control group.

The investigators concluded: “Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood.

Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment.”

Tineke Vandenbroucke, MSc, Magali Verheecke, MD, and Dr. Amant, all from University Hospitals Leuven, Belgium, contributed equally to The New England Journal of Medicine article. n Disclosure: The study was supported by Research Foundation–Flanders, Stichting tegen Kanker, Belgian Cancer Plan (Ministry of Health), KU Leuven, and University Hospitals Leuven.

Reference 1. Amant F, Vandenbroucke T, Verheecke M, et al: Pediatric outcome after maternal cancer diagnosed during pregnancy.

N Engl J Med. September 28, 2015 (early release online).

The ASCO Post | OCTOBER 25, 2015

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In the Clinic Melanoma

Nivolumab in Combination With Ipilimumab in BRAF V600 Wild-Type Unresectable or Metastatic Melanoma

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.

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n September 30, 2015, the U.S. Food and Drug Administration granted accelerated approval to nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the treatment of patients with BRAF V600 wildtype unresectable or metastatic melanoma, including those with previously untreated disease.1,2

Supporting Efficacy Data Approval was based on demonstration of improved objective response rate, prolonged response duration, and improved progression-free survival in an international, multicenter, doubleblind phase II trial in 142 previously untreated patients.3 Patients were randomly assigned 2:1 to receive intravenous

groups consisted of history of brain metastasis (6% vs 0%), acral/mucosal melanoma (10% vs 24%), and cutaneous melanoma (82% vs 57%).

Among patients with wild-type BRAF V600, the objective response rate was 60% in the combination group vs 11% in the ipilimumab group (P < .001).

Median progression-free survival was 8.9 months (95% confidence interval [CI] = 7.0 months to not estimable) vs 4.7 months (95% CI = 2.8–5.3 months; hazard ratio = 0.40, P < .002). Of the 43 patients with objective response in the nivolumab-plus-ipilimumab group, 9 (21%) had disease progression after responses of 3 to 7 months, and 34 (79%) had ongoing responses at the time of last analysis (6 to < 9 months in 14 and ≥ 9 months in 20).

How It Works Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds the programmed cell death protein (PD-1) receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking

Nivolumab for Melanoma ■■ Nivolumab (Opdivo) has been approved for use in combination with ipilimumab (Yervoy) to treat patients with BRAF V600 wild-type unresectable or metastatic melanoma.

■■ The recommended dose of nivolumab in this setting is 1 mg/kg via intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for four doses. The recommended subsequent dose as a single agent is 3 mg/kg via 60-minute infusion every 2 weeks until disease progression or unacceptable toxicity.

nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks for four doses and then nivolumab at 3 mg/kg every 2 weeks (n = 95, including 72 with wild-type BRAF V600) or intravenous ipilimumab at 3 mg/kg and placebo every 3 weeks for four doses followed by intravenous placebo every 2 weeks (n = 47, including 37 with wild-type BRAF V600) until disease progression or unacceptable toxicity.

Among the 109 patients with BRAF V600 wild-type disease, median age was 66 years, Eastern Cooperative Oncology Group performance score was 0 in 84% and 1 in 15%, 46% had M1c disease, and 20% had elevated lactate dehydrogenase. Baseline differences between the combination and ipilimumab

PD-1 pathway–mediated inhibition of immune response, including antitumor immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production.

Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse tumor models, blocking PD-1 activity results in decreased tumor growth.

Combined PD-1 inhibition with nivolumab and CTLA-4 inhibition with ipilimumab produces enhancement of T-cell function that is greater than with either agent alone, resulting in improved antitumor responses in

metastatic melanoma. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased antitumor activity.

How It Is Used The recommended dose of nivolumab in this setting is 1 mg/kg via intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for four doses. The recommended subsequent dose as a single agent is 3 mg/kg via 60-minute infusion every 2 weeks until disease progression or unacceptable toxicity.

Nivolumab treatment should be withheld for grade 2 pneumonitis, grade 2 or (when used as a single agent) grade 3 diarrhea or colitis, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 to 5 times the upper limit of normal or total bilirubin > 1.5 to 3 times the upper limit of normal, serum creatinine > 1.5 to 6 times the upper limit of normal or > 1.5 times baseline level, grade 2 or 3 hypophysitis, grade 2 adrenal insufficiency, grade 3 rash, and first occurrence of other grade 3 adverse reactions.

There are no recommended dose modifications for hypothyroidism or hyperthyroidism. No dose adjustment is required in patients with renal impairment or mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment. Ipilimumab should be withheld when nivolumab is withheld.

Nivolumab should be discontinued for grade 3 diarrhea or colitis with combined use, grade 4 hypophysitis, grade 3 or 4 adrenal insufficiency, grade 4 rash, any life-threatening or grade 4 adverse reaction, grade 3 or 4 pneumonitis, grade 4 colitis, AST or ALT > 5 times the upper limit of normal or total bilirubin > 3 times the upper limit of normal, serum creatinine > 6 times the upper limit of normal, any recurring severe or grade 3 treatment-related adverse reaction, inability to reduce corticosteroid dose to ≤ 10 mg/d of prednisone or equivalent within 12 weeks, and persistent grade 2

OF NOTE Nivolumab carries warnings/precautions for immune-mediated adverse reactions and embryofetal toxicity.

OF NOTE Combined PD-1 inhibition with nivolumab and CTLA-4 inhibition with ipilimumab produces enhancement of T-cell function that is greater than with either agent alone.

or 3 treatment-related adverse reactions that do not recover to grade 0 or 1 within 12 weeks after the last dose.

Infusion should be interrupted or slowed in patients with mild or moderate infusion reactions. Nivolumab should be discontinued for severe or life-threatening infusion reactions.

Safety Profile Among 140 patients in the phase II trial who received at least one dose of study drug, the most common adverse events of any grade occurring more frequently in the combination group were rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs 11%). Grade 3 or 4 adverse events occurred in 69% of the combination group vs 43% of the ipilimumab group; the most common in the combination group that occurred more frequently than in the ipilimumab group was dehydration (3.2% vs 2.2%).

The most common laboratory abnormalities of any grade occurring more frequently in the combination group were increased ALT (45% vs 20%), increased AST (43% vs 22%), anemia (40% vs 35%), hyponatremia (38% vs 20%), lymphopenia (37% vs 30%), increased lipase (36% vs 17%), and increased alkaline phosphatase (30% vs 17%). The most common grade 3 or 4 abnormalities occurring more frequently in the combination group were increased ALT (13% vs 0%), increased lipase (13% vs 7%), increased AST (10% vs 0%), hyponatremia (9% vs 2%), and lymphopenia (9% vs 2%).

Serious adverse events occurred in 62% vs 39% of patients, with the most common in the combination group being colitis (17% vs 9%), diarrhea (9% vs 7%), pyrexia (6% vs 7%), and pneumonitis (5% vs 0%). Adverse events led to dose delay in 47% vs 22% and permanent discontinuation in 43% vs 11%. The most common causes of discontinued on page 65

ASCOPost.com | OCTOBER 25, 2015

PAGE 65

Announcements

Three Young Investigators Named Winners of 2015 Paul Marks Prize for Cancer Research

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emorial Sloan Kettering Cancer Center (MSKCC) has named three investigators as recipients of this year’s Paul Marks Prize for Cancer Research. The award recognizes promising investigators aged 45 or younger for their efforts in advancing cancer research.

The winners are Bradley E. ­Bernstein, MD, PhD, of Massachusetts General Hospital; Howard Y. Chang, MD, PhD, of Stanford University; and Daniel Durocher, PhD, of the Lunenfeld-Tanenbaum Research Institute.

Bradley E. Bernstein, MD, PhD

would be a fitting tribute to him.”

Since it was first presented in 2001, the biennial prize has recognized 25 young scientists and has awarded more than $1 million.

Bradley E. Bernstein, MD, PhD Dr. Bernstein is a Professor of Pathology at Massachusetts General Hospital and Harvard Medical School and an Institute Member of the Broad Institute of MIT and Harvard. He earned his medical degree and a doctorate in bio-

Howard Y. Chang, MD, PhD

Daniel Durocher, PhD

Each will receive an award of $50,000 and speak about his research at a scientific symposium on December 3, 2015.

The award was created to honor Paul Marks, MD, President Emeritus of MSKCC, for his contributions as a scientist, teacher, and leader during the 19 years he led the organization.

“The Marks Prize was established to recognize the young scientists whose work is improving the understanding of cancer across many different fields in biological research,” said Craig B. Thompson, MD, MSKCC President and CEO. “Because mentoring young talent was so important to Dr. Marks, the MSKCC Board felt this prize

chemistry from the University of Washington School of Medicine.

Dr. Bernstein’s research is focused on epigenetics. Specifically, his laboratory studies how the protein scaffold called chromatin packages long strands of DNA in the nucleus of each cell and how this packaging influences both normal development and cancer.

His discoveries have implications for understanding many types of cancer— brain tumors and leukemia, in particular.

One of Dr. Bernstein’s goals is to translate the laboratory tools he’s developed into diagnostics that characterize a patient’s tumor at the molecular level.

“The idea is to ensure that patients re-

Nivolumab With Ipilimumab

adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, and hypothyroidism and hyperthyroidism, and embryofetal toxicity.

Patients should be monitored for liver, kidney, and thyroid function. Breastfeeding women should discontinue breastfeeding.

Other causes should be excluded for suspected immune-mediated adverse reactions. Based on the severity of the adverse reaction, nivolumab should be withheld or discontinued, and highdose corticosteroids and, if appropriate, thyroid hormone replacement should be given. Upon improvement of adverse reactions to no worse than grade 1, corticosteroid taper should

continued from page 64

continuation were colitis (16% vs 2%), diarrhea not treated with corticosteroids (4% vs 4%), increased ALT (4% vs 0%), pneumonitis (3% vs 0%), and increased AST (3% vs 0%).

Among immune-related adverse events in the combination group, pneumonitis occurred in 6% of patients, colitis in 33%, hepatitis in 15%, hypophysitis in 13%, adrenal insufficiency in 9%, hypothyroidism in 19%, hyperthyroidism in 2.1%, nephritis or renal dysfunction in 2.1%, and rash in 37%. Guillain-Barré syndrome and hypopituitarism were observed in 1%.

Nivolumab carries warnings/ precautions for immune-mediated

ceive a drug regimen that eliminates all of the different types of cells in their tumor,” Dr. Bernstein said.

Howard Y. Chang, MD, PhD Dr. Chang is a Professor of Dermatology at Stanford University and a faculty member of its Cancer Biology and Epithelial Biology Programs. He is also Director of the Center for Personal Dynamic Regulomes. He earned his doctorate degree in biology from the Massachusetts Institute of Technology and his medical degree from Harvard Medical School.

His laboratory studies how cells know where they’re located in the body. In his recent work, Dr. Chang discovered that genetic material called long noncoding RNAs (lncRNAs) helps cells sense where they are. These lncRNAs are part of what is sometimes called the “dark matter” of the genome—the 98% of genetic material that does not encode for proteins.

One of the first lncRNAs he discovered is called HOTAIR, which he found could be used to predict whether breast cancer will spread. “If a woman’s breast cancer has high levels of HOTAIR, she is two to three times more likely to die of the disease,” Dr. Chang said. Many lncRNAs are now known to be intimately involved in many types of cancer, and the U.S. Food and Drug Administration has approved diagnostic tests to measure lncRNAs for certain forms of the disease.

Daniel Durocher, PhD Dr. Durocher is Assistant Director of the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health System, be started and continued over at least 1 month. Restarting of nivolumab can be considered after completion of the corticosteroid taper. n References 1. U.S. Food and Drug Administration: Nivolumab in combination with ipilimumab. Available at www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm465274.htm. Accessed October 7, 2015.

2. Opdivo (nivolumab) injection for intravenous use prescribing information, Bristol-Myers Squibb Company, September 2015. Available at www.accessdata.fda.gov/dr ugsatfda_docs/ label/2015/125554s002lbl.pdf. Accessed October 7, 2015.

3. Postow MA, Chesney J, Pavlick AC,

and Professor of Molecular Genetics at the University of Toronto. He earned his doctorate degree in experimental medicine at McGill University.

He is being recognized for his research on how cells maintain the integrity of their genomes and especially how they deal with a particular type of damage called the DNA double-strand break.

DNA double-strand breaks can be caused by phenomena like ionizing radiation and exposure to certain chemicals, but they can also occur when cells undergo regular division. Dr. Durocher’s work is focused on two different aspects of this biologic problem. “One question is how cells repair double-strand breaks,” he explained.

“The other is how cells respond when a break is detected. It turns out they send out a signal to coordinate the repair.”

Much of his recent research has focused on how the BRCA1 protein helps cells respond to DNA damage, since BRCA1 is a tumor suppressor.

“We’re trying to understand how this damage response is controlled,” Dr. Durocher explains. “For example, women with BRCA1 mutations with ovarian cancer respond very well at first to chemotherapy with platinum-based drugs, but then they develop resistance. Resistance can develop because cells reorganize how they deal with double-strand breaks. We hope that by understanding this control mechanism, we’ll be able to develop ways to intervene in the future.”

His laboratory is also looking at ways to apply laboratory techniques such as RNA interference and genome editing to better understand the response to DNA breaks. n et al: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006-2017, 2015.

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

The ASCO Post | OCTOBER 25, 2015

PAGE 66

FDA Update

FDA Approves Use of Nivolumab in Metastatic Nonsquamous Lung Cancer

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he U.S. Food and Drug Administration (FDA) has approved nivolumab (Opdivo) to treat patients with metastatic nonsquamous non– small cell lung cancer (NSCLC) whose disease progressed during or after platinum-based chemotherapy. Nivolumab is a monoclonal antibody that that blocks the PD-1/PD-L1 [programmed cell death protein 1 and its ligand] cellular pathway.

The FDA approved nivolumab earlier this year to treat patients with advanced squamous NSCLC whose disease progressed during or after platinum-based chemotherapy.

Clinical Trial Results The safety and effectiveness of nivolumab for this indication were demonstrated in an international, open-label, randomized study of 582 participants with advanced NSCLC whose disease progressed during or after treatment with platinum-based chemotherapy and appropriate biologic therapy.1 Participants were treated with nivolumab or docetaxel.

The primary endpoint was overall survival, and the secondary endpoint was objective response rate. Those treated with nivolumab lived an average of 12.2 months compared with 9.4 months in those treated with docetaxel. Additionally, 19% of those treated with nivolumab experienced complete or partial shrinkage of their tumors, an effect that lasted an average of 17 months, compared with 12% among those taking docetaxel, which lasted an average of 6 months.

While patients who received ni­volumab lived longer than those who received docetaxel across the study, an evaluation of samples from a subgroup of patients’ tumors suggested that the level of PD-L1 expression in NSCLC tumors may help identify patients who are more likely to live longer due to treatment with nivolumab.

Therefore, the FDA also approved the PD-L1 IHC 28-8 pharmDx test to detect PD-L1 protein expression levels and help physicians determine which patients may benefit most from nivolumab treatment.

Safety Profile The most common side effects of nivolumab are fatigue, musculoskeletal pain, decreased appetite, cough and constipation. Nivolumab also has the potential to cause severe immune-

mediated side effects.

The FDA granted nivolumab Breakthrough Therapy designation for this indication based on preliminary clinical evidence that suggested nivolumab may offer a substantial improvement over available therapies. It also re-

ceived Priority Review status.

The approval of nivolumab occurred approximately 3 months ahead of the prescription drug user fee goal date of January 2, 2016, the date when the agency was scheduled to complete its review of the application. n

Reference 1. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in advanced nonsquamous non–smallcell lung cancer. N Engl J Med. September 27, 2015 (early release online).

ASCOPost.com | OCTOBER 25, 2015

PAGE 67

FDA Update

FDA Grants Orphan Drug Designation to Bivalent Vaccine for Neuroblastoma

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he U.S. Food and Drug Administration (FDA) has granted orphan drug designation to MabVax Therapeutics’ vaccine for the treatment of relapsed or recurrent high-risk neuroblastoma in remission or with limited residual disease after best available treatment. The

bivalent vaccine is intended to elicit a targeted immune response against the two most common antigens on neuroblastoma cells, GD2 and GD3.

Results of a recent phase I trial published in Clinical Cancer Research showed encouraging outcomes with

the vaccine in a small cohort of patients with relapsed neuroblastoma.1 Antibody responses against GD2 and/ or GD3 were seen in 12 of 15 patients, and disappearance of minimal residual disease was documented in 6 of 10 patients assessable for response. n

Reference 1. Kushner BH, Cheung IY, Modak S, et al: Phase I trial of a bivalent gangliosides vaccine in combination with β-glucan for high-risk neuroblastoma in second or later remission. Clin Cancer Res 20:1375-1382, 2014.

The ASCO Post | OCTOBER 25, 2015

PAGE 68

FDA Update

FDA Grants Accelerated Approval to Pembrolizumab for Advanced NSCLC

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he U.S. Food and Drug Administration (FDA) has granted accelerated approval for pembrolizumab (Keytruda) to treat patients with metastatic non–small cell lung cancer (NSCLC) whose disease has progressed after other treatments and with tumors that express

programmed cell death-ligand 1 (PDL1). Pembrolizumab is approved for use with a companion diagnostic, the PDL1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 expression in non–small cell lung tumors.

Pembrolizumab works by targeting the

cellular pathway PD-1/PD-L1. By blocking this pathway, it may help the body’s immune system fight the cancer cells.

In 2014, pembrolizumab was approved to treat patients with advanced melanoma following treatment with ipilimumab (Yervoy). Another drug,

nivolumab (Opdivo), also targets the PD-1/PD-L1 pathway and was approved to treat squamous NSCLC in 2015.

Study Details The safety of pembrolizumab was studied in 550 patients with advanced NSCLC. The most common side effects of pembrolizumab included fatigue, decreased appetite, dyspnea, and cough. Pembrolizumab also has the potential to cause severe immune-mediated side effects.

The effectiveness of pembrolizumab for this use was demonstrated in a subgroup of 61 patients enrolled within a larger multicenter, open-label, multipart study. The subgroup consisted of patients with advanced NSCLC that progressed following platinum-based chemotherapy or, if appropriate, tar-

geted therapy for certain genetic mutations (ALK or EGFR). This subgroup also had PD-L1–positive tumors based on the results of the 22C3 pharmDx diagnostic test. Study participants received 10 mg/kg of pembrolizumab every 2 or 3 weeks.

The major outcome measure was overall response rate. Tumors shrank in 41% of patients treated with pembrolizumab, and the effect lasted between 2.1 and 9.1 months.

In the 550 study participants with advanced NSCLC, severe immune-mediated side effects occurred involving the lungs, colon, and hormone-producing glands.

Other uncommon immune-mediated side effects were rash and vasculitis. Women who are pregnant or breastfeeding should not take pembrolizumab because it may cause harm to a developing fetus or newborn baby. Across clinical studies, GuillainBarré syndrome has also occurred.

Pembrolizumab also received priority review status and was approved under the Agency’s accelerated approval program. An improvement in survival or disease-related symptoms in patients being treated with pembrolizumab has not yet been established. n Reference 1. Soria JC, et al: Efficacy and safety of pembrolizumab for patients with previously treated advanced non–small cell lung cancer enrolled in KEYNOTE-001.

2015 European Cancer Congress. Abstract 33LBA. Presented September 28, 2015.

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PAGE 69

In the Clinic Thoracic Oncology

Pembrolizumab in Previously Treated PD-L1–Positive Metastatic NSCLC

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

O

n October 2, 2015, the U.S. Food and Drug Administration granted pembrolizumab (Keytruda) accelerated approval for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) with progression on or after platinum-containing therapy and with tumors expressing programmed cell death ligand 1 (PD-L1).1 Initially indicated for the treatment of metastatic melanoma, pembrolizumab is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test (Dako), which is designed to detect PD-L1 expression in NSCLC. Patients with EGFR or ALK tumor aberrations should have disease progression on approved therapy for these aberrations prior to receiving pembrolizumab treatment.

Supporting Efficacy Data Approval was based on objective response rate in a subgroup of 61 patients, from a larger multicenter open-label multicohort study (N = 550), who had advanced NSCLC progressing after platinum-based chemotherapy and, if appropriate, targeted therapy for ALK or EGFR aberrations and who had PD-L1–positive tumors (≥ 50% tumor cells) based on the results of the 22C3 pharmDx diagnostic

OF NOTE Pembrolizumab is an anti–PD-1 monoclonal antibody that blocks the interaction of the PD-1 receptor with PD-L1 and PD-L2 ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response.

test.2 This group received pembrolizumab at 10 mg/kg every 2 (n = 27) or 3 (n = 34) weeks until unacceptable toxicity or disease progression.

Patients had a median age of 60 years (34% ≥ 65 years), 61% were male, 79% were white, 34% and 64% had Eastern Cooperative Oncology Group performance status of 0 and 1, 21% had squamous and 75% nonsquamous histology, 98% had M1 disease, 11% had brain me-

tastases, 10% had EGFR aberrations and 0% had ALK aberrations, and the number of prior therapies was one in 26%, two in 30%, and at least three in 44%.

Response rates and duration of response were similar with every-2-week and every-3-week dosing. On independent review, the overall objective response rate was 41% (95% confidence interval = 29%–54%, all partial responses). Median response duration had not been reached at last analysis. Among the 25 patients with response, 21 patients (84%) had an ongoing response at the last analysis, with 11 (44%) having an ongoing response of at least 6 months.

How It Works Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Pembrolizumab is an anti–programmed cell death (PD-1) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and

OF NOTE Pembrolizumab carries warnings/ precautions for immune-mediated adverse reactions, infusion-related reactions, and embryofetal toxicity.

total bilirubin > 1.5 to 3 times the upper limit of normal, and any other severe or grade 3 treatment-related adverse reaction.

Treatment can be resumed when adverse reactions recover to grade 0 or 1.

Pembrolizumab should be permanently discontinued for any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy), grade 3 or 4 pneumonitis or recurrent grade 2 pneumonitis, grade 3 or 4 nephritis, AST or ALT > 5 times normal or total bilirubin > 3 times normal, AST or ALT increases of ≥ 50% in patients with liver metastasis who began treatment with grade 2 increased AST or ALT, grade 3 or 4 infusion-related reactions, inability to

Expanded Indication for Pembrolizumab ■■ Pembrolizumab (Keytruda) is now approved for the treatment of patients with metastatic non–small cell lung cancer with progression on or after platinum-containing therapy and with tumors expressing PD-L1.

■■ The recommended dose of pembrolizumab is 2 mg/kg via intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

PD-L2 ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response.

Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.

How It Is Used The recommended dose of pembrolizumab is 2 mg/kg via intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Pembrolizumab infusion should be stopped and treatment permanently discontinued for grade 3 or 4 infusion-related reactions. Treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, grade 3 or 4 endocrinopathies, grade 2 nephritis, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 to 5 times the upper limit of normal or

reduce corticosteroid dose to ≥ 10 mg/d of prednisone or the equivalent within 12 weeks, persistent grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) that do not recover to grade 0 or 1 within 12 weeks of the last dose, and any recurrent severe or grade 3 treatment-related adverse reaction.

No dose adjustment is needed for patients with renal impairment. No dose adjustment is needed for patients with mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment

Safety Profile Among the 550 patients with metastatic NSCLC in the large open-label trial receiving nivolumab (Opdivo) at 2 mg/kg every 3 weeks (n = 61) or 10 mg/kg every 2 or 3 weeks (n = 489), the most common adverse events of any grade were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%). The most common grade 3 adverse events were fa-

tigue (4%) and dyspnea (4%).

The most common laboratory abnormalities of any grade were hyperglycemia (48%), hyponatremia (38%), anemia (36%), and hypoalbuminemia (32%); the most common grade 3 or 4 events were hyponatremia (6%) and hyperglycemia (3%). The incidence of adverse events and serious adverse events were similar with the every-2-week and every3-week 10 mg/kg schedules.

Serious adverse events occurred in 38% of patients, with the most common occurring in ≥ 2% of patients being pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Treatment was discontinued due to adverse events in 14% of patients.

Among immune-related adverse events, pneumonitis occurred in 3.5% of patients, colitis in 0.7%, hypophysitis in 0.2%, hyperthyroidism in 1.8%, and hypothyroidism in 6.9%. Rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis were each observed in < 1%.

Pembrolizumab carries warnings/precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, and type I diabetes), and nephritis, infusion-related reactions, and embryofetal toxicity. Hepatic, renal, and thyroid function should be routinely monitored. Breastfeeding women should discontinue breastfeeding.

Other causes should be excluded for suspected immune-mediated adverse reactions. Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroid treatment started. Upon improvement of adverse reactions to no worse grade 1 or less, corticosteroid taper should be started and continued over at least 1 month. Pembrolizumab can be resumed when the adverse reaction remains no greater than grade 1 after steroid taper. n References 1. U.S. Food and Drug Administration: Pembrolizumab injection. Available at www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm465650.htm.

Accessed October 7, 2015.

2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck Sharp & Dohme Corp, October 2015.

Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s005lbl.pdf.

Accessed October 7, 2015.

The ASCO Post | OCTOBER 25, 2015

PAGE 70

Journal Spotlight Thoracic Oncology

Addition of Necitumumab to First-Line Gemcitabine/Cisplatin Improves Overall Survival in Stage IV Squamous NSCLC

By Matthew Stenger

I

n the phase III SQUIRE trial reported in The Lancet Oncology, Nick Thatcher, PhD, FRCP, of The Christie Hospital NHS Trust, Manchester, UK, and colleagues found that the addition of the second-generation epidermal growth factor receptor (EGFR) antibody necitumumab to first-line gemcitabine/cisplatin improved overall survival among patients with stage IV squamous non–small cell lung cancer (NSCLC).1

Study Details In this open-label trial, 1,093 patients from 26 countries were randomly assigned between January 2010 and February 2012 to receive gemcitabine/ cisplatin with (n = 545) or without (n = 548) necitumumab. Necitumumab (800 mg intravenously) was given on days 1 and 8 of 3-week cycles and continued after the end of chemotherapy until disease progression or intolerable toxicity. Gemcitabine (1,250 mg/m²) was given on days 1 and 8 and cisplatin (75 mg/m²) was given on day 1 of 3-week cycles.

Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status and geographic region. The primary endpoint was overall survival in an intent-to-treat analysis.

The necitumumab and control groups were generally balanced for age (median, 62 years in both; 19% and 20% 65–69 years, 20% and 18% ≥ 70 years), sex (83% and 84%), ECOG performance status (0 for 30% and 33%, 1 for 61% and 58%, 2 for 9% in both), race/ethnicity (84% and 83% white, 8% Asian in both), geographic region (North America, Europe, or Australia for 87% in both, South America, South Africa, or India for 6% in both, Eastern Asia for 8% and 7%), smoking history (92% and 90% current smokers), meta-

static disease involving more than two organ systems (55% in both), metastatic disease sites (eg, lung in 83% in both, lymph nodes in 79% and 82%, bone in 22% and 24%), and previous therapies (surgery in 21% and 19%, radiotherapy in 8% in both, adjuvant/neoadjuvant systemic therapy in 4% and 3%).

Increased Overall Survival The median number of gemcitabine/cisplatin cycles was six in the necitumumab group and five in the control group. Median follow-up was 25.2 months in the necitumumab group and 24.8 months in the control group.

New Data for Necitumumab in Lung Cancer ■■ The addition of necitumumab to gemcitabine/cisplatin improved overall survival.

■■ Significant prolongation of progression-free survival was also observed.

0.90, 95% CI = 0.75–1.07).

Median progression-free survival was 5.7 months (95% CI = 5.6–6.0 months) vs 5.5 months (95% CI = 4.8–5.6 months; stratified HR = 0.85, P = .02), with a benefit of necitumumab being observed in nearly all subgroups. The benefit of necitumumab did not appear to be greater among pa-

[T]he addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease.

—Nick Thatcher, PhD, FRCP, and colleagues

Median overall survival was 11.5 months (95% confidence interval [CI] = 10.4–12.6 months) in the necitumumab group vs 9.9 months (95% CI = 8.9–11.1 months) in the control group (stratified hazard ratio [HR] = 0.84, P = .01). Subgroup analyses showed a benefit of necitumumab in most examined subgroups, with hazard ratios being significant in patients aged 65 to 69 years, men, white patients, and current smokers.

EGFR protein expression level was available for 982 patients. The benefit of necitumumab appeared to be greater among 374 patients with high expression (H-score ≥ 200; HR = 0.75, 95% CI = 0.60–0.94) than among 608 patients with lower expression (HR =

tients with high EGFR protein expression (HR = 0.88, 95% CI = 0.70–1.11) than among those with low expression (HR = 0.83, 95% CI = 0.69–0.99). Objective response was observed in 31% vs 29% of patients, and disease control rates were 82% vs 77% (P = .043).

Poststudy systemic therapy was received by 47% of the necitumumab group and 45% of the control group, with the most common being docetaxel (31% and 23%) and erlotinib (10% and 14%).

Adverse Events Grade ≥ 3 adverse events were more common in the necitumumab group (72% vs 62%). Among adverse

events of interest of grade ≥ 3, the most common were neutropenia (24% vs 28%), anemia (10% vs 10%), thrombocytopenia (10% vs 10%), hypomagnesemia (9% vs 1%), and rash (7% vs < 1%). Venous thromboembolism occurred in 9% vs 5% (grade ≥ 3 in 5% vs 3%). Fatal arterial or venous thromboembolic events occurred in < 1% of both groups.

Serious adverse events occurred in 48% vs 38%. Adverse events led to delay or modification of at least one study drug in 60% vs 58% (due to neutropenia, thrombocytopenia, anemia, or leukopenia in 40% and 42%) and to discontinuation of at least one study drug in 31% vs 25% (most commonly due to neutropenia and thrombocytopenia).

Death considered related to treatment occurred in 3% vs 2% of patients.

The investigators concluded: “Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease.” n

Disclosure: The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Thatcher N, Hirsch FR, Luft AV, et al: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial. Lancet Oncol 16:763-774, 2015.

More on Novel Therapy for Stage IV Squamous NSCLC See page 72 for “Anti-EGFR Therapy in Squamous Cell Lung Carcinoma: Swimming With or Against the Tide?” by Aline Fusco Fares, MD, Daniel Vilarim Araujo, MD, and Natasha B. Leighl, MD.

ASCOPost.com | OCTOBER 25, 2015

PAGE 71

FDA Update

FDA Approves Expanded Indication for Medical Device to Treat Newly Diagnosed Glioblastoma Multiforme

T

he U.S. Food and Drug Administration (FDA) has approved an expanded indication for the Optune tumor-treating fields device to treat patients with newly diagnosed glioblastoma multiforme. It is given along with the chemotherapy drug temozolomide following standard treatments that include surgery, chemotherapy, and radiation therapy.

In the clinical study used to support the expanded indication, patients treated with the device and temozolomide lived on average 3 months longer than those treated with temozolomide alone.

Optune was initially approved in

zolomide group survived for an average of 19.4 months after diagnosis compared with 16.6 months for those who were treated with temozolomide alone.

Optune for newly diagnosed glio-

blastoma multiforme was reviewed under the FDA’s Priority Review program, which provides for an expedited review of certain devices that treat life-threatening conditions.

The most common side effect experienced with the device was skin irritation. Clinical trial participants also experienced a slightly higher incidence of neurologic side effects. n

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 CASES OF PROGRESSION WITH FIRSTGENERATION EGFR TKIs ARE RELATED TO THE T790M MUTATION1,2 Lung cancer is the leading cause of cancer-related deaths both in the US and worldwide.3,4 For NSCLC EGFRm+ patients, the recommended frst-line treatment is EGFR tyrosine kinase inhibitors (TKIs).5

The majority of tumors will acquire EGFR TKI–resistance mutations

T790M Is the Most Common Mechanism of Acquired Resistance to First-Generation EGFR TKI Therapy1

2011 to treat patients with glioblastoma multiforme that recurred or progressed after chemotherapy. With this expanded indication, the device can be used as part of a standard treatment for glioblastoma multiforme before the disease progresses.

For newly diagnosed glioblastoma multiforme, Optune is not intended to be used as a substitute for standard treatments, but rather as an adjunct therapy, and should not be used without a physician’s supervision.

When using the device, a healthcare professional places electrodes on the surface of the patient’s scalp to deliver low-intensity, alternating electrical fields called tumor-treating fields.

The unique shape and special characteristics of rapidly dividing tumor cells make them susceptible to damage when exposed to tumor-treating fields, which could halt tumor growth.

The device is portable and can be powered with batteries or plugged into an electrical outlet. Patients can use the device at home or work, allowing them to continue their normal daily activities.

Despite initial high response rates with frst-generation EGFR TKIs, many tumors will develop new mutations and become resistant.6,7 A major barrier to disease control is resistance to treatment. Resistance to frst-generation therapy will develop in most patients with EGFRm+ advanced NSCLC on a currently approved EGFR TKI.7

Clinical Trial Results

AstraZeneca is a leader in lung cancer research

The FDA based its approval of the expanded indication of the device on results from a clinical trial involving 695 patients newly diagnosed with glioblastoma multiforme that compared those who used Optune with temozolomide with those receiving temozolomide alone.

Patients who used the device along with temozolomide lived, on average, about 7 months with no disease progression compared with 4 months for those who had the drug alone. The Optune-plus-temo-

AstraZeneca is conducting ongoing research to understand the science of the T790M mutation as a driver of resistance.

After disease progression, clinical guidelines recommend subsequent treatments including either continuing with an EGFR TKI therapy or beginning platinum-based chemotherapy.5

Nearly 2 out of 3 cases of progression with first-generation EGFR TKIs are related to the T790M mutation In patients with NSCLC who are EGFRm+, T790M is an acquired mutation and has been identifed as the most common mechanism of acquired resistance in nearly 2 out of 3 patients.1,2 Development of T790M mutation may confer resistance through several potential mechanisms, which may include8,9: - Steric hindrance, which reduces receptor binding of reversible EGFR TKIs - Increased binding affnity of EGFR for ATP, resulting in reduced TKI potency

63%

T790M (98/155)

CI, (9555 –70 ) %

%

MET amplifcation (4/75)

5% (95% CI, 1%–13%)

HER2 amplifcation (3/24)

NEARLY 2 OUT OF 3

%

13% (95% CI, 3%–32%)

0%

10% 20% 30% 40% 50% 60% 70%

Study of 155 patients with radiographic progression following a response or durable stable disease with frst-generation EGFR TKI therapy.

CASES ARE RELATED TO T790M

Other rare mechanisms of acquired resistance may include BRAF, FGFR, and PIK3CA mutations, and transformation to small-cell histology.10,11

Discovering the cause of resistance Patients should be monitored for radiologic or clinical progression. Tumors can also be assessed for molecular progression to uncover additional acquired mutations.1,12-16 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).5

Find out more at EGFRevolution.com.

References: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 2. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. American Cancer Society.

Cancer Facts & Figures 2015. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed March 17, 2015. 4. GLOBOCAN 2012. http://globocan.iarc.fr. Accessed February 9, 2015. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 7. Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334. 8. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to geftinib. N Engl J Med. 2005;352:786-792. 9. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affnity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070-2075. 10. Cheng L, Alexander RE, MacLennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347-369. 11. Ware KE, Marshall ME, Heasley LY, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One. 2010;5:e14117. doi:10.1371/journal.pone.0014117.12. Johnson KR, Ringland C, Stokes BJ, et al. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet. 2006;7:741-746. 13. Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specifc microRNAs. PLoS One. 2012;7:e50141. doi:10.1371/journal.pone.0050141. 14. Jackman DM, Miller VA, Cioffredi, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non–small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009;15:5267-5273. 15. Noronha V, Joshi A, Gokarn A, et al. The importance of brain metastasis in EGFR mutation positive NSCLC patients. Chemother Res Pract. doi:10.1155/2014/856156. 16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. ©2015 AstraZeneca. All rights reserved. 3140404 6/15

The ASCO Post | OCTOBER 25, 2015

PAGE 72

Perspective

Anti-EGFR Therapy in Squamous Cell Lung Carcinoma: Swimming With or Against the Tide?

By Aline Fusco Fares, MD, Daniel Vilarim Araujo, MD, and Natasha B. Leighl, MD

L

ung cancer is the most common, lethal, and costly cancer worldwide, accounting for at least 1.8 million new cases per year (12.9% of the total).1 Over the past decade, there has been a major shift in the treatment of non–small cell lung cancer (NSCLC), especially in adenocarcinoma, accompanied by a better understanding of cancer pathways and identification of highly effective targeted therapies (targeting EGFR mutations and ALK translocations). This has led to significant improvements in patient outcomes with minimal toxicity.

Progress in squamous cell carcinoma of the lungs has lagged behind.

Although molecular alterations have been described, effective targeted therapies have not yet been developed, and platinum-based chemotherapy remains standard as initial therapy in advanced squamous cell carcinoma. However, the recent approval of nivolumab (Opdivo) and pembrolizumab (Keytruda) as second-line therapy in advanced lung carcinoma including squamous cell carcinoma has led to renewed hope for better outcomes in this disease.2

SQUIRE Trial The SQUIRE trial, published in The Lancet Oncology earlier this year by Thatcher et al3 and reviewed in this issue of The ASCO Post, is a phase III, multicenter, open-label, randomized trial examining the impact of adding necitumumab, a second-generation anti-EGFR antibody, to first-line gemcitabine/ cisplatin in advanced squamous cell lung carcinoma patients. Between 2010 and 2012, the trial randomly assigned 1,093 patients and demonstrated improved overall survival with the addition of necitumumab to chemotherapy, with a 1.6-month median increase from 9.9 months to 11.5 months (hazard ratio [HR] = 0.84, P = .01).

The addition of necitumumab to chemotherapy did not meaningfully improve progression-free survival— despite a statistically significant difDr. Fares and Dr. Araujo are in the Department of Medical Oncology at A.C. Camargo Cancer Center, São Paulo, Brazil. Dr. Leighl is in the Division of Medical Oncology at Princess Margaret Cancer Centre, Toronto.

ference (median = 5.7 vs 5.5 months, HR = 0.86, P = .02)—or response rate (31.2% vs 28.8%). Higher tumor EGFR expression (immunohistochemistry H score ≥ 200) did not significantly predict better progression-free survival or overall survival, although there was a trend toward better survival with necitumumab in this subgroup (HR = 0.75, 95% confidence interval [CI] = 0.60–0.94, interaction P value = .235). Half of the study patients had tumor assessment of EGFR copy number by fluorescence in situ hybridization (FISH); those with a high copy number or amplification had a trend toward progression-free survival and overall survival benefit (median overall survival

closed due to an excess of thrombotic events in the necitumumab arm. Survival was similar in both arms, but toxicity was significantly higher with necitumumab, including severe rash, hypomagnesemia, and venous thromboembolic events. High EGFR expression (H score ≥ 200) was neither predictive of necitumumab benefit nor prognostic in INSPIRE.

Addition of Cetuximab Multiple studies have also been conducted with cetuximab, a firstgeneration anti-EGFR antibody, in combination with first-line chemotherapy in NSCLC, with results ranging from negative to modestly positive. FLEX6 is the best-known phase

Both necitumumab and cetuximab give rise to remaining questions about the magnitude and value of their benefit in lung cancer, the role of biomarker selection, and incremental toxicities, including cost.

Perhaps it is time to swim with the tide and await the results of phase III trials of first-line PD-1 checkpoint inhibitors before determining the best place for necitumumab in squamous cell lung carcinoma.

——Aline Fusco Fares, MD, Daniel Vilarim Araujo, MD, and Natasha B. Leighl, MD

= 12.6 vs 9.2 months, HR = 0.70, 95% CI = 0.52–0.96, interaction P value = .066).4 More toxicity was seen in the necitumumab arm—in particular, hypomagnesemia, rash, venous and arterial thromboembolic events, and infusion reactions.

Monoclonal antibodies targeting EGFR are not new to lung cancer. The INSPIRE trial,5 similar to SQUIRE, evaluated necitumumab plus pemetrexed (Alimta)/cisplatin vs pemetrexed/cisplatin alone in advanced nonsquamous lung cancer patients.

After accrual of 633 patients, this study

III trial of this combination, with a median 1.2-month overall survival benefit with cetuximab in an unselected advanced NSCLC population (median = 11.3 vs 10.1 months with chemotherapy alone, HR = 0.87, P = .04). No improvement in progressionfree survival was seen, and toxicity was worse in the cetuximab arm (rash, diarrhea, and febrile neutropenia). In the subgroup of patients with squamous carcinoma (25%), outcomes were similar (median survival gain of 1.3 months, 10.2 vs 8.9 months, HR = 0.80, 95% CI = 0.69–1.0).

In exploratory analyses, high EGFR protein expression (H score ≥ 200) was associated with cetuximab benefit (median survival = 12.0 vs 9.6 months, HR = 0.73, P = .011), whereas no benefit was seen in those with low EGFR expression (interaction P value = .044).7 The benefit appeared even greater in squamous cell carcinoma patients with high EGFR expression (HR = 0.62, 95% CI = 0.43–0.88, 1-year survival of 44% vs 25%). However, those with FISHpositive tumors (ie, EGFR gene amplification or high polysomy) did not derive preferential benefit.8 The phase III BMS-099 study, similar in design to FLEX, did not achieve its primary endpoint of increasing progression-free survival, nor did it show increased overall survival, and biomarker studies were negative.9 A meta-analysis of FLEX, BMS-099, and two smaller trials suggested a minor overall survival gain with cetuximab (median = 10.3 vs 9.4 months, HR = 0.88, P = .009), and a better progression-free survival (median = 4.7 vs 4.5 months, HR = 0.90, P = .045) and response rate (32% vs 24%, odds ratio = 1.46, P < .001).10 Exploratory analysis suggested greater survival benefit in squamous cell lung carcinoma patients, with a hazard ratio of 0.77 (95% CI = 0.64–0.93).

These marginal benefits were not sufficient to convince the medical community that adding anti-EGFR therapy to first-line platinum doublet therapy should be a new standard but raised questions about its utility in subgroups such as squamous cell carcinoma and EGFR-positive tumors. A recent report of the SWOG S0819 study confirmed a lack of benefit from adding cetuximab to firstline therapy in unselected NSCLC patients, with exploratory analyses suggesting greater effect in squamous cell lung carcinoma with FISH-positive tumors (HR = 0.56, 95% CI = 0.37–0.84, P = .006).11

Meaningful Gains Defining clinically meaningful outcomes has become a challenge in oncology, particularly with the evolution of targeted therapies and immune checkpoint inhibitors yielding major improvements in outcomes for

ASCOPost.com | OCTOBER 25, 2015

PAGE 73

Perspective

selected patient populations. Ellis et al12 recently published the perspective of the ASCO Cancer Research Committee, highlighting the importance of raising the bar for oncology clinical trial outcomes in order to achieve meaningful gains in patient care. A relative improvement in median survival of at least 20% was defined as the minimum necessary to define a clinically meaningful improvement in outcome.

For squamous cell carcinoma of the lungs, a minimum improvement of 2.5 to 3 months in median survival was recommended, corresponding to a survival hazard ratio of ≤ 0.80.

Unfortunately, the trend in lung cancer has been the reverse, with a decreasing magnitude of survival gain seen in positive lung cancer trials over time (3.9 months in 1980–1990, 2.5 months in 2001–2010; P = .11).13 Investigators appear progressively less stringent in deeming treatments of value even when the statistically significant advantage achieved is no longer clinically relevant.

Despite this, progress in lung cancer therapy has been a rising tide, with novel targeted therapies and immunotherapy leading to dramatic and durable responses, better quality of life, and even improved survival in selected cases, often with less toxicity than standard chemotherapy. For example, nivolumab as second-line therapy in squamous cell lung carcinoma yielded an absolute median survival improvement of 3.2 months (9.2 vs 6.0 months, HR = 0.59, P < .01), a doubling of response rate (20% vs 9%), and a markedly longer duration of response (median not reached vs 8 months with chemotherapy), with significantly less toxicity and better quality of life compared with docetaxel.2

Remaining Questions Given all the recent progress in lung cancer, should we embrace necitumumab plus platinum-based chemotherapy as the new first-line standard of care for advanced squamous cell lung carcinoma? Does it meet the high bar set by ASCO? Does it yield the dramatic, durable responses of EGFR or ALK tyrosine kinase inhibitors or

programmed cell death protein (PD1) checkpoint inhibitors? Does it yield less toxicity than the current standard and improve quality of life? The answer to these last three questions is no.

And what about financial toxicity? Goldstein and colleagues have recommended pricing in the range of US$500 to US$1,300 per cycle of necitumumab to achieve reasonable cost-effectiveness in today’s economic climate.14 Will necitumumab’s future cost further outweigh its benefit for our patients?

Both necitumumab and cetuximab give rise to remaining questions about the magnitude and value of their benefit in lung cancer, the role of biomarker selection, and incremental toxicities, including cost. Perhaps it is time to swim with the tide and await the results of phase III trials of first-line PD-1 checkpoint inhibitors before determining the best place for necitumumab in squamous cell lung carcinoma. n Disclosure: Drs. Fares, Araujo, and Leighl reported no potential conflicts of interest.

References 1. Ferlay J, Soerjomataram I, Dikshit R, et al: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012.

Int J Cancer 136:E359-E386, 2015.

2. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373:123-135, 2015.

3. Thatcher N, Hirsch FR, Luft AV, et al: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as firstline therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial.

Lancet Oncol 16:763-774, 2015.

4. Hirsch FR, Boyle TA, Thatcher N, et al: EGFR IHC and FISH correlative analyses (SQUIRE trial): Necitumumab + gemcitabine-cisplatin vs. gemcitabine-cisplatin in 1st-line squamous NSCLC. World Conference on Lung Cancer. Abstract ORAL32.05.

Presented September 9, 2015.

5. Paz Ares L, Mezger J, Ciuleanu

TE, et al: Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous nonsmall-cell lung cancer (INSPIRE): An open-label, randomized, controlled phase 3 study. Lancet Oncol 16:328-337, 2012.

6. Pirker R, Pereira JR, Szczesna A, et al: Cetuximab plus chemotherapy in patients with advanced non-smallcell lung cancer (FLEX): An open-label randomised phase III trial. Lancet 373:1525-1531, 2009.

7. Pirker R, Pereira JR, von Pawel J, et al: EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: Analysis of data from the phase 3 FLEX study. Lancet Oncol 13:33-42, 2012.

8. O’Byrne KJ, Gatzemeier U, Bondarenko I, et al: Molecular biomarkers in non-small-cell lung cancer: A retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 12:795-805, 2011.

9. Lynch TJ, Patel T, Dreisbach L, et al: Cetuximab and first-line taxane/ carboplatin chemotherapy in advanced non-small-cell lung cancer: Results of the randomized multicenter phase III trial BMS099. J Clin Oncol 28:911-917, 2010.

10. Pujol JL, Pirker R, Lynch TJ, et al:

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer 83:211-218, 2014.

11. Herbst R, Redman M, Kin ES, et al: A randomized phase III study comparing carboplatin/paclitaxel or carboplatin/paclitaxel/bevacizumab with or without concurrent cetuximab in patients with advanced non-small cell lung cancer (NSCLC): SWOG S0819.

World Conference on Lung Cancer. Abstract PLEN04.01. September 9, 2015.

12. Ellis LM, Bernstein DS, Voest EE, et al: American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol 32:1277-1280, 2014.

13. Sacher AG, Le LW, Leighl NB: Shifting patterns in the interpretation of phase III clinical trial outcomes in advanced non-small-cell lung cancer: The bar is dropping. J Clin Oncol 32:14071411, 2014.

14. Goldstein DA, Chen Q, Ayer T, et al: Necitumumab in metastatic squamous cell lung cancer: Establishing a value-based cost. JAMA Oncol. August 27, 2015 (early release online).

ASCO 2015 Breast Cancer Symposium

ASCO Immediate Past President Peter Paul Yu, MD, FACP, FASCO, presented Matthew J. Ellis, MD, BChir, PhD, with the Gianni Bonadonna Award & Lecture at the ASCO 2015 Breast Cancer Symposium in San Francisco, Saturday, September 26, 2015. Photo by ©ASCO/Scott Morgan.

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The ASCO Post | OCTOBER 25, 2015

PAGE 76

Journal Spotlight Gynecologic Cancer

Addition of Bevacizumab to Standard Chemotherapy Improves Overall Survival Only in High-Risk Ovarian Cancer

By Matthew Stenger

F

inal overall survival results of the phase III ICON7 trial reported in The Lancet Oncology by Amit M. Oza, MD, and colleagues indicate no significant improvement with the addition of bevacizumab (Avastin) to standard chemotherapy in women with newly diagnosed ovarian cancer.1 However, an overall survival benefit of bevacizumab was observed among women with highrisk disease. ICON7 had shown that bevacizumab improved progression-free survival, the primary endpoint, with the largest benefit in high-risk disease.2

Study Details A total of 1,528 women from Europe, Canada, Australia, and New Zealand took part in the open-label ICON7 trial.

They were randomized between December 2006 and February 2009 to receive chemotherapy (n = 764; six 3-weekly cycles of carboplatin AUC [area under the receiver operating characteristic curve] 5 or 6 and paclitaxel 175 mg/m²) or the same regimen plus bevacizumab 7.5 mg/kg every 3 weeks given concurrently and continued with up to 12 additional 3-weekly cycles of maintenance therapy (n = 764). Patients had to have newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, International Federation of Gynecology and Obstetrics (FIGO) 1988 stage IIb to IV or high-risk (grade 3 or clear cell histology) stage I to IIa disease, and have undergone debulking cytoreductive surgery or, in advanced disease, a biopsy with no further surgery planned.

Totals of 254 chemotherapy group patients and 248 bevacizumab group patients were categorized as being at high risk of progression due to stage IV disease, inoperable stage III disease, or suboptimally debulked (> 1 cm) stage III disease.

Overall, patients had a median age of 57 years; 94% had an ECOG performance status of 0 or 1; 89% of those with cancer originating from a single site had cancer of ovarian origin; 69% had serous histology; 11% had FIGO stage III, IIIA, or IIIB disease; and 70% had stage IIIC or IV disease. After primary surgery, 26% of patients had residual disease > 1 cm, 24% had residual disease ≤ 1 cm, and 48% had no visible residual disease.

Overall Survival The median follow-up was 48.9 months. In the primary analysis, the median overall survival was 58.0 months (95% confidence interval [CI] = 52.4–

Bevacizumab and Chemotherapy in Newly Diagnosed Ovarian Cancer ■■ The addition of bevacizumab to chemotherapy did not improve overall survival among all patients with newly diagnosed ovarian cancer, according to the results of the phase III ICON7 trial.

■■ However, a survival benefit (20.0 vs 15.9 months, P = .001) was observed among patients with high-risk disease.

vs 44.6 months, hazard ratio [HR] = 0.99, 95% CI = 0.85–1.14). However, a significant benefit was observed among the 502 patients with poor-prognosis disease (restricted mean survival time = 39.3 vs 34.5 months, HR = 0.78, 95% CI = 0.63–0.97). No difference was ob-

Bevacizumab, added to platinumbased chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poorprognosis patients….

—Amit M. Oza, MD, and colleagues

66.9 months) in the total bevacizumab group vs 58.6 months (95% CI = 53.5– 67.5 months) in the total chemotherapy group (P = 0.85) and 39.7 months vs 30.2 months (P = .003) among the 502 patients with poor-prognosis disease.

However, the results showed evidence of nonproportional hazards for outcome among all patients and among poorprognosis patients (P values for nonproportionality = .02 and .01).

Thus, analysis estimating survival differences during a 5-year period (difference in restricted mean survival time) was used as the primary estimate of effect. On this analysis, no benefit of bevacizumab was observed among all patients (restricted mean survival = 45.5

served among the patients without poorprognosis disease (48.4 vs 49.7 months, HR = 1.14, 95% CI = 0.93–1.40).

29.2 vs 27.7 months, P = .25), although a significant benefit was observed among high-risk patients (20.0 vs 15.9 months, P = .001). That said, Dr. Oza commented to The ASCO Post that in terms of progression-free survival analysis, the initial significant finding should be considered the primary result for consideration.

The investigators concluded: “Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218 and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer.” n

Updated Progression-Free Survival

Disclosure: The study was funded by the National Institute for Health Research through the UK National Cancer Research Network, Medical Research Council, and Roche. For full disclosures of the study authors, visit www. thelancet.com.

In the primary progression-free survival analysis, reported at 759 events, restricted mean progression-free survival was 21.8 months in the bevacizumab group vs 20.3 months in the chemotherapy group (HR = 0.81, P = .004), with an increased benefit observed in the high-risk subgroup (HR = 0.73, P = .002).2 In the current updated analysis, at 1,080 events, there was no longer a significant benefit with bevacizumab (restricted mean progression-free survival =

References 1. Oza AM, Cook AD, Pfisterer J, et al: Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial. Lancet Oncol 16:928-936, 2015.

2. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:24842496, 2011.

Don’t Miss These Important Reports in This Issue of The ASCO Post Cora N. Sternberg, MD, Discusses the CheckMate 025 Trial in Renal Cell Carcinoma see page 4

Enrique Grande, MD, on Everolimus in Neuroendocrine Tumors see page 17

Visit The ASCO Post online at ASCOPost.com

Barrie R. Cassileth, MS, PhD, on Avoiding Bogus Remedies Promoted as Alternative Therapies see page 44

ASCOPost.com | OCTOBER 25, 2015

PAGE 77

Perspective

Bevacizumab in Ovarian Cancer: Results of ICON7

By Maurie Markman, MD

B

ased on preclinical (in vitro and in vivo) data, there is a strong biologic rationale for the addition of an antiangiogenic drug strategy in the treatment of epithelial ovarian cancer.1 Single-agent trials have confirmed both the biologic and clinical activity of bevacizumab (Avastin) in the management of ovarian cancer.2 This experience naturally led to the development and conduct of a number of phase III randomized studies in several clinical settings, examining the potential clinical utility of this agent in combination with chemotherapy.1

viewed in this issue of The ASCO Post—supports this basic conclusion.3 In this large (1,528 patients) international phase III trial examining the addition of bevacizumab to carboplatin plus paclitaxel as primary treatment of ovarian cancer, patients were randomized to receive either chemotherapy alone delivered on an every-3-week schedule or chemotherapy with bevacizumab (delivered during chemotherapy and as a subsequent maintenance strategy).

Although the trial demonstrated a statistically significant improvement

These provocative results suggest the patient population with the most advanced ovarian cancers (as defined in this protocol) may experience the greatest clinical benefit when bevacizumab (or perhaps other antiangiogenic agents) is added to a standard cytotoxic chemotherapy regimen.

—Maurie Markman, MD

The results of these trials exploring the addition of bevacizumab to standard cytotoxic chemotherapy have now been published in the peerreviewed literature.1 Of considerable interest, the universal finding, regardless of the study setting (primary therapy, recurrent platinum-sensitive or -resistant disease), has been that the addition of the antiangiogenic agent resulted in a statistically significant improvement in progressionfree survival, but these studies have failed to demonstrate this strategy leads to longer overall survival.

Closer Look at ICON7 The publication of the overall survival results from the ICON7 study by Oza and colleagues—reDr. Markman is President of the Medicine and Science Unit, Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, and Clinical Professor, Department of Medicine, Drexel University College of Medicine, Philadelphia.

in progression-free survival (median 21.8 months with bevacizumab vs 20.3 months with chemotherapy alone with 759 total events; hazard ratio [HR] = 0.81, P = .004), there was no evident statistically significant impact on overall survival when the entire population entered into the trial was considered (median 58.0 months with bevacizumab vs 58.6 months with chemotherapy only).

However, among a prespecified group of patients (n = 502) defined as being at particularly high risk for progression when they entered the trial (eg, inoperable stage III, unable to be debulked to < 1 cm maximum disease, stage IV disease), an improvement in overall survival was observed with bevacizumab (median 39.7 months vs 30.2 months, P = .003).

In another analysis, the restricted mean survival time in this poor-risk population was 39.3 months vs 34.5 months (HR = 0.78; 95% confidence interval [CI] = 0.63–0.97).

In addition, progression-free survival was prolonged in this subgroup (20.0 months vs 15.9 months, P = .001). There was no difference in overall survival among those without a poor prognosis.

In fact, it should be noted that in the updated analysis involving 1,080 events, in contrast with the initial report on progression-free survival from the trial,4 progression-free survival of the entire population entered into the trial was no longer statistically significant (restricted mean progression-free survival, 29.2 months vs 27.7 months, P = .25), with a statistically defined benefit appearing to be relatively limited to the high-risk patient population.

More About Overall Survival One well-discussed and critical reason other studies have failed to date to confirm an overall survival benefit associated with adding antiangiogenic agents to primary chemotherapy in the management of ovarian cancer is the demonstrated utility of a variety of treatment approaches following the completion of the front-line therapeutic regimen. Such treatment may include the use of this specific class of agents in the second-line (or later) setting or alternative programs.1 The difficulty in demonstrating an improvement in survival in a setting in which it is known there may be extended survival due to both the natural history of a cancer and the availability of clinically active antineoplastic agents has been extensively discussed in the literature.5

Critical Questions Remain These provocative results suggest that the patient population with the most advanced ovarian cancers (as defined in this protocol) may experience the greatest clinical benefit when bevacizumab (or perhaps other antiangiogenic agents) is added to a standard cytotoxic chemotherapy regimen. Support for this hypothesis comes from the suggestion that the most advanced or aggressive ovarian cancers may be the malignancies that are most “driven” by angiogenic factors. Although other clinical data support this concept, it

is premature to draw any definitive conclusions regarding this perspective.

This report by Oza and colleagues adds to the growing body of peer-reviewed literature that has documented the unquestionable clinical utility of antiangiogenic agents in the management of advanced epithelial ovarian cancer.

However, critical questions remain, including further defining the population that is most likely to benefit (to which the results reported in this study are particularly relevant), the establishment of a molecular profile of specific cancers that are likely (or unlikely) to benefit from this strategy, and whether the use of this approach may be beneficial in multiple lines of treatment. It is hoped that future studies of the quality reported by Oza and colleagues will help provide answers to these highly relevant questions. n

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

References 1. Eskander RN, Tewari KS: Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications. Gynecol Oncol 132:496-505, 2014.

2. Cannistra SA, Matulonis UA, Pernon RT, et al: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25:5180-5186, 2007.

3. Oza AM, Cook AD, Pfisterer J, et al: Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial. Lancet Oncol 16:928-936, 2015.

4. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:24842496, 2011.

5. Tate Thigpen J: Contemporary phase III clinical trial endpoints in advanced ovarian cancer: Assessing the pros and cons of objective response rate, progression-free survival, and overall survival. Gynecol Oncol 136:121-129, 2015.

The ASCO Post | OCTOBER 25, 2015

PAGE 78

Announcements

Alexander Eggermont, MD, PhD, to Lead Gustave Roussy for 5 More Years

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lexander Eggermont, MD, PhD, the General Director of Gustave Roussy since 2010, has had his appointment at the Head of the Institute renewed by the French Minister of Health for 5 years, with this term beginning October 1, 2015.

113 million euros were invested to facilitate rapid access to the latest therapeutic developments and to improve the quality of care for our patients,” said Dr. Eggermont.

There are many developments that reflect the success of the Institute’s strategy.

They include the construction of a build-

ing dedicated to molecular medicine; the creation of the Drug Development Department; architectural renovation of the infrastructure of departments; and the purchase of major equipment for surgery, imaging, and radiotherapy. In addition, there has been an amalgama-

tion with the Chevilly-Larue Hospital Centre and the development of partnerships with foreign centers.

Future Plans

B:1

Dr. Eggermont will continue to follow the policies and effect the

Success of 2010–2015 Period The 2010–2015 period was primarily one in which Gustave Roussy made advances in patient care through an ambitious investment program. “We increased our workload by 15% and established more than 440 posts in care and research, while maintaining budgetary balance and improving our financial situation. Almost

(filgrastim-sndz) Subcutaneous or Intravenous Injection 300 mcg/0.5 mL | 480 mcg/0.8 mL

California Agency Invests $20 Million in Clinical Trial for Glioblastoma Vaccine

C

alifornia’s Stem Cell Agency (CIRM) has awarded $19.9 million to ImmunoCellular Therapeutics to carry out a phase III clinical trial in patients with newly diagnosed glioblastoma using an immunotherapeutic ­vaccine.

“This kind of deadly disease is precisely why we created CIRM 2.0, our new approval process to accelerate the development of therapies for patients with unmet medical needs,” said C. Randal Mills, PhD, CIRM’s President and CEO. “People battling glioblastoma cannot afford to wait years for us to agree to fund a treatment when their survival can often be measured in just months. We wanted a process that was more responsive to the needs of patients, and that could help companies like ImmunoCellular get their potentially lifesaving therapies into clinical trials as quickly as possible.”

The ImmunoCellular therapy targets six cell surface proteins that are found on glioblastoma cancer stem cells. The company plans to recruit about 400 patients at 120 clinical trial sites around the United States, Canada, and Europe.

“We share [the Agency’s] commitmenttoadvancingpotentialbreakthrough stem cell–based therapies to patients with unmet medical needs,” said Andrew Gengos, ImmunoCellular President and CEO. “With this important grant [plus other revenue], we are in position to cover the full cost of conducting the trial and ensure high-quality trial execution.” n

Supported by the totality of evidence for biosimilarity and the expertise of Sandoz, a Novartis company1,2 • First FDA-approved biosimilar2 • Approved in Europe in 2009 3 • More than 7.5 million patient-exposure days outside of the US3 • Confirmed biosimilarity to Neupogen® (filgrastim)2,3

PRODUCT ATTRIBUTE

ZARXIO1,4

Neupogen4

Identical routes of administration Identical dosing schedule Identical dosage strengths For the ZARXIO prefilled syringe, direct administration of less than 0.3 mL is not recommended due to potential for dosing errors.

Important Safety Information CONTRAINDICATIONS • ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products.

WARNINGS AND PRECAUTIONS • Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Patients who report left upper abdominal or shoulder pain should be evaluated.

• Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated. Discontinue ZARXIO in patients with ARDS. • Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure.

Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZARXIO in patients with serious allergic reactions.

• Sickle cell crisis, in some cases fatal, has been reported with the use of filgrastim products in patients with sickle cell trait or sickle cell disease.

• Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim.

If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of ZARXIO. • Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim products undergoing peripheral blood progenitor cell (PBPC) collection mobilization.

Hemoptysis resolved with discontinuation of filgrastim. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication.

• Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive appropriate treatment.

• Confirm the diagnosis of severe chronic neutropenia (SCN) before initiating ZARXIO therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also

T:15

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ASCOPost.com | OCTOBER 25, 2015

PAGE 79

Announcements

17”

5.5”

14”

Alexander Eggermont, MD, PhD

changes on which he has already embarked, which are incorporated in the Gustave Roussy 2015–2020 Hospital Plan. They are focused on benefiting patients by investment and support for innovation, underpinned by integrated research. He will guide the development of Cancer Campus and the creation of the

PRECAN platform for preclinical research in ­o ncology.

His objectives also include the implementation of a robust scientific strategy; the development of the relationship with the Paris-Sud University and the future Paris-Saclay (a research-intensive and business cluster currently under construction

south of Paris); to establish a Department of Oncology within the Faculty of Medicine; and the strengthening of international links through the Cancer Core Europe consortium. Dr. Eggermont also wishes to contribute to plans for establishments abroad (in the Middle East and Eurasia, among others). n

ZARXIO™ shares the following 5 indications with Neupogen® (filgrastim)1,4 1

Patients with Cancer Receiving Myelosuppressive Chemotherapy ZARXIO is indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.

2

Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy ZARXIO is indicated to reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).

3

Patients with Cancer Undergoing Bone Marrow Transplantation ZARXIO is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.

4

Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy ZARXIO is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

5

Patients with Severe Chronic Neutropenia ZARXIO is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g., fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.

Important Safety Information (cont’d) • The safety and efficacy of ZARXIO given simultaneously with cytotoxic chemotherapy have not been established. Do not use ZARXIO in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. The safety and efficacy of ZARXIO have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of ZARXIO with chemotherapy and radiation therapy.

• Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes on nuclear imaging.

References: 1. Zarxio Prescribing Information. Sandoz, Inc. August 2015.

2. Data on file. Sandoz Inc, Princeton, NJ. 3. US Food and Drug Administration.

Christi L. Overview of the regulatory pathway and FDA’s guidance for the development and approval of biosimilar products in the US (approved in European Union under the trade name Zarzio). 4. Neupogen® Prescribing Information. Amgen, Inc. July 2015.

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

ZARXIO is a trademark of Novartis AG. Neupogen is a registered trademark of Amgen Inc. © 2015 Sandoz Inc. All Rights Reserved.

ZARX 0045

09/2015

T:10.5”

Please see the Brief Summary on the following pages.

B:11.25”

ADVERSE REACTIONS Most common adverse reactions in patients: • With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥5% difference in incidence compared to placebo) are thrombocytopenia, nausea, pyrexia, chest pain, pain, fatigue, back pain, arthralgia, bone pain, pain in extremity, dizziness, cough, dyspnea, rash, blood lactate dehydrogenase increased and blood alkaline phosphatase increased • With AML (≥2% difference in incidence) are epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular • With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥5% difference in incidence) are rash and hypersensitivity • Undergoing peripheral blood progenitor cell mobilization and collection (≥5% incidence) are bone pain, pyrexia, blood alkaline phosphatase increased and headache • With severe chronic neutropenia (SCN) (≥5% difference in incidence) are arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, urinary tract infection, epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia

S:10”

been observed in patients treated with filgrastim products for SCN. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia.

The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered.

• Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

• Leukocytosis: • Patients with Cancer Receiving Myelosuppressive Chemotherapy: White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving ZARXIO as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that ZARXIO therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred.

Monitor CBCs at least twice weekly during therapy.

• Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: During the period of administration of ZARXIO for PBPC mobilization in patients with cancer, discontinue ZARXIO if the leukocyte count rises to >100,000/mm3.

• Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold ZARXIO therapy in patients with cutaneous vasculitis. ZARXIO may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

• The possibility that filgrastim acts as a growth factor for any tumor type cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When ZARXIO is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. Available data is limited and inconclusive.

The ASCO Post | OCTOBER 25, 2015

PAGE 80

Announcements

Cancer Researchers Receive the Nobel Prize in Chemistry 2015

T

he Nobel Prize in Chemistry 2015 recipients were recently announced. They are Tomas Lindahl, PhD, Paul Modrich, PhD, and Aziz Sancar, PhD, for having mapped, at a molecular level, how cells repair damaged DNA and safeguard the genetic

information. Their work has provided fundamental knowledge of how living cells function and is used for the development of new cancer treatments.

Each day, ultraviolet (UV) radiation, free radicals, and other carcinogenic substances damage our DNA, but

even without such external attacks, a DNA molecule is inherently unstable.

Thousands of spontaneous changes to T:7.75”on a daily basis. a cell’s genome occur S:7” when DNA is Defects can also arise copied during cell division, a process that occurs several million times every

ZARXIOTM (filgrastim-sndz) BRIEF SUMMARY OF PRESCRIBING INFORMATION DOSAGE AND ADMINISTRATION Dosage in Patients with Cancer Receiving Myelosuppressive Chemotherapy or Induction and/or Consolidation Chemotherapy for AML The recommended starting dosage of ZARXIO is 5 mcg/kg/day‚ administered as a single daily injection by subcutaneous injection‚ by short intravenous infusion (15 to 30 minutes)‚ or by continuous intravenous infusion. Obtain a complete blood count (CBC) and platelet count before instituting ZARXIO therapy and monitor twice weekly during therapy. Consider dose escalation in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the absolute neutrophil count (ANC) nadir.

Recommend stopping ZARXIO if the ANC increases beyond 10‚000/mm3 [see Warnings and Precautions].

Administer ZARXIO at least 24 hours after cytotoxic chemotherapy. Do not administer ZARXIO within the 24-hour period prior to chemotherapy [see Warnings and Precautions]. A transient increase in neutrophil count is typically seen 1 to 2 days after initiation of ZARXIO therapy. Therefore, to ensure a sustained therapeutic response‚ administer ZARXIO daily for up to 2 weeks or until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. The duration of ZARXIO therapy needed to attenuate chemotherapyinduced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed.

ZARXIO prefilled syringe with BD UltraSafe Passive® Needle Guard is not designed to allow for direct administration of doses of less than 0.3 mL (180 mcg). The springmechanism of the needle guard apparatus affixed to the prefilled syringe interferes with the visibility of the graduation markings on the syringe barrel corresponding to 0.1mL and 0.2 mL. The visibility of these markings is necessary to accurately measure doses of ZARXIO less than 0.3 mL (180 mcg) for direct administration to patients. Thus, the direct administration to patients requiring doses of less than 0.3 mL (180 mcg) is not recommended due to the potential for dosing errors.

ZARXIO is supplied in single-dose prefilled syringes (for subcutaneous use) [see Dosage Forms and Strengths]. Prior to use‚ remove the prefilled syringe from the refrigerator and allow ZARXIO to reach room temperature for a minimum of 30 minutes and a maximum of 24 hours. Discard any prefilled syringe left at room temperature for greater than 24 hours. Visually inspect ZARXIO for particulate matter and discoloration prior to administration (the solution is clear and colorless to slightly yellowish). Do not administer ZARXIO if particulates or discoloration are observed.

Discard unused portion of ZARXIO in prefilled syringes. Do not save unused drug for later administration.

Administration Instructions for the Prefilled Syringe Persons with latex allergies should not administer the ZARXIO prefilled syringe, because the needle cap contains natural rubber latex (derived from latex).

Dilution If required for intraveneous administration, ZARXIO may be diluted in 5% Dextrose Injection, USP to concentrations between 5 mcg/mL and 15 mcg/ml. ZARXIO diluted to concentrations from 5 mcg/mL to 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% Dextrose Injection, USP, or 5% Dextrose plus Albumin (Human)‚ ZARXIO is compatible with glass, polyvinylchloride, polyolefin, and polypropylene.

Do not dilute with saline at any time, because the product may precipitate.

Diluted ZARXIO solution can be stored at room temperature for up to 24 hours. This 24 hour time period includes the time during room temperature storage of the infusion solution and the duration of the infusion.

CONTRAINDICATIONS ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture.

Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue ZARXIO in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure.

Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZARXIO in patients with serious allergic reactions. ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products.

day in the human body. The reason our genetic material does not disintegrate into complete chemical chaos is that a host of molecular systems continuously monitor and repair DNA. The Nobel Prize in Chemistry 2015 awards these three pioneering scientists, who have

Sickle Cell Disorders Sickle cell crisis, in some cases fatal, has been reported with the use of filgrastim products in patients with sickle cell trait or sickle cell disease.

Glomerulonephritis Glomerulonephritis has occurred in patients receiving filgrastim. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim. If glomerulonephritis is suspected, evaluate for cause.

If causality is likely, consider dose-reduction or interruption of ZARXIO. Alveolar Hemorrhage and Hemoptysis Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim products undergoing peripheral blood progenitor cell (PBPC) collection mobilization. Hemoptysis resolved with discontinuation of filgrastim. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication.

Capillary Leak Syndrome Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

Patients with Severe Chronic Neutropenia Confirm the diagnosis of SCN before initiating ZARXIO therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy.

Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim products for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered.

Thrombocytopenia Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

Leukocytosis Patients with Cancer Receiving Myelosuppressive Chemotherapy White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving ZARXIO as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that ZARXIO therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapyinduced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy [see Warnings and Precautions]. Dosages of ZARXIO that increase the ANC beyond 10‚000/mm3 may not result in any additional clinical benefit. In patients with cancer receiving myelosuppressive chemotherapy‚ discontinuation of filgrastim therapy usually resulted in a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days.

Peripheral Blood Progenitor Cell Collection and Therapy During the period of administration of ZARXIO for PBPC mobilization in patients with cancer, discontinue ZARXIO if the leukocyte count rises to > 100,000/mm3.

Cutaneous Vasculitis Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold ZARXIO therapy in patients with cutaneous vasculitis. ZARXIO may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

Potential Effect on Malignant Cells ZARXIO is a growth factor that primarily stimulates neutrophils. The granulocyte-colony stimulating factor (G-CSF) receptor through which ZARXIO acts has also been found on tumor cell lines. The possibility that ZARXIO acts as a growth factor for any tumor type cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When ZARXIO is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied‚ and the limited data available are inconclusive.

Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended The safety and efficacy of ZARXIO given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use ZARXIO in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy [see Dosage and Administration].

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Announcements

mapped how several of these repair systems function at a detailed molecular level.

Exceptional Findings In the early 1970s, scientists believed that DNA was an extremely stable molecule, but Dr. Lindahl demonstrated that DNA decays at a rate that ought to

T:7.75” S:7”

Filgrastim (N = 294)

Placebo (N = 157)

Blood and lymphatic system disorders Thrombocytopenia

43%

32%

General disorders and administration site conditions Pyrexia

48%

29%

Chest pain

13%

6%

Pain

12%

6%

Fatigue

20%

10%

Musculoskeletal and connective tissue disorders

asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite, oropharyngeal pain, and alopecia.

Adverse Reactions in Patients with Acute Myeloid Leukemia Adverse reaction data below are from a randomized, double-blind, placebo-controlled study in patients with AML (Study 4) who received an induction chemotherapy regimen of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5 and up to 3 additional courses of therapy (induction 2, and consolidation 1, 2) of intravenous daunorubicin, cytosine arabinoside, and etoposide.

The safety population included 518 patients randomized to receive either 5 mcg/kg/day filgrastim (n = 257) or placebo (n = 261). The median age was 54 (range 16 to 89) years and 54% were male.

Adverse reactions with ≥ 2% higher incidence in filgrastim patients compared to placebo included epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular.

Adverse events with ≥ 2% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy included diarrhea, constipation, and transfusion reaction.

Adverse Reactions in Patients with Cancer Undergoing Bone Marrow Transplantation The following adverse reaction data are from one randomized, no treatment-controlled study in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving high-dose chemotherapy (cyclophosphamide or cytarabine, and melphalan) and total body irradiation (Study 5) and one randomized, no treatment controlled study in patients with Hodgkin’s disease (HD) and NHL undergoing high-dose chemotherapy and autologous bone marrow transplantation (Study 6). Patients receiving autologous bone marrow transplantation only were included in the analysis. A total of 100 patients received either 30 mcg/kg/day as a 4 hour infusion (Study 5) or 10 mcg/kg/day or 30 mcg/kg/day as a 24 hour infusion (Study 6) filgrastim (n = 72), no treatment control or placebo (n = 28). The median age was 30 (range 15 to 57) years, 57% were male.

Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included rash and hypersensitivity.

Adverse reactions in patients receiving intensive chemotherapy followed by autologous BMT with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included thrombocytopenia, anemia, hypertension, sepsis, bronchitis, and insomnia.

Adverse Reactions in Patients with Cancer Undergoing Autologous Peripheral Blood Progenitor Cell Collection The adverse reaction data in Table 3 are from a series of 7 trials in patients with cancer undergoing mobilization of autologous peripheral blood progenitor cells for collection by leukapheresis. Patients (n = 166) in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 8 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dosage of filgrastim ranged between 5 to 30 mcg/kg/day and was administered subcutaneously by injection or continuous infusion. The median age was 39 (range 15 to 67) years, and 48% were male.

Adverse Reactions in Patients with Cancer Undergoing Autologous PBPC in the Mobilization Phase (≥ 5% Incidence in Filgrastim Patients) System Organ Class Preferred Term

Mobilization Phase (N = 166)

Musculoskeletal and connective tissue disorders

Back pain

15%

8%

Bone pain

Arthralgia

9%

2%

General disorders and administration site conditions

Bone pain

11%

6%

Pyrexia

Pain in extremity*

7%

3%

Investigations

14%

3%

Nervous system disorders Dizziness

Blood alkaline phosphatase increased

Respiratory, thoracic and mediastinal disorders 14%

8%

Dyspnea

13%

8%

Skin and subcutaneous tissue disorders Rash

14%

5%

Blood lactate dehydrogenase increased

6%

1%

Blood alkaline phosphatase increased

6%

1%

Investigations

*Percent difference (Filgrastim – Placebo) was 4%.

Adverse events with ≥ 5% higher incidence in filgrastim patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy delivered included anemia, constipation, diarrhea, oral pain, vomiting,

16% 11%

Nervous system disorders Headache

Cough

30%

10%

Adverse Reactions in Patients with Severe Chronic Neutropenia The following adverse reaction data were identified in a randomized, controlled study in patients with SCN receiving filgrastim (Study 7). 123 patients were randomized to a 4 month observation period followed by subcutaneous filgrastim treatment or immediate subcutaneous filgrastim treatment. The median age was 12 years (range 7 months to 76 years) and 46% were male. The dosage of filgrastim was determined by the category of neutropenia.

Initial dosage of filgrastim: • Idiopathic neutropenia: 3.6 mcg/kg/day • Cyclic neutropenia: 6 mcg/kg/day • Congenital neutropenia: 6 mcg/kg/day divided 2 times per day The dosage was increased incrementally to 12 mcg/kg/day divided 2 times per day if there was no response. Adverse reactions with ≥ 5% higher incidence in filgrastim patients compared to patients receiving no filgrastim included arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, and urinary tract infection (upper respiratory

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29%

continued on page 82

Aziz Sancar, PhD

S:10”

S:10”

T:10.5”

38%

Gastrointestinal disorders Nausea

Paul Modrich, PhD

Tomas Lindahl, PhD

The safety and efficacy of ZARXIO have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of ZARXIO with chemotherapy and radiation therapy.

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

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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy The following adverse reaction data in Table 2 are from three randomized, placebocontrolled studies in patients with: • small cell lung cancer receiving standard dose chemotherapy with cyclophosphamide‚ doxorubicin‚ and etoposide (Study 1) • small cell lung cancer receiving ifosfamide, doxorubicin‚ and etoposide (Study 2), and • non-Hodgkin’s lymphoma (NHL) receiving doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and methotrexate (“ACVBP”) or mitoxantrone, ifosfamide, mitoguazone, teniposide, methotrexate, folinic acid, methylprednisolone, and methotrexate (“VIM3”) (Study 3).

A total of 451 patients were randomized to receive subcutaneous filgrastim 230 mcg/m2 (Study 1), 240 mcg/m2 (Study 2) or 4 or 5 mcg/kg/day (Study 3) (n = 294) or placebo (n = 157). The patients in these studies were median age 61 (range 29 to 78) years and 64% were male. The ethnicity was 95% Caucasian, 4% African American, and 1% Asian.

Adverse Reactions in Patients with Cancer Receiving Myelosuppressive Chemotherapy (With ≥ 5% Higher Incidence in Filgrastim Compared to Placebo) System Organ Class Preferred Term

have made the development of life on Earth impossible. This insight led him to discover molecular machinery, base excision repair, which constantly counteracts the collapse of our DNA. Dr. Lindahl is Emeritus Group Leader at the Francis Crick Institute and Emeritus Director of Cancer Research UK at

The ASCO Post | OCTOBER 25, 2015

PAGE 82

Announcements Nobel Prize in Chemistry continued from page 81

the Clare Hall Laboratory. He received his doctorate from the Karolinska ­Institutet.

Dr. Modrich has demonstrated how the cell corrects errors that occur when DNA is replicated during cell division.

This mechanism, mismatch repair, re-

duces the error frequency during DNA replication by about a thousandfold.

Congenital defects in mismatch repair are known, for example, to cause a hereditary variant of colon cancer.

T:7.75” Dr. Modrich is a Howard Hughes S:7” Institute Investigator and the James B. Duke Professor of Biochemistry at Duke University School of Medicine.

Geriatric Use Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of filgrastim treated-patients receiving myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Clinical studies of filgrastim in other approved indications (i.e., BMT recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects.

OVERDOSAGE The maximum tolerated dose of filgrastim products has not been determined.

In filgrastim clinical trials of patients with cancer receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm3 have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects.

Patients in the BMT studies received up to 138 mcg/kg/day without toxic effects‚ although there was a flattening of the dose response curve above daily doses of greater than 10 mcg/kg/day.

Pharmacokinetics Specific Populations The pharmacokinetics of filgrastim were studied in pediatric patients with advanced neuroblastoma [see Use in Specific Populations], in subjects with renal impairment, and in subjects with hepatic impairment.

Pediatric Patients: The pharmacokinetics of filgrastim in pediatric patients after chemotherapy are similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim products.

Renal Impairment: In a study with healthy volunteers, subjects with moderate renal impairment, and subjects with end stage renal disease (n=4 per group), higher serum concentrations were observed in subjects with end-stage renal disease. However, dose adjustment in patients with renal impairment is not necessary.

Hepatic Impairment: Pharmacokinetics and pharmacodynamics of filgrastim are similar between subjects with hepatic impairment and healthy subjects (n = 12/group). The study included 10 subjects with mild hepatic impairment (Child-Pugh Class A) and 2 subjects with moderate hepatic impairment (Child-Pugh Class B). Therefore, dose adjustment for ZARXIO in patients with hepatic impairment is not necessary.

Michael Reney, MBA, Named CFO at Dana-Farber Cancer Institute

D

ana-Farber Cancer Institute has named Michael Reney, MBA, its Chief Financial Officer (CFO), where he will be responsible for all financial operations, including accounts payable, financial planning and reporting, payroll, capital asset management, tax, and general and patient accounting.

Michael Reney, MBA

“Financial management of health care has become increasingly complex,” said Edward J. Benz, Jr, MD, President and CEO of Dana-Farber. “Michael’s substantial financial experience, both in health-care delivery and in research, as well as his ability to identify business opportunities and develop long-term strategic plans, will make him a critical contributor to the leadership of the Institute.”

Mr. Reney has more than 25 years of experience working in leading Boston hospitals and health-care systems, most recently serving as Senior Vice President and CFO at Brigham and Women’s Health Care (BWHC). He has also served as Assistant Controller at Massachusetts General Hospital, Director of Corporate Accounting and Financial Reporting in the Partners Healthcare System, and Executive Director for Finance/Controller at BWHC. “The opportunity to guide a worldclass leader in cancer care through the new economic reality of health care is exciting to me. I’m passionate about Dana-Farber’s mission and vision,,” said Mr. Reney. n S:10”

ZARXIOTM (filgrastim-sndz) ZARXIO is a trademark of Novartis AG Manufactured by: Sandoz Inc., Princeton, NJ 08540 US License No. 2003 At: GP Grenzach Produktions GmbH Grenzach-Wyhlen, Germany Product of Austria REV 08/2015

sion repair to correct defects caused by mutagenic substances, among other things.

Dr. Sancar is the Sarah Graham Kenan Professor of Biochemistry and Biophysics at the University of North Carolina School of Medicine. He received his doctorate from the University of Texas, Dallas. n

T:10.5”

tract infection and urinary tract infection were higher in the filgrastim arm, total infection related events were lower in filgrastim treated patients), epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia.

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving filgrastim has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to filgrastim, the nature and specificity of these antibodies has not been adequately studied. In clinical studies using filgrastim, the incidence of antibodies binding to filgrastim was 3% (11/333). In these 11 patients, no evidence of a neutralizing response was observed using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, timing of sampling, sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to filgrastim reported in this section with the incidence of antibodies in other studies or to other filgrastim products may be misleading.

Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. The potential risk to the fetus is unknown. Reports in the scientific literature have described transplacental passage of filgrastim products in pregnant women when administered ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation). ZARXIO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of filgrastim on prenatal development have been studied in rats and rabbits.

No malformations were observed in either species. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses. In pregnant rabbits showing signs of maternal toxicity, reduced embryo-fetal survival (at 20 and 80 mcg/kg/day) and increased abortions (at 80 mcg/kg/ day) were observed. In pregnant rats, no maternal or fetal effects were observed at doses up to 575 mcg/kg/day.

Offspring of rats administered filgrastim during the peri-natal and lactation periods exhibited a delay in external differentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival rate (100 mcg/kg/day).

Nursing Mothers It is not known whether filgrastim products are excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised if ZARXIO is administered to women who are breastfeeding.

Pediatric Use ZARXIO prefilled syringe with BD UltraSafe PassiveTM Needle Guard may not accurately measure volumes less than 0.3 mL due to the needle spring mechanism design.

Therefore, the direct administration of a volume less than 0.3 mL is not recommended due to the potential for dosing errors.

In patients with cancer receiving myelosuppressive chemotherapy‚ 15 pediatric patients median age 2.6 (range 1.2 – 9.4) years with neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide) followed by subcutaneous filgrastim at doses of 5, 10, or 15 mcg/kg/day for 10 days (n = 5/dose) (Study 8). The pharmacokinetics of filgrastim in pediatric patients after chemotherapy are similar to those in adults receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim. In this population‚ filgrastim was well tolerated. There was one report of palpable splenomegaly and one report of hepatosplenomegaly associated with filgrastim therapy; however‚ the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.

The safety and effectiveness of filgrastim have been established in pediatric patients with SCN [see Clinical Studies]. In a phase 3 study (Study 7) to assess the safety and efficacy of filgrastim in the treatment of SCN, 123 patients with a median age of 12 years (range 7 months to 76 years) were studied. Of the 123 patients, 12 were infants (7 months to 2 years of age), 49 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 731 patients in the surveillance study, 429 were pediatric patients < 18 years of age (range 0.9 -17) [see Indications and Usage, Dosage and Administration, and Clinical Studies].

Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of filgrastim treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function.

Pediatric patients with congenital types of neutropenia (Kostmann’s syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic filgrastim treatment. The relationship of these events to filgrastim administration is unknown [see Warnings and Precautions, Adverse Reactions].

He received his doctorate from Stanford University.

Dr. Sancar has mapped nucleotide excision repair, the mechanism that cells use to repair UV damage to DNA. People born with defects in this repair system will develop skin cancer if they are exposed to sunlight.

The cell also utilizes nucleotide exci-

ASCOPost.com | OCTOBER 25, 2015

PAGE 83

In the Clinic Gastrointestinal Cancer

Trifluridine/Tipiracil in Previously Treated Metastatic Colorectal Cancer

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

O

n September 22, 2015, trifluridine/tipiracil (Lonsurf) was approved for treatment of patients with metastatic colorectal cancer who have previously received fluoropyrimidine-, oxaliplatin- , and irinotecan-based chemotherapy, an anti-VEGF (vascular endothelial growth factor) biologic product, and an anti-­EGFR (epidermal growth factor receptor) monoclonal antibody if RAS wild-type.1,2

OF NOTE Trifluridine/tipiracil carries warnings/precautions for severe myelosuppression and embryo-fetal toxicity.

Supporting Efficacy Data Approval was based on findings in a double-blind phase III trial in which 800 patients with previously treated metastatic colorectal cancer were randomized 2:1 to receive trifluridine/tipiracil (n = 534) or placebo (n = 266) plus best supportive care.2,3 Patients received trifluridine/tipiracil 35 mg/m2 (based on trifluridine component) or placebo orally twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle until disease progression or unacceptable toxicity. Eligibility requirements included Eastern Cooperative Oncology Group performance status of 0 or 1, absence of brain metastasis, and absence of ascites requiring drainage in the past 4 weeks.

Patients had a median age of 63 years, 61% were male, 58% were white and 35% were Asian, the primary disease site was the colon in 62% and the rectum in 38%, and KRAS status was wild-type in 49% and mutant in 51%. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, all except one received bevacizumab (Avastin), and all except two with KRAS wild-type tumors received panitumumab (Vectibix) or cetuximab (Erbitux).

Median overall survival was 7.1 months (95% confidence interval [CI] = 6.5–7.8 months) in the trifluridine/tipiracil group vs 5.3 months (95% CI = 4.3–

6.0 months) in the placebo group (hazard ratio [HR] = 0.68, P < .001). Progressionfree survival was also significantly prolonged in the trifluridine/tipiracil group (HR = 0.47, P < .001).

How It Works The agent consists of the thymidinebased nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil (molar ratio = 1:0.5; weight ratio = 1:0.471). Tipiracil acts to increase trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. After uptake into cancer cells, trifluridine is incorporated into DNA, interfering with DNA synthesis and inhibiting cell proliferation. Trifluridine/tipiracil exhibited antitumor activity against KRAS wildtype and mutant colorectal cancer xenografts in mice.

How It Is Used The recommended starting dose is 35 mg/m2 up to a maximum of 80 mg per dose (based on the trifluridine component) orally twice daily within 1 hour of completion of morning and evening meals on days 1 through 5 and days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity.

Doses should be rounded to the nearest 5-mg increment.

Complete blood cell counts must be obtained prior to and on day 15 of each cycle. A treatment cycle should not be started until absolute neutrophil count (ANC) is ≥ 1,500/mm3 or febrile neutropenia is resolved, platelet count is ≥ 75,000/mm3, and grade 3 or 4 nonhematologic adverse reactions are resolved to grade 0 or 1. Within a treatment cycle, the drug should be withheld for an ANC < 500/mm3 or febrile neutropenia, platelet count < 50,000/mm3, or grade 3 or 4 nonhematologic adverse reactions.

After recovery, treatment can be resumed after reducing the dose by 5 mg/ m2 per dose from the previous dose level if the patient experiences febrile neutrope-

nia, uncomplicated grade 4 neutropenia or thrombocytopenia that delays the start of the next cycle by > 1 week, or nonhematologic grade 3 or 4 adverse reactions (except for grade 3 nausea and/or vomiting controlled by antiemetic therapy or grade 3 diarrhea responsive to antidiarrheal medication). A maximum of three dose reductions are permitted to a minimum dose of 20 mg/m2 twice daily. The dose should not be increased after it has been reduced.

OF NOTE The thymidine phosphorylase inhibitor tipiracil acts to increase exposure to the thymidine-based nucleoside analog trifluridine by inhibiting its metabolism by thymidine phosphorylase.

Trifluridine and tipiracil are not metabolized by CYP450 enzymes and do not inhibit or induce CYP450 enzymes or inhibit or act as a substrate for uptake and efflux transporters.

No dose modification is recommended in patients with mild hepatic impairment. No patients with moderate or severe impairment were enrolled in the phase III study. No adjustment is recommended for patients with mild or moderate renal impairment.

However, patients in the phase III trial with moderate impairment had a higher rate of grade ≥ 3 adverse events, serious adverse events, and dose delays and reductions compared with patients with normal renal function or mild impairment. Thus, patients with moderate renal impairment may require dose modification for increased toxicity. No patients with severe renal impairment were enrolled in the phase III study.

Safety Profile In the phase III trial, the most common adverse events of any grade occurring > 2% more frequently in the trifluridine/tipiracil

New Secondary Treatment for Metastatic Colorectal Cancer ■■ Trifluridine/tipiracil (Lonsurf) was approved for treatment of patients with metastatic colorectal cancer who have previously received fluoropyrimidine-, oxaliplatin- , and irinotecan-based chemotherapy, an anti-VEGF biologic product, and an anti-EGFR monoclonal antibody if RAS wild-type.

■■ The recommended starting dose is 35 mg/m2 up to a maximum of 80 mg per dose (based on the trifluridine component) orally twice daily within 1 hour of completion of morning and evening meals on days 1 through 5 and days 8 through 12 of each 28-day cycle.

group were anemia (77% vs 33%), neutropenia (67% vs 1%), asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), thrombocytopenia (42% vs 8%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), and abdominal pain (21% vs 18%). The most common grade 3 or 4 adverse events were neutropenia (38% vs 0%), anemia (18% vs 3%), asthenia/fatigue (7% vs 9%), thrombocytopenia (5% vs <1%), and decreased appetite (4% vs 5%). Infections occurred in 27% vs 15% of patients. Pulmonary embolism was observed in 2% vs 0%. Grade 3 or 4 neutropenia and thrombocytopenia and grade 3 anemia were more common in patients aged older than 65 years. As noted, patients with moderate renal impairment had increased rates of adverse events and dose modifications.

Adverse events led to drug discontinuation in 3.6% of trifluridine/tipiracil patients and to dose reduction in 13.7%; the most common causes of dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.

Trifluridine/tipiracil carries warnings/ precautions for severe myelosuppression and embryo-fetal toxicity. Women should not breastfeed while receiving the drug. n References 1. U.S. Food and Drug Administration: Approved drugs. Trifluridine/tipiracil.

Available at http://www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm463743.htm. October 7, 2015.

2. Lonsurf (trifluridine and tipiracil) tablets prescribing information, Taiho Oncology, Inc, September 2015. Available at https://www.taihooncology.com/us/prescribing-information.pdf. October 7, 2015.

3. Mayer RJ, Van Cutsem E, Falcone A, et al: Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372:1909-1919, 2015.

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

OVERALL SURVIVAL AT 5 YEARS IN DLBCL IS

60%

1 Could a better understanding of this disease be within our grasp?

Š 2015 Genentech USA, Inc. All rights reserved. HEM/062915/0011a Printed in USA.

DLBCL is an aggressive disease2 Remarkably, more than half of patients are able to survive diffuse large B-cell lymphoma (DLBCL) for 5 years or longer.1,3

Although strides have been made in the science of DLBCL, weâ&#x20AC;&#x2122;re casting an even wider net to further our knowledge of this aggressive disease

To learn more, visit BCellResearch.com

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012. National Cancer Institute website. http://seer.cancer.gov/csr/1975_2012/results_single/sect_19_table.29_2pgs.pdf. Updated April 23, 2015. Accessed June 15, 2015. 2. Jaffe ES, Harris NL, Stein H, Campo E, Pileri SA, Swerdlow SH. Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:158-166. 3. Larouche J-F, Berger F, Chassagne-ClĂŠment C, et al. Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol.

2010;28(12):2094-2100.

The ASCO Post | OCTOBER 25, 2015

PAGE 86

Book Review

Glimpses of the Human Condition Through Lively, Medically Themed Short Stories

By Ronald Piana

T

he field of medicine, ripe with dramatic tension, offers an endless array of material for books about the life-and-death issues of health care— the shelves of local libraries sag under their weight. The short story, however, is rarely used in the medical genre. For one reason, it’s difficult. Within several pages, an author must spin a yarn that captures the imagination of the reader and leaves the reader satisfied at its conclusion. But in its brevity, a well-told short story has a certain instant gratification and punch that is harder to find in a 300-page novel. Now, a recently published book of short stories titled A View From the Inside, by Augustine L. Perrotta, DO, makes a strong case for this often-neglected genre.

Dr. Perrotta, a board-certified hematologist-oncologist, is Clinical Professor of Medicine Emeritus at Michigan State University College of Osteopathic Medicine, among other distinguished positions. His book is organized into 15 chapters, with enticing names like “Babe Ruth’s Cancer” and “The Deadly Dentist.” But clever chapter titles aside, a book needs a purpose, and the author needs to be able to answer a simple, straightforward question: Why should I read your book? Dr. Perrotta answers it eloquently in his preface, writing: In this collection of medically oriented short stories, I have attempted to describe characters and events derived from personal experiences in my life and my connection with them.… I have tried to fill the stories with trivia relevant and pertinent to the subject matter, while providing a glimpse of human nature and the human condition in a realworld context.

Commanding Style Dr. Perrotta accomplishes his goal, and does so with commanding style in this thoroughly enjoyable read. He leads off with “Babe Ruth’s Cancer,” a cleverly woven story that begins at the Gate of Heaven cemetery in Mount Pleasant, where Dr. Perrotta’s father, mother, and sister are interred along with a host of celebrities—one of whom is Babe Ruth.

Following his mother’s burial in 1995, Dr. Perrotta asks the family funeral director to show him where “The Sultan of Swat” was laid to rest. While looking at the massive gravestone, he reminisces about Babe Ruth’s battle with cancer.

“The first symptoms of the cancer that took Babe Ruth’s life began in the late summer of 1946. His voice became progressively hoarse and he experienced severe pain behind the left eye.… Ruth would describe the sound of his voice ‘like somebody gargling ashes.’”

Following superb colorful details that transport the reader back to the days of Ruth, Dr. Perrotta deftly describes Babe Ruth’s diagnosis of nasopharyngeal cancer and the treatment modalities that ensued, including an experimental chemotherapy called teropterin. “Ruth responded dramatically to the experimental drug. The mass in his neck disappeared. Not only did he gain weight, but he also experienced substantial reductions in his hoarseness and face pain,” writes Dr. Perrotta.

Unfortunately, Ruth’s remarkable remission to the experimental drug was short-lived, and the baseball legend died in 1948 at Memorial Hospital (now Memorial Sloan Kettering Cancer Center),

Bookmark Title: A View From the Inside: A Collection of Medically Oriented Short Stories Author: Augustine L. Perrotta, DO Publisher: Keith Publications, LLC Publication date: March 31, 2015 Price: $14.95, paperback; 246 pages

6 months are listening to a priest’s passionate sermon when Dr. Perrotta’s pager goes off and the hospital operator’s voice reverberates through the church: “Dr. Perrotta! Dr. Perrotta! Emergency room! Stat! Snakebite victim!”

It’s obvious that Dr. Perrotta has had a rich and exciting life. These fine medical stories are a testament to that. It is also obvious that he is a man of faith and compassion who understands that each human being, no matter what his or her station in life, has a story. Understanding that is essential to the delivery of good medical care. where Dr. Perrotta did his fellowship 22 years later. The then-and-now contrast in cancer diagnosis and treatment proves fascinating, giving an otherwise fun read the gravity it deserves.

Rich Life Experiences Leading with an interesting chapter like “Babe Ruth’s Cancer” will certainly draw readers into the book, eager for more. However, an author then runs the risk of reader letdown if he doesn’t continue to fulfill that initial promise.

Dr. Perrotta delivers the goods chapter after chapter. His rich life experiences have been a wellspring for lively stories, told in tightly constructed prose; he writes using strong nouns and verbs as his tools, never dipping into the ornate.

For sheer reading pleasure, two chapters stand out in a field of standouts. The chapter “Snakebite!” opens in a towering cathedral in Tulsa, Oklahoma, where Dr. Perrotta and his wife of

To the astonishment of the priest and the crowded church, Dr. Perrotta leapt from his pew and “ran the length of the center aisle toward the large oak doors…. The priest was speechless for what seemed like the entire time I was sprinting toward the exit. He must have been stunned that I had just destroyed his eloquent sermon, which had been delivered with the cadence and rhythm of a Southern evangelist.”

It was May 1971, and Dr. Perrotta was a resident in internal medicine at Oklahoma Osteopathic Hospital in Tulsa. Adding to the comic setup, as Dr. Perrotta drove to the hospital, he realized that since they only had one car, he’d left his young wife stranded at the church. Moreover, Dr. Perrotta, a native of New York, had no experience with snakes, except for seeing them in the reptile house of the Bronx Zoo. What follows is an exciting trip into the emergency room. There, a laid-back

“good old boy” physician calmed the excited intern down and, with the help of a surgeon, saved the leg of the snakebite victim—a ranch hand who was bitten by an often-deadly cottonmouth. In this unusually charming vignette, Dr. Perrotta handily uses a medical emergency to highlight what good doctoring is all about.

The reader is also treated to a few pages of interesting medical care, coming away educated about snakebites and think-on-your-feet doctoring. Of course, there is humor: I turned to the ER doctor and asked, “How did you know it was a cottonmouth?” Instead of answering, he reached into a water basin that was on a stand near where the gurney had been. Then he turned and handed me a dark—almost black—snake about 4 feet long…. The prankster pried open the snake’s mouth to show me its white interior … hence, the name cottonmouth.”

Vital Medical Theme In “The Leper on the Bus,” Dr. ­ errotta details the compelling medical P case history of a man who immigrated to Seattle, Washington, from São Paulo, Brazil. After about a year, he developed a series of complicated medical conditions, and during one of his hospital stays, a dermatology resident noticed a bump over the temporal nerve.

A biopsy was performed, and several days later, the dermatologist received the results. “In a state of utter shock and amazement, she read that the submitted tissue was teeming with Mycobacterium continued on page 87

ASCOPost.com | OCTOBER 25, 2015

PAGE 87

Book Review

Pain, Still Undertreated and Misunderstood

By Ronald Piana

T

he subject of pain has been written about extensively, from the intriguing sociopolitical history of opium to the current national convulsions over the growing abuse of “pain pills” by recre-

ational drug users. Over the past few decades, the oncology community has had its own introspective discussions about the clinical challenges of undertreated cancer pain. But what makes pain a most

compelling subject—one that we want to read more about—is its universality: Every human suffers pain and is fearful of it.

Although our scientific knowledge of the causes and treatment of pain has

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grown at an exponential rate, vast numbers of people still suffer needlessly from untreated or undertreated pain.

Remarkably, there are whole countries in the developing world where opioids are not available to assuage the suffering of cancer patients.

According to a new book called A Nation in Pain, the lack of adequate pain control is one of the most urgent health problems in America. And although the book doesn’t center on cancer pain, it is a worthwhile read for the oncology community in its thorough examination of undertreated pain.

Personal Story Encyclopedic in scope, this new book on chronic pain also tells the personal story of the author, Judy Foreman, a Boston-based, nationally syndicated health columnist. When she developed chronic neck pain, Ms. Foreman’s savvy medical background and reporter’s skills were little help. According to the author, she suffered the same stigmatizing it’s-all-in-your-head reaction that many chronic pain patients experience.

Finally, an MRI showed the arthritis, bone spurs, and sliding vertebrae of her cervical spine that caused her agony.

Ms. Foreman spent 5 years interviewing experts, reviewing the literature, and talking to patients to summarize what America is doing about pain.

The answer? Not nearly enough—decontinued on page 88

A View From the Inside continued from page 86

leprae…. The patient had leprosy.”

The patient subsequently becomes the subject of a lecture given by a haughty Harvard-educated infectious disease specialist, who gets a well-deserved comeuppance from an old doctor in the audience.

This story has several layers, all built upon one vital medical theme: Arrogance diminishes wisdom. It is a terrific story, handled with the care it deserves.

It’s obvious that Dr. Perrotta has had a rich and exciting life. These fine medical stories are a testament to that. It is also obvious that he is a man of faith and compassion who understands that each human being, no matter what his or her station in life, has a story. Understanding that is essential to the delivery of good medical care.

This book is highly recommended to readers of The ASCO Post. n

The ASCO Post | OCTOBER 25, 2015

PAGE 88

Book Review A Nation in Pain continued from page 87

spite a 2011 report by the Institute of Medicine of the National Academies of Science revealing that 100 million Americans live in chronic pain.

The book leads off with an informative section called “How to Read This Book,” which is a nice touch, rarely seen. Ms. Foreman understands that when writing for an audience of mixed preferences, not everyone will choose to tackle her book with a cover-to-cover approach. She writes, “If you’re a patient who’s outraged at the way you’ve

Another chapter that will be interesting to The ASCO Post readership centers on the relationship between chronic pain and depression. Her consideration of pharmacologic treatments for pain patients suffering concomitant depression adds little to the discussion. However, a more interesting topic is fleshed out in a subchapter called “Catastrophizing,” which is defined as “a maladaptive cognitive and emotional habit that leads to focusing obsessively on pain, imagining all sorts of worst case scenarios and generally believing that the pain will be endless, life-wrecking, horrible, and unfixable.”

What makes pain a most compelling subject—one that we want to read more about—is its universality: Every human suffers pain and is fearful of it. been treated—or not treated—for your pain, Chapter 1 is a must-read…. If you … absolutely hate science, just skim through Chapter 2 on how the body turns acute pain into chronic pain and Chapter 3 on the genes that rev pain up or damp it down.” Sound advice.

Informative Discussions The author’s discussion on the genetics of pain, although written in layperson prose, is informative and spot on. She’s done her research, and it shows in one of the subchapters called “The Hottest Genes to Watch.” She takes the reader through some of the nation’s most dedicated pain-gene research laboratories, such as the Pain Genetics Lab headed by Jeffrey Mogil, PhD, at McGill University.

At last count, Dr. Mogil and his associates have found roughly 370 potential pain genes, with new ones being discovered almost daily. Dr. Mogil says that the task “is like putting together a 1,000-piece puzzle, and we are nowhere near putting it all together.”

To counter “Catastrophizing,” the author runs through a litany of self-reporting methods, acupuncture, biofeedback, meditation, and other “distraction techniques. The author makes it clear that pain is associated with a number of psychological issues related to depression, fatigue, and anxiety, all of which are overlooked far too often by medical professionals, some of whom still perpetuate the age-old stigmatization of pain.

Unfortunate Missteps Ms. Foreman follows this thoughtful chapter with two chapters on opioids that are unfortunately poor. The author spends the better part of these chapters discussing drug abuse, citing story after story of people “inadvertently addicted” to life-destroying opioids. In hyperbolic prose she writes, “Because the issue of drug abuse is so heated and the emotions it generates so raw, the rhetoric often becomes extreme. Some law enforcers have likened [pain] doctors to terrorists and the Taliban and

have called [oxycodone] in particular a ‘seductive, deadly menace.’”

Then there are disjointed sentences such as, “Opioids are kind of like airplane food: not that great—but for some people with pain, impossible to get enough of.” This leads to a section called, “How Effective Are Opioids Long Term?”

Seemingly intent on downplaying the effectiveness of opioids, she interviews a young man dying of esophageal cancer who is in intractable pain. His exact clinical scenario is never fully laid out, but she segues into a section stating that physicians who treat cancer pain should “err on the side of caution.” This is the kind of philosophical dead end that has long exacerbated the undertreatment of pain.

Moreover, a couple of chapters are one-sided to the point of hype. For instance, she totally advocates the use of cannabis for the treatment of pain, suggesting that it be sold as a dietary supplement and suggests that it is as effective as opioids for the treatment of pain. In contrast, she gives short shrift to some important therapeutic advances, such as mixed serotonin-norepinephrine reuptake inhibitors like duloxetine and venlafaxine. And her chapter on the immune system’s contribution to chronic pain is equally one-sided and dubious.

Good Information Ms. Foreman does regain her footing with a surprisingly good discussion on chemotherapy-induced neuropathy, noting that painful peripheral neuropathy is the most common reason patients have to stop their treatments. Here she explains with confidence the biochemical causes of neuropathy and some of the interesting research in this difficult setting.

A Nation in Pain concludes with several short chapters on accessing information and resource support for pain patients. It’s good information, because people in pain often feel they are being

Bookmark Title: A Nation in Pain: Healing Our Biggest Health Problem Author: Judy Foreman Publisher: Oxford University Press Publication date: May 1, 2015 Price: $19.95, paperback; 464 pages judged by a society bombarded in the lay press with stories of prescription pain pill abuse and deadly overdoses.

Abuse of opioids is a serious problem, but these drugs have an appropriate role in pain control. Hyperbolic language calling pain doctors terrorists or the claim that oxycodone is a “seductive deadly menace” only adds to the undertreatment of pain. Ms. ­Foreman has written a good book, but like many other writers, she drops the ball when discussing opioids. n

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ASCOPost.com | OCTOBER 25, 2015

PAGE 89

Book Review

A Neurologist’s Life: Oliver Sacks, MD

By Ronald Piana

Before and After Neurology

Bookmark Title: On the Move: A Life Author: Oliver Sacks, MD Publisher: Alfred A. Knopf Publication date: April 28, 2015 Price: $27.95, hardcover; 416 pages

O

ur ability to detect cancer has grown markedly over the past several decades, with the advent of more sensitive screening methods, new biomarkers, and advanced imaging tools. The unraveling of the human genome will further increase the detection, treatment, and prevention processes, leading to better outcomes for patients. Although cancer cells are microscopic, their greatly magnified malignant forms become visible to the human eye on a stained slide. Not so with many of the maladies that hide deep inside the human brain. Therefore, neurologists must also be detectives, creating inventive ways to diagnose and treat their patients.

One such neurologic detective is British expat Oliver Sacks, MD, best known for his collections of neurologic case histories, including The Man Who Mistook His Wife for a Hat, Musicophilia: Tales of Music and the Brain, and An Anthropologist on Mars. Awakenings, his book about a group of patients who had survived the great encephalitis lethargica epidemic of the early 20th century, inspired the 1990 Academy Award–nominated feature film starring Robert De Niro and Robin Williams.

A Compelling Writer Dr. Sacks recently added a new book to his impressive oeuvre, On The Move: A Life, which begins with this arresting sentence: “When I was at boarding school, sent away during the war as a little boy, I had a sense of imprisonment and powerlessness, and I longed for movement and power, ease of movement, and superhuman powers.” Besides being a provocative and absorbing physician, Dr. Sacks is a compelling writer.

Unfortunately, On the Move was destined to be his final book. In a February 2015 op-ed piece in The New York Times,

he announced that widespread metastases from an ocular tumor had been discovered. Measuring his anticipated remaining time in months, he expressed his intent to “live in the richest, deepest, most productive way I can.” He added: “I want and hope in the time that remains to deepen my friendships, to say farewell to those I love, to write more, to travel if I have the strength, to achieve new levels of understanding and insight.”

Sadly, Dr. Sacks passed away on August 30, 2015.

Dr. Sacks—“the poet laureate of medicine”—has capped his illustrious career with a fine book that peels off the white coat and bares the man behind the MD, with the same unbridled honesty and

Those who know of Dr. Sacks through his best-selling books on the oddities of his neurologic work will be pleasantly surprised to read about his life as a drug-loving motorcycle aficionado and Muscle Beach powerlifter. He writes, “I indulged in staggering bouts of pharmacologic experimentation, underwent a fierce regimen of bodybuilding at Muscle Beach (for a time I held a California record, after I performed a full squat with 600 pounds across my shoulders), and racked up more than 100,000 leatherclad miles on my motorcycle. And then one day I gave it all up—the drugs, the sex, the motorcycles, the bodybuilding.”

When Dr. Sacks began practicing as a neurologist, the theoretical understanding of the relationship of the brain to the conscious mind was still based on gross anatomy: If a portion of the brain was damaged, we might be able to discover by observation of the patient what its function was. Advances in brain imaging have informed new conceptions of the brain as a highly plastic environment in which there is constant reorganization. However, in the early 1990s, Dr. Sacks became acquainted with Gerald Edelman, MD, and his telling of that eventful philosophy-shaping relationship is done with spunk and humor.

Dr. Edelman’s theory of neural Darwinism, by which individual consciousness is explained as the function of a pro-

Dr. Sacks closes his final book in a way that will leave his readers wanting more. But everything comes to an end. humor seen in the memoir Megalies, by well-known oncologist Lodovico Balducci, MD. Dr. Sacks’ candor erupts early in the book with a discussion of his sex life, which was psychologically demolished when he was 18 years old by his mother’s dramatic reaction to his homosexuality: “You are an abomination. I wish you were never born.”

Dr. Sacks reminds the reader that his mother, one of the first female surgeons in England “and so open and supportive in many ways,” was a product of the times and her orthodox Jewish upbringing. Moreover, in Britain in the 1950s, not only was homosexuality frowned upon, but it was also a criminal offense punishable by prison. He ends that distressing section noting that his mother’s words haunted him throughout his life.

cess of natural selection between cohorts of competing nerve cells, greatly influenced Dr. Sacks’ career. He described Dr. Edelman’s theory as the “first truly global theory of mind and consciousness.”

There was, of course, a certain amount of professional combativeness.

Dr. Sacks writes that Dr. Edelman once said to him, “You’re no theoretician.” To which Dr. Sacks replied, “I know, but I’m a field-worker, and you need the sort of fieldwork I do for the sort of theorymaking you do.” Dr. Edelman agreed, and they settled it over a cold beer.

Uplifting Life Story Dr. Sacks’ life story is fascinating and uplifting on many levels, and reading about him rarely disappoints. He has suffered from lifelong, crippling shy-

ness—hard to imagine when his biggerthan-life personality is on display page after page. More comfortable in water than on land, he has been a lifelong swimmer and scuba diver.

He has also waged a lifelong battle against prosopagnosia, known popularly as “face blindness,” a condition that does not allow his brain to keep a record of people’s faces. As a result, everyone becomes a stranger after the first meeting unless certain prompts are used.

The section on the clinical and social challenges of this condition is riveting as well as humorous.

Most people were first introduced to Dr. Sacks in the movie Awakenings. Although a good movie, it does not open the clinical window into the neurologic challenges that Dr. Sacks puzzled out daily in his postencephalitic patients. Of that experience he writes: What fascinated me was the spectacle of a disease that was never the same in two persons.… When I wandered among my postencephalitic patients, I sometimes felt like a naturalist in a tropical jungle, sometimes, indeed, in an ancient jungle, witnessing prehistoric, pre-human behaviors—grooming, clawing, lapping, sucking, panting, and a whole repertoire of strange respiratory and phonatory behaviors.

This is the kind of medical intrigue and writing that have made Dr. Sacks famous, and On the Move is one big roiling celebration of writing, science, and a life lived to its fullest.

Powerful Ending The closing chapter, “Home,” is where the otherwise robust doctor confronts the disease that readers of The ASCO Post engage daily: cancer. “As I entered my seventies, I was in excellent health; I had a few orthopedic problems but nothing serious or life-threatening.…

In December of 2005, however, cancer made its presence, suddenly and dramatically known.…”

Closing a book with a powerful ending is very difficult, even for the most accomplished writer. Dr. Sacks closes his final book in a way that will leave his readers wanting more. But everything comes to an end. On the Move has a few missteps, mainly when the author toggles time periods—tough to do and maintain a fluid narrative—but that small gripe aside, Dr. Sacks’ book is highly recommended. n

The ASCO Post | OCTOBER 25, 2015

PAGE 90

Book Review

Confessions of a Neurosurgeon

By Ronald Piana

“I

often have to cut into the brain and it is something I hate doing. With a pair of diathermy forceps I coagulate the beauty and intricate red blood vessels that lie on the brain’s shining surface.” So begins Do No Harm, a bracing and fascinating book by neurosurgeon Henry Marsh, CBE, FRCS. The human brain possesses about 100 billion neurons with roughly 1 quadrillion synapses. If each neuron of a single human brain were laid end to end, they could be wrapped around the Earth twice over. Deciphering the biologic conundrum of this most complex of organs makes unraveling the genome, for example, look like child’s play. Within this mind-boggling complexity lurk our memories, hopes, fears, and aspirations. No wonder the author hates cutting into it.

However much Dr. Marsh may talk about the detachment that doctors must learn, it’s clear from this book how much he cares for his patients.

When he sees the tears in a patient’s eyes, he has to struggle for a moment to control his own.

eration—he felt, he writes, “like a conquering general,” having averted disaster and safely delivered his patient: “It was a deep and profound feeling which I suspect few people other

than surgeons ever get to experience.”

But while he’s made many patients S:6.75” very happy with successful operations, he says that there have also been “many terrible failures and most neurosur-

geons’ lives are punctuated by periods of deep despair.”

This bit of introspection, which, in various ways, punctuates each chapter, is one aspect that makes this book

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

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

As he makes clear on page 1, “Brain surgery is dangerous, and modern technology has only reduced the risk to a certain extent…. [I]f I stray into the wrong area, into what neurosurgeons call eloquent brain, I will be faced by a damaged and disabled patient when I go round to the Recovery Ward after the operation to see what I have achieved.”

Dr. Marsh studied medicine at the Royal Free Hospital in London and became a fellow of the Royal College of Surgeons. He has been the subject of two major documentary films on brain surgery. He is also a very capable writer who uses delicate personal and clinical brushstrokes to illustrate the drama of brain surgery. And for readers of The ASCO Post, several of his most compelling chapters are devoted to brain cancers.

Valuable Introspection When he was younger, Dr. Marsh recalls, he used to feel an “intense exhilaration” after a successful op-

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.

Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%).

Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA

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Book Review

a valuable read for doctors and those aspiring to the profession. No doubt, Dr. Marsh’s despair will ring true to those in the oncology community who experience a sense of failure when running out of treatment options for their patients. The oncology community will also relate to the fact that many of the most difficult moments the author re-

counts take place not in the operating room but in conversations before or after surgery—conversations in which Dr. Marsh tries to balance realism with patients’ need for hope and his own knowledge that “they are being stalked S:6.75” by death and I am trying to hide, or at least disguise, the dark figure that is slowly approaching them.”

Dr. Marsh gives a compelling account of a surgery gone wrong and how it affected his confidence as he moved to his next patient, a high-powered executive in denial who had a pineal tumor. The night before the operation, he met with the patient and his wife, “who was sitting beside him looking quite sick with fear.” In carefully chosen

words, Dr. Marsh explained the operation’s risks of stroke and death, as well as the tumor’s chances of being benign or malignant, and what those two possible scenarios meant for the outcomes.

This well-written section, and others like it, bring the reader into the patient’s realm of apprehension and hope. They continued on page 92

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

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

ED

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

PFS

1.0

COMETRIQ® (n=219) Placebo (n=111)

0.9 0.8 0.6

CW

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

0.7 0.5 0.4

median

median

4.0 4.0

0.3

11.2 11.2 months months

months months

0.2

CD

Probability of patients who are progression free

AE/AS

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

31 3

12 2

2 0

1 0

Months 219 111

121 35

78 11

55 6

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.

Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330).

Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).

Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).

In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.

Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

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also describe the complicated calculus of risk involved in making decisions— weighing the possibility of saving patients from slow deterioration or constant pain against the danger of making them worse.

He writes, “Early the next morning I lay in bed thinking about the young

woman I had operated on the previous week. She had had a tumour in her spinal cord … and although the procedure seemed to proceed uneventfully, she awoke from the operation paralysed down the right side of her body.” He realizes that he was probably too aggressive in his approach to get it “all out.” This is tough stuff, but he has

another patient counting on him, so he needs to push past this patient and put on his scrubs.

Spellbinding Account Dr. Marsh’s account of the pineocytoma operation is S:6.75” spellbinding, even for the most seasoned readers of medical literature. And for readers who are

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning.

Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules.

Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions.

Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment.

In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.

In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg.

4. CONTRAINDICATIONS None.

5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively.

All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients.

Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.

5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

not surgeons, the “action” is blunt and dramatic.

He writes, “‘Knife,’ I said to Agnes, the scrub nurse.… I quickly cut down through the back of the man’s head.

Mike [his assistant surgeon] used a sucker to clear the blood away and I then split the neck muscles apart so that we could start drilling through the

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days.

The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

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

Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5 Palmar-plantar erythrodysesthesia syndrome.

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Book Review

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Price: $25.99, hardcover; 288 pages

erate again, he said, “It’s a bit inappropriate, but all I can say is good luck….

It’s been an honor to look after you.”

He was unable to say goodbye, since he knew it was the last time he’d see a patient he’d grown fond of.

This book is not all operating room drama, which adds to its value. Dr. Marsh gets into some excellent gripe sessions about health-care disparities in the United Kingdom, taking a few swipes across the pond at the U.S. system. And in a chapter called “Hubris,” the author engages in some riveting psychoanalysis of himself and the profession of neurosurgery. “Sometimes we go too far into the brain. We should know when to stop, but we’re a prideful bunch,” he writes.

Perhaps the strongest chapter is one called “Carcinoma.” Here, his elderly mother is dying of breast cancer, and Dr. Marsh’s description of her last days, replete with discussions of high-value palliative care, is excellent. He ends this fine book with his mother’s final words, “It’s been a wonderful life. We have said everything there is to say.” n

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Table 3.

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

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose).

8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.

8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility.

Cabozantinib impaired male and female fertility in animal studies.

8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal).

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established.

8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.

10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy.

• COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

QC

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

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.

2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

3 Subjects with at least two blood pressure measurements after the first dose.

must learn, it’s clear from this book how much he cares for his patients.

When he sees the tears in a patient’s eyes, he has to struggle for a moment to control his own.

In a subsequent chapter, Dr. Marsh describes a patient with glioblastoma.

After he breaks the bad news to his patient, telling him it will be no use to op-

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

Marsh returns to the theater, where “the nurses were tidying the instruments on the trolleys and stuffing the discarded drapes and cables and tubes into plastic rubbish bags. One of the porters was already mopping the blood off the floor in preparation for the next case.”

S:6.75” However much Dr. Marsh may talk about the detachment that doctors

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bone of his skull.” He describes the tumor, noting, “Each brain tumour is different. Some are hard as a rock, some soft as jelly. Some completely dry, some pour with blood.”

In this particular operation, the tumor turns out to be benign, and the operation is a success. After giving the good news to the patient’s wife, Dr.

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Pioneers in Oncology Hematology

Early Research of David G. Nathan, MD, Ushered in the Field of Pediatric Hematology

By Jo Cavallo

W

hen David G. Nathan, MD, was admitted to Harvard University in 1947, he had every intention of becoming an English professor. It was only his lack of writing talent that dissuaded him from a life in the classroom and propelled him into a medical career that has spanned more than 5 decades and has led to the establishment of pediatric hematology/oncology as a new field of research and clinical care.

cal studies at Harvard Medical School, an event during his second year there changed the trajectory of his career and led him to study the production of red blood cells and the treatment of children with leukemia and other blood diseases, especially thalassemia and sickle cell anemia.

“While making ward rounds with a resident at Boston City Hospital, I saw a patient in a coma and asked what was

If I am going to leave you with any thought that sums up my life, it is that life in academic medicine is about family. My trainees are my second family, and watching their success is probably the thing that gives me the greatest happiness.

—David G. Nathan, MD

“I was very interested in writing and literature in college, and I had the whole uniform to become an English professor. I had the jacket with the leather elbow patches, the book bag, and the pipe. The only thing lacking was talent, and by the end of my sophomore year, I decided to major in medicine,” laughed Dr. Nathan, although, he admits, the seeds of a career in medicine were planted long before.

Born on May 25, 1929, in Boston, Dr. Nathan credits both his grandfather, Jacob Nathan, and his father, Geoffrey Nathan, with influencing his career choice, although for opposite reasons.

“My grandfather had nothing but contempt for doctors because he said they didn’t do anything but sell people witchcraft,” said Dr. Nathan. “My father studied chemistry at Harvard University and went to work for my grandfather’s company, Roxbury Chemical Works, and then applied to Harvard Medical School and was accepted, but my grandfather wouldn’t allow him to study medicine. It was a missed opportunity for my father, but then I got to fulfill his dream.”

Decoding the Mystery of Disease Although Dr. Nathan had planned to open a group medical practice in Cambridge after completing his medi-

wrong with him. The resident said he didn’t know, but that the patient went into a coma every day after lunch,” said Dr. Nathan. “Although there was a theory that the problem was disordered ammonia metabolism, the doctors didn’t know for sure what was wrong with the patient, and that is what turned me into a physician/scientist.

That incident was a turning point for me because I suddenly realized that what fascinates me is: (1) determining what’s wrong, and (2) figuring out what I can do about it.”

After completing his residency in internal medicine at Peter Bent Brigham Hospital (now Brigham and Women’s Hospital) in 1955, Dr. Nathan became a Clinical Associate at the National Cancer Institute (NCI).

It was at the NCI that Dr. Nathan decided that he would devote his medical career to the clinical care and research of blood disorders.

“I don’t know how I was selected for the position at the NCI, but once there I was ordered into hematology by my research mentor, Nathaniel I. Berlin, MD, and I had 2 years training in hematology/oncology, mainly in disorders of the red blood cells, but also in leukemia,” said Dr. Nathan. “What a way to select a career—to be ordered into it— and I loved it. Once I got into hematology I never turned back.”

Charting a New Career Course The use of multiple chemotherapy agents in the treatment of childhood leukemia, including methotrexate and mercaptopurine, had been initiated a few years before Dr. Nathan arrived at the NCI. But the therapy’s success rate was so low, Dr. Nathan lost every patient he treated with the two-combination therapy. It wasn’t until the four-drug combination of vincristine, doxorubicin, methotrexate, and prednisone was introduced in the early 1960s that oncologists finally started realizing cures in acute lymphocytic leukemia and in advanced Hodgkin lymphoma.

By then, however, Dr. Nathan had returned to Peter Bent Brigham Hospital to complete his senior residency in medicine. His interest in red blood cell abnormalities led him out of the study of internal medicine and into a focus on pediatric hematology.

“At the time, Brigham was highly advanced in kidney disease and in kidney transplant, and I got involved in the study of the red cell production in the transplant patients and learned a lot about the source of erythropoietin,” said Dr. Nathan. During this time, Dr. Nathan was also exposed to patients with difficult anemias and later developed hydroxyurea, the first successful treatment for sickle cell anemia.

Over the next 3 decades, Dr. Nathan had other major successes in the treatment of inherited blood disorders, including demonstrating how the continuous administration of deferoxamine, an iron-chelating agent, prolongs cardiac disease-free survival in thalassemia patients; and utilizing fetoscopy procedures in the prenatal detection of sickle cell anemia and thalassemia, which have contributed to the reduction of these diseases worldwide.

As Dr. Nathan’s research of inherited blood disorders became more widely known, he began treating young patients sent to him from Boston Children’s Hospital. In 1966, he decided to change his specialty from internal medicine to pediatrics and became Chief of the Division of Hematology and Oncology at Boston Children’s Hospital and the Sidney Farber Cancer Center, now the Dana-Farber Cancer Institute.

“At the time, I wasn’t thinking very much about the cancer problem, and I went to Children’s Hospital with the

agreement that I wouldn’t be responsible for patients with cancer,” said Dr. Nathan. “They were the province of Dr. Sidney Farber [then Physician-in-Chief at Dana-Farber Cancer Institute], and I was very glad of that because I had had such a rough experience curing children of cancer at the NCI, and I really didn’t want to go through that again.”

Weighing Risk vs Benefit However, by then, the aggressive use of combination chemotherapy in the treatment of acute lymphocytic leukemia and Hodgkin lymphoma was achieving complete remissions in about 25% to 30% of children with these cancers— and up to 60% by the end of the decade.1 This trend convinced Dr. N ­ athan that even though the treatment toxicities, including chemotherapy-induced bleeding, were difficult for patients, they were worth the potential chance at a cure, which ignited a feud with Dr. Farber that lasted until his death in 1973.

“Dr. Farber wanted to continue treating these children with sequential single-agent chemotherapy because he was terrified of injuring a child with these combination drugs, and I could understand his feeling,” said Dr. Nathan. “But I also knew that we would never cure patients unless we got over our fear, and I had a very hard time arguing with him about treating our young patients and begging him to use combination therapy. He would not do it, and we did not part as friends. He was furious with me and never spoke with me again. He died before I could reconcile with him.”

Combining the Fields Dr. Nathan found an ally in Emil “Tom” Frei III, MD, who had succeeded Dr. Farber as Physician-in-Chief at Dana-Farber Cancer Institute, and who had pioneered, along with Emil J ­Freireich, MD, the use of combination chemotherapy as a multipronged assault on childhood leukemia at the NCI. “The arrival of Dr. Frei changed everything, and we combined the two units of hematology and oncology, which I ran until 1985,” said Dr. Nathan.

Over the next decade, from 1985 to 1995, Dr. Nathan served as Physicianin-Chief of Boston Children’s Hospital and became President of Dana-Farber Cancer Institute in 1995, remaining in

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PAGE 95

Pioneers in Oncology that position until 2000. During those 5 years, Dr. Nathan transformed the institution from an insular cancer center into a central hub of oncology care, uniting five academic medical centers and two Harvard schools, and the organization is now known as the DanaFarber/Harvard Cancer Center.

In addition to his research and clinical accomplishments, Dr. Nathan is acclaimed for his contribution to the training of hundreds of hematologists—many of whom now hold leading positions in pediatrics, oncology, and internal medicine—and for fostering collaboration among colleagues.

“We are in the biology business, and biology is terribly complicated,” said Dr. Nathan. “My feeling is that if you have a very tough problem, you want to pull all the best minds together to solve it. Sid-

ney Farber was a sort of solo genius; it was hard to work with him because he was into himself. But the problems today are just so complicated, there is no way to solve them unless you collaborate with the best minds you can find.

We owe it to our patients to bring our best efforts to the problem of cancer.”

Lasting Legacy in Patient Care Today, Dr. Nathan is President Emeritus of Dana-Farber Cancer Institute, Physician-in-Chief Emeritus of Boston Children’s Hospital, and Robert A. Stranahan Distinguished Professor of Pediatrics and Professor of Medicine at Harvard Medical School. He still maintains an office for clinical research and teaching at Dana-Farber, where he is continuing his research in the inflammatory component of sickle cell anemia.

He is the recipient of numerous awards, including Boston Children’s Hospital Lifetime Award, John ­Stearns Medal for Lifetime Achievement in Medicine of the New York Academy of Medicine, George M. Kober Medal of the Association of American Physicians, Howland Medal of the American Pediatric Society, Annual Award for Excellence in Clinical Research from the National Institutes of Health, The President’s National Medal of Science, and the Henry Stratton and Wallace H. Coulter Medals of the American Society of Hematology, among others.

Looking back on his long career, Dr. Nathan said he is a “lucky guy” and credits his wife of 64 years, Jean, and their three children, Deborah, Linda, and Geof, with helping him achieve professional success.

He also credits his “other” children—the

many medical students and fellows he has mentored over the past 50 years— with contributing to his personal sense of accomplishment and satisfaction.

“Over the years, I’ve trained scores of students, and they have gone on to mentor their trainees, and that is the great multiplier. Frankly, I think my success is the result of the work of all those trainees,” said Dr. Nathan. “If I am going to leave you with any thought that sums up my life, it is that life in academic medicine is about family. My trainees are my second family, and watching their success is probably the thing that gives me the greatest happiness.” n Reference 1. DeVita VT, Chu E: A history of cancer chemotherapy. Cancer Res 68:8643-8653, 2008.

Announcements

$12 Million Multi-institutional SPORE Grant to Focus on Mutations in the NF1 Gene

A

new, multi-institution research endeavor brings together scientists from nine leading institutions to find treatments for a group of rare cancers, all caused by a particular gene mutation.

to take on a group of cancers linked to mutations in the NF1 gene. It will analyze cancer-promoting signaling pathways and cancer genetics to try to find new effective treatments and drug targets for cancers caused by the loss of NF1 function.

Neurofibromatosis, Ras

D. Wade Clapp, MD

The researchers won a 5-year, $12 million grant through the National Cancer Institute’s (NCI) competitive NCI Specialized Programs of Research Excellence (SPORE) Initiative. The effort, which is led by the Indiana University (IU) School of Medicine and the University of California San Francisco (UCSF), is the first such project

Rather than funding studies for one cancer type, the grant takes a new approach by targeting multiple cancers that develop because of NF1 mutations. The mutations cause a genetic disorder known as neurofibromatosis type 1, which frequently develops in children and young adults, and can cause tumors in the skin, nervous system, and blood. The disorder occurs in about 3,000–4,000 people per year worldwide, according to the National Institutes of Health’s Genetics Home Reference.

With the award, researchers will be testing treatments that are designed to

block cancer-causing changes that occur because of NF1 mutations. Specifically, they will be testing drugs that block enzyme activities that occur because of abnormal activity of a gene called Ras, which is the most commonly mutated oncogene in human cancers. The NF1 gene normally codes for a protein that helps control Ras. Because NF1 is mutated in people with neurofibromatosis type 1, it leads to uncontrolled Ras activity. Ras, in turn, drives activation of a number of different kinases, which help drive tumor growth.

A technique to determine kinase activities in cells is hoped to help determine how patients respond to different drugs targeting the Ras pathway, as well as to find new clinical drug targets.

Multiple Sites The trial requires collaboration across multiple institutions because of the rare nature of the disorder. The grant is led by investigators at the In-

diana University School of Medicine and UCSF, along with researchers from Johns Hopkins University School of Medicine; the National Institutes of Health; University of Texas Southwestern; Memorial Sloan Kettering Cancer Center; The Children’s Hospital of Philadelphia; and City of Hope National Medical Center.

“This award is the first Specialized Programs of Research Excellence grant to ever be focused on a series of cancers in a common biochemical pathway, and a SPORE grant focused on orphan diseases in children, adolescents, and young adults,” said D. Wade Clapp, MD, a principal investigator with the project and the Chairman of the Department of Pediatrics at the IU School of Medicine, as well as a member of the IU Melvin & Bren Simon Cancer Center and the Herman B. Wells Center for Pediatric Research. “This SPORE is by design multi-institutional, because of the rare nature of this disease.” n

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | OCTOBER 25, 2015

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2015-2016 Oncology Meetings October Modern Management of Urologic Cancers: A Multidisciplinary Approach (Memorial Sloan Kettering) October 29-31 • New York, New York For more information: http://www. themerzgroup.com/mskcc/mskccurologic-conference/

Lynn Sage Breast Cancer Symposium October 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org Caring for the Caregivers X October 30 • Waltham, Massachusetts For more information: http://www.massmed.org Continuing-Education-and-Events/ Event-Information/?code=CFC2015

November NRCI Cancer Conference November 1-4 • Liverpool, UK For more information: http://conference.ncri.org.uk 3rd International Conference on Hematology & Blood Disorders November 2-4 • Atlanta, Georgia For more information: http:// hematology.conferenceseries.com 2015 Oncofertility Conference November 3-5 • Chicago, Illinois For more information: https:// oncofertility.northwestern.edu/2015Conference 33rd Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® November 4-6 • New York, New York For more information: http://www.chemotherapyfoundationsymposium.org/CMS/

Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.sitcancer.org/2015

2015-2016

ESMO Summit Americas 2015 Oncology Updates: From Evidence to Practice November 6-8 • Miami, Florida For more information: www.esmo.org/Conferences/ESMOSummit-Americas-2015

Society for Integrative Oncology 12th International Conference November 14-16 • Boston, Massachusetts For more information: http://www.integrativeonc.org/ conference

JADPRO Live at APSHO for Advanced Practitioners in ­Oncology November 5-8, 2015 • Phoenix, Arizona JW Marriott Desert Ridge For more information: jadprolive.com City of Hope Presents: Multidisciplinary Approaches to Cancer Symposium November 5-8 • Las Vegas, Nevada For more information: https://cme.cityofhope.org/ eventinfo_5980.html Advanced Breast Cancer Third International Consensus Conference November 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org 13th Annual School of Breast Oncology November 5-7 • Atlanta, Georgia For more information: http://www.gotoper.com/ conferences/sobo/meetings/13thAnnual-School-of-Breast-Oncology

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics November 5-9 • Boston, Massachusetts For more information: http:// www.aacr.org/Meetings/Pages/ MeetingDetail 14th International Kidney Cancer Symposium November 6-7 • Miami, Florida For more information: http://registeruo.niu.edu/ iebms/wbe/wbe_p1_main. aspx?oc=40&cc=WBE4014167

Joint Conference: Acupuncture, Oncology, and Fascia November 14 • Boston, Massachusetts For more information: http:// oshercenter.org/joint-conferenceacupuncture-oncology-fascia/

10th Annual New York Lung Cancer Symposium November 7 • New York, New York For more information: http://www.gotoper.com/ conferences/nyl/meetings/10thAnnual-New-York-Lung-CancerSymposium 17th Annual Brain Tumor Update and 6th Annual International Symposium on Long-Term Control of Metastases to the Brain and Spine November 7-8 • Las Vegas, Nevada For more information: http://www. clevelandclinicmeded.com/live/ courses/2015/brainmets15/.aspx?Ev entItemID=52&DetailItemID=196#.

VSZlr_msXpU Best of ASTRO November 13-14 • San Diego, CA For more information: www.astro.org/Meetings-andEvents/2015-Best-of-ASTRO/Index.aspx 2015 Oncologic Emergency Medicine Conference November 13-14 • Houston, Texas For more information: http:// www.mdanderson.org/educationand-research/education-andtraining/schools-and-programs/ cme-conference-management/ conferences/d114243-2015-oncologicemergency-medicine-conference.html 8th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved November 13-16 • Atlanta, Georgia For more information: http:// www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=68#.Vba1EqTbJjq

4th Cancer Epigenetics Conference November 16-17 • San Francisco, California For more information: www.gtcbio.com/conferences Advances in Cancer ImmunotherapyTM November 18 • San Francisco, California For more information: www.sitcancer.org/sitc-meetings/ aci2015/casf 11th Annual Personalized Medicine Conference November 18-19 • Boston, Massachusetts For more information: http://personalizedmedicine. partners.org/Education/PersonalizedMedicine-Conference/Program.aspx 12th International Congress of the Society for Melanoma Research November 18-21 • San Francisco, California For more information: www.melanomacongress.com/ 20th Annual Scientific Meeting of the Society for Neuro-Oncology November 19-22 • San Antonio, Texas For more information: www.soc-neuro-onc.org ESMO Symposium on Immuno-Oncology November 20-21 • Lausanne, Switzerland For more information: www.esmo.org/Conferences/ Immuno-Oncology-2015

continued on page 103

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2015-2016 Oncology Meetings Meetings Calendar continued from page 96

December 9th European Colorectal Congress (ECC) December 1-4 • St. Gallen, Switzerland For more information: www.colorectalsurgery.eu

January 2016

February

4th AACR-IASLC International Joint Conference: Lung Cancer Translational Science January 4-7 • San Diego, California For more information: http:// www.aacr.org/Meetings/Pages/ MeetingDetail.aspx?EventItemID=74#.

VbbijqTbJjo

4th State of the Science Cancer Survivorship Research Symposium February 4 • Houston, Texas For more information: www.mdanderson.org/educationand-research/education-andtraining/schools-and-programs/ cme-conference-management/ conferences/cme/conferencemanagement-fourth-state-of-thescience-cancer-survivorship-researchsymposium.html

Advances in Cancer ImmunotherapyTM December 4 • New Orleans, Louisiana For more information: www.sitcancer.org/sitc-meetings/ aci2015/la 10th Annual Practical Course in Dermoscopy & Update on Malignant Melanoma 2015 December 4-6 • Scottsdale, Arizona For more information: https://ce.mayo.edu/dermatology/ node/2463 57th Annual ASH Meeting & Exposition December 5-8 • Orlando, Florida For more information: www.hematology.org/ San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org American Society for Cell Biology Annual Meeting December 12-16 • San Diego, Callifornia For more information: http://ascb.org/2015meeting/ European Society for Medical Oncology Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ESMOAsia-2015-Congress

2015-2016

Genitourinary Cancers Symposium January 7-9 • San Francisco, CA For more information: http://gucasym.org Cancer Survivorship Symposium: Primary Care and Oncology Collaboration January 15-16 • San Francisco, California For more information: www.survivorsym.org/ Gastrointestinal Cancers Symposium January 21-23 • San Francisco, California For more information: http://gicasym.org

Cancer Center Business Summit February 24-25 • Phoenix, Arizona For more information: http://cancerbusinesssummit.com

March Society of Surgical Oncology Annual Cancer Symposia March 2-5 • Boston, Massachusetts For more information: www.surgonc.org

10th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics February 16-20 • Maui, Hawaii For more information: www.aacr.org

22nd Annual Blood-Brain Barrier and Neuro-oncology Meeting March 3-5 • Stevenson, Washington For more information: www.ohsu.edu/bbb

The Biomarker Conference February 18-20 • San Diego, California For more information: www.mnmconferences.com/thebiomarker-conference-florida.html

8th Annual Asian Oncology Summit March 3-6 • Kyoto, Japan For more information: www.asianoncologysummit.com

Multidisciplinary Head and Neck Cancer Symposium February 18-20 • Scottsdale, Arizona For more information: www.headandnecksymposium.org

Second Annual New Treatments in Oncology March 5-6 • Scottsdale, Arizona For more information: www.cvent.com/events/annualnew-treatments-in-oncologyconference-presented-by-cancertreatment-centers-of-america-/ event-summary-2fb116562f6447cca49 2c89064760b02.aspx

25th Conference of the Asian Pacific Association for the Study of the Liver February 20-24 • Tokyo, Japan For more information: http://www.apasl2016.org

Personalized World Medicine Conference January 24-27 • Mountain View, California For more information: http://2016sv. pmwcintl.com/index.php

3rd St. Gallen International Gastrointestinal Cancer Conference March 10-12 • St. Gallen, Switzerland For more information: www.oncoconferences.ch/dynasite .cfm?dsmid=500294

8th Immunotherapeutics & Immunomonitoring Conference January 25-26 • San Diego, California For more information: https:// www.gtcbio.com/conferences/ immunotherapeuticsimmunomonitoring-overview

33rd Annual Miami Breast Cancer Conference March 10-13 • Miami, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/33rd-Annual-MiamiBreast-Cancer-Conference

ASCO Quality Care Symposium February 26-27 • Phoenix, Arizona For more information: http://quality.asco.org

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Hematology Expert Review

Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Part 1: Approach to Diagnosis in the Immunocompetent Host

By Syed Abutalib, MD, and Rimas V. Lukas, MD

H

ematology Expert Review is an occasional feature that includes a case report followed by questions, answers, and expert commentary.

In this issue of The ASCO Post, Drs. Abutalib and Lukas present part 1 of a case report on primary diffuse large B-cell lymphoma. Part 2 will be published in an upcoming issue.

T

he ASCO Post is pleased to present Hematology Expert Review, an occasional feature that includes a case report detailing a particular hematologic condition followed by questions. Answers to each question appear on page 105 with expert commentary. In this installment, we present a 70-year-old man who complained of newly developed neurologic symptoms over the course of 2 weeks. “Part 2: Accurate Assessment of Disease Burden and Prognosis” will appear in an upcoming issue of The ASCO Post.

Case Study: A 70-year-old man presented with complaints of newly developed neurologic symptoms over the course of 2 weeks. He stated that he had been getting lost driving while performing his job delivering pizzas, which

A

he has had for the past 10 years. He has also experienced abulia, an inability to make decisions or lack of will, while listening to sports on the radio, and he found himself singing while driving, both of which were atypical behaviors for him and a substantial variation from his normal baseline. He reported no headaches or visual symptoms and is otherwise healthy, with no medical or surgical history. He denied travel outside of his city for the past 5 years.

The neurologic exam was normal.

The complete blood cell count (CBC) and complete metabolic profile were also normal. The hepatitis panel and HIV test were negative. These constellations of new symptoms led to brain imaging. Magnetic resonance imaging (MRI) with contrast demonstrated a homogeneously enhancing lesion in the left frontal lobe (Fig. 1). A similar, smaller, noncontiguous lesion was also noted in the right frontal lobe.

Question 1 What is the most likely diagnosis for this patient?

A. Solid tumor metastasis B. Primary central nervous system lymphoma C. Glioma

GUEST EDITORS

Syed A. Abutalib, MD

Syed A. Abutalib, MD, Assistant Director, Hematology & Bone Marrow Transplantation Service, Cancer Treatment Centers of America, Zion, Illinois

Question 2 What is the next best step to confirm the diagnosis of primary central nervous system lymphoma?

A. Immediate initiation of steroids and surgical resection B. Immediate initiation of steroids and stereotactic biopsy C. Immediate stereotactic biopsy

Question 3

Rimas V. Lukas, MD

Rimas V. Lukas, MD, Director of Medical Neuro-Oncology, Associate Professor, Department of Neurology, University of Chicago

ing in an immunocompetent host with primary diffuse large B-cell lymphoma of the central nervous system?

A. Perivascular growth pattern B. Areas of extensive necrosis C. Presence of Epstein-Barr virus in the tumor cells

See page 105 for answers.

What is the characteristic biopsy find-

B

Fig. 1: (A) This axial T1-weighted postcontrast brain MRI image shows a homogeneously enhancing lesion in the left frontal lobe. A smaller similar appearing lesion (not shown) was also present in the right frontal lobe of the brain. (B) Axial diffusion-weighted imaging sequence demonstrates restricted diffusion throughout the area of the enhancing lesion, which was confirmed on the apparent diffusion coefficient sequence (not shown).

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PAGE 105

Hematology Expert Review

Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Part 1: Approach to Diagnosis in the Immunocompetent Host Answers to Hematology Expert Review Questions on Page 104 Question 1: What is the most likely diagnosis for this patient?

Correct Answer: B. Primary central nervous system lymphoma.

Table 1: Brain MRI Sequences and Their Interpretation Brain MRI Sequence

Interpretation

T1-weighted imaging post contrast

Standard imaging sequence after gadolinium contrast is injected intravenously. Normal vasculature will enhance, as will vessels with increased permeability, such as those seen in malignancies.

T2-weighted imaging

A sequence often more sensitive (fluid appears bright) but less specific for detecting abnormalities. Areas of increased signal can be seen with tumor, infections, autoimmune disease, vascular disease, and radiation treatment effects.

Fluid-attenuated inversion recovery

Special sequence to remove the effects of fluid. Cerebrospinal fluid signal is dark (as opposed to bright on T2 sequence), allowing for easier detection of periventricular lesions.

Diffusion-weighted imaging (DWI)

Sequence that detects decreased movement of free water. This restricted diffusion can be seen in acute stroke, where free water enters the cells causing cytotoxic edema. It can also be seen in neoplastic etiologies, particularly central nervous system lymphoma. Abnormalities on DWI appear bright.

Apparent diffusion coefficient (ADC)

The source images from which DWI images are obtained. Areas of restricted diffusion on DWI appear dark. If an abnormality is noted on DWI, it can be confirmed on ADC that the finding is not artifactual.

Expert Perspective In an immunocompetent host, the differential diagnosis of isolated or multiple brain lesion(s) includes autoimmune etiologies such as neurosarcoidosis, multiple sclerosis, and acute disseminated encephalomyelitis; and neoplastic etiologies such as solid tumor metastasis, glioma, and primary or secondary central nervous system (CNS) lymphoma. In addition, infectious etiologies should be considered in an immunocompetent host, although they are much more common in an immuncompromised host; they include bacterial, fungal, or tubercular abscesses or parasitic infections such as toxoplasmosis and cysticercosis.1,2 Solid tumor brain metastases may present with single or multiple lesion(s).

Similar to abscesses, they may also be ring-enhancing; however, solidly enhancing or heterogeneously enhancing lesions can be seen as well. Solid tumor brain metastases typically do not demonstrate restricted diffusion, and the lesions are often seen at the interface between the cortex and the underlying white matter, although they can appear

anywhere in the brain parenchyma.

High-grade infiltrating gliomas, such as glioblastoma, occur in older adults, similar to primary CNS lymphoma.

High-grade gliomas can be unifocal or multifocal; however, the lesion(s) are most often heterogeneously enhancing surrounded by substantial areas of increased signal on T2-weighted/fluid-

Fig. 2: This axial T1-weighted postcontrast brain MRI shows a heterogeneously enhancing lesion, which is a glioblastoma. Cystic areas are noted within the lesion, which would not be expected in primary CNS lymphoma.

attenuated inversion recovery (FLAIR) MRI sequences (Fig. 2; MRI of the brain in a patient with glioblastoma). Gliomas may at times have cystic components, which can also be seen in solid tumor metastases, but they are extremely rare MRI findings in primary CNS lymphoma.

High-grade gliomas may demonstrate some restricted diffusion ­(Table 1); however, this is most often patchy as opposed to homogeneous distribution. Restricted diffusion is also more likely to be seen after disease progression on antiangiogenic therapies, as opposed to treatment-naive patients with glioma.

Primary CNS lymphoma lesion(s) on MRI with contrast are isointense to hypointense on T1-weighted images (Table 1), homogeneous contrast enhancement is seen in more than 90% of cases, and the lesions occur in the subcortical white matter (often in proximity to the lateral and third ventricles). Of primary CNS lymphoma deposits, 60% are multiple.3 In contrast, MRI of metastatic brain disease and gliomas usually demonstrates more heterogeneous lesions, with frequent presence of central necrosis and microhemorrhage in the lesion(s).

Moreover, the lesion(s) of the primary CNS lymphoma usually have irregular borders, and the amount of surrounding edema is variable, compared with the reliably prominent edema seen in gliomas and some solid tumor meta-

static disease. The characteristic neuroradiologic findings observed in CNS lymphoma with absence of leptomeningeal enhancement and lack of lymphoma history with a normal CBC, and a negative positron-emission tomography–computed tomography (PET-CT) scan (outside the brain) in our patient, strongly favor the diagnosis of primary, not secondary, CNS lymphoma.4 Question 2: What is the next best step to confirm the diagnosis of primary CNS lymphoma?

Correct Answer: C. Immediate stereotactic biopsy.

Expert Perspective Based on MRI neuroradiologic criteria, primary CNS lymphoma is the most likely diagnosis, but histologic confirmation via stereotactic biopsy (not resection) from one of the lesions is mandatory. In this situation, steroids should be avoided until a biopsy specimen is secured.5 It is safe to defer steroids in most patients.2 If there is concern for increased intracranial pressure, a hyperosmotic agent such as mannitol or hypertonic saline can be emergently employed.

Steroids prior to stereotactic biopsy may lyse the neoplastic B cells (necrosis), leaving the reactive T cells behind and leading to misdiagnosis of an incontinued on page 106

The ASCO Post | OCTOBER 25, 2015

PAGE 106

Hematology Expert Review Hematology Quiz continued from page 105

flammatory reaction; this microscopic finding is sometimes referred to as a “vanishing tumor.”6 In rare cases, immediate initiation of steroids with surgical resection of the tumor may be considered to decompress a rapidly expanding mass in patients presenting with herniation. In these patients, resection is lifesaving and restores neurologic function, allowing appropriate medical therapy to follow.7 In our patient, the stereotactic biopsy confirmed the histologic diagnosis of primary diffuse large B-cell lymphoma of the CNS. Question 3: What is the characteristic biopsy finding in an immunocompetent host with primary diffuse large B-cell lymphoma of the CNS? Correct Answer: A. Perivascular growth pattern.

Expert Perspective In an immunocompetent host, the diagnosis of CNS lymphoma is typically established following a successful stereotactic biopsy, as opposed to tissue samples from larger resections, as there is a paucity of data to support therapeutic benefit with extensive resection.7 The vast majority of CNS lymphomas are of B-cell origin, predominantly diffuse large B-cell lymphoma, but Burkitt lymphoma, acute lymphoblastic lymphoma, marginal zone lymphoma, extraosseous plasmacytoma, and intravascular B-cell lymphoma are also rarely seen. Moreover, less than 4% of primary CNS lymphomas are of T-cell origin.8 Microscopically, primary diffuse large B-cell lymphoma of the CNS is composed of high-grade neoplastic cells that grow in a characteristic perivascular pattern in concentric rings around the blood vessel wall (“angiocentric”) without invasion of the lumen6 (Fig. 3A and 3B). The prominent perivascular growth pattern, creating a favorable growth en-

vironment, might be explained by overexpression of interleukin-4 in the tumor cells and vessels.9 Necrosis and reactive T cells may be seen, particularly in patients treated with steroids before biopsy, resulting in diagnostic difficulties.10 Primary CNS lymphomas do not have the degree of vascular proliferation commonly observed in glioblastomas.

In an immunocompromised patient with primary CNS lymphoma, findings of necrosis and hemorrhage are not uncommon on a biopsy specimen.6 On immunophenotyping, all primary diffuse large B-cell lymphomas of the CNS are positive for the B-cell markers CD20, CD22, or CD79a. CD10 expression is present in approximately 10% to 20%, and BCL-6 is present in 60% to 80%, with a strong MUM1/IRF4 in approximately 90% of cases. BCL-2 is often present but is not related to t(14;18) (q32;q21). MIB1 is often markedly elevated; most tumor lesions have a proliferative index that exceeds 50%11 (Fig. 3C). Programmed cell death protein 1 (PD-1; CD279) and its ligand (PD-L1; CD274) have been reported in CNS lymphomas as well as tumor-infiltrating lymphocytes and tumor-associated macrophages.12 These histologic findings might be of therapeutic value.

The V600E BRAF protein expression has not been detected in these tumors.13 In an immunocompetent host, EpsteinBarr virus is generally absent in the tumor cells. However, in an immunocompromised host, the tumor cells are infected with Epstein-Barr virus in the majority (> 95%) of patients with primary diffuse large B-cell lymphoma of the CNS. n

Disclosure: Drs. Abutalib and Lukas reported no potential conflicts of interest.

References 1. Blondin NA, Baehring JM, Hochberg FH: Primary CNS lymphoma, in Abutalib SA, Markman M (eds): Cancer Consult: Expertise for Clinical Practice, pp 308-315.

Hoboken, NJ, Wiley-Blackwell, 2015.

A

C 2. Ney DE, Deangelis LM: Management of central nervous system lymphoma, in Mauch PM, Armitage JO, Coiffier B, et al (eds): Non-Hodgkin Lymphomas, 2nd ed, pp 527-539. Philadelphia, Lippincott Williams & Wilkins, 2010.

3. Hochberg FH, Miller DC: Primary central nervous system lymphoma. J Neurosurg 68:835-853, 1988.

4. Barrington SF, Mikhaeel NG, Kostakoglu L, et al: Role of imaging in the staging and response assessment of lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 32:3048-3058, 2014.

5. Boiardi A, Silvani A: Primary cerebral non-Hodgkin’s lymphoma (PCNSL): A review of new trends in management. Ital J Neurol Sci 18:1-7, 1997.

6. Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon, France, International Agency for Research on Cancer, 2008.

7. Gerstner E, Batchelor T: Primary CNS lymphoma. Expert Rev Anticancer Ther 7:689-700, 2007.

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B Fig. 3: Primary diffuse large B-cell lymphoma of the CNS. (A) Accumulation of tumor cells within the perivascular space. (B) High-powered field, with accumulation of abnormal large B cells in the perivascular space forming a concentric ring. (C) Strong MIB1 staining is found in approximately 60% to 70% of large B cells in the perivascular space. (Photos courtesy of Supriya Raina-Hukku, MD, Department of Pathology, Cancer Treatment Centers of America)

8. Shenkier TN, Blay JY, O’Neill BP, et al: Primary CNS lymphoma of T-cell origin: A descriptive analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol 23:2233-2239, 2005.

9. Rubenstein JL, Fridlyand J, Shen A, et al: Gene expression and angiotropism in primary CNS lymphoma. Blood 107:37163723, 2006.

10. Singh A, Strobos RJ, Singh BM, et al: Steroid-induced remissions in CNS lymphoma. Neurology 32:1267-1271, 1982.

11. Deckert-Schlüter M, Rang A, Wiestler OD: Apoptosis and apoptosis-related gene products in primary non-Hodgkin’s lymphoma of the central nervous system.

Acta Neuropathol 96:157-162, 1998.

12. Berghoff AS, Ricken G, Widhalm G, et al: PD1 (CD279) and PD-L1 (CD274, B7H1) expression in primary central nervous system lymphomas. Clin Neuropathol 33:42-49, 2014.

13. Berghoff AS, Capper D, Preusser M: Lack of BRAF V600E protein expression in primary central nervous system lymphoma.

Appl Immunohistochem Mol Morphol 21:351-353, 2013.

Trusted to take a bite out * of G-CSF acquisition costs GRANIX® has gained >34% share of the US short-acting G-CSF hospital market in its first 17 months1 » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)2 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)2 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)2 » Offering a presentation for self-administration

Indication

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

Important Safety Information

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

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

For more information, visit GRANIXhcp.com. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of March 2015. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

References: 1. This information is an estimate derived from the use of information under license from the following IMS Health Information Service: IMS National Sales Perspective, GRANIX micrograms by non-federal hospital channel March 2015. IMS expressly reserves all rights, including rights of copying, distribution, and republication (micrograms calculated as eaches x strength). 2. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40681 May 2015.

The ASCO Post | OCTOBER 25, 2015

PAGE 108

Tumor Immunology

A Snapshot of Early Immunotherapy

By Ronald Piana

O

ver the past several years, immunotherapy has had a renaissance of sorts, emerging as one of the most active areas in cancer research. For instance, we have seen the therapeutic promise of dis-

rupting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) immune checkpoints in cancer, which has encouraged large clinical studies in this and other promising investigations in im-

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

4 CONTRAINDICATIONS None.

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

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

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

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

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

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

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

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

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

724-43395

DIGITAL

mune therapy. And although immunotherapy’s potential is now energizing the oncology community, this pioneering line of cancer treatment has been around, in one form or another, for centuries.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Job Number: 21282 Revision No: 0

The First Clinical Trial The early paradigm that shaped the development of most cancer therapies, until recently, was grounded in the observations based on infectious disease.

And those observations began early in human history. Thucydides, a prominent Greek historian, first recorded resistance to a specific disease in 430 B.C. After the devastating plague of Athens, Thucydides, a survivor himself, noticed that the disease never attacked the same survivor twice. In his writings, he postulated that those surviving the plague had acquired some uncanny form of resistance to the disease, which is one of the first known observations of the immune system in action.

Thucydides, a Greek historian, first recorded resistance to a specific disease in 430 B.C.

The first recorded immunotherapy trial was conducted in Newgate Prison, London, in 1721. During her travels, the Princess of Wales had heard of miraculous resistance following deliberate or accidental exposure to smallpox exposure. Fearing her children might contract the dreaded disease, she granted Charles Maitland, MD, permission to perform a trial on six condemned prisoners. The subjects were infected with pus from individuals who had smallpox, and then he exposed them to active cases. All of the prisoners on the “smallpox trial” survived; out of gratitude for their participation, they were released from prison 1 month later.

In 1796, the British physician, ­Edward Jenner, MD, demonstrated that the deliberate infection with the Vaccinia virus, which caused cowpox—an infection akin to smallpox but much weaker—was protective against smallpox. Building on Dr.

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PAGE 109

Tumor Immunology

Edward Jenner, MD

­Jenner’s work, Louis Pasteur, ScD, in the 1880s, demonstrated that immunity to one condition protected patients against reexposure to the same condition, without affording protection to an unrelated condition.

Louis Pasteur, ScD

Dr. Pasteur’s experiments also showed for the first time that artificially mitigated pathogens could be effective protective agents against disease. Dr. Pasteur named these agents “vaccines” in honor of Dr. Jenner’s work with the Vaccinia virus. This groundbreaking research would lead to smallpox vaccinations, which eventually eradicated the scourge of smallpox, saving countless millions of lives.

Infectious Disease and Tumor Immunology As our knowledge of the specifics of tumor immunology expands, we will be able to fully capitalize on the exquisite specificity of the immune system’s ability to treat cancer in highly targeted ways, with minimal side effects. The earliest reports of an immune response related to cancer came from the documents of a priest named Peregrine Laziosi, who was born around 1260, in northern Italy.

In his early 40s, Peregrine was conducting his business as a resident priest—converting and reconciling

sinners—when he noticed a growth emerging on his leg. It was on his tibia, and the leading doctor of the day pronounced it as malignant. The lesion grew to the point where it broke through the skin and became severely infected, “giving off such a stench that it could be endured by no one sitting by him.”

His only option was to have the diseased leg amputated. A few days before the brutal procedure was to take place, the physician was astonished when he noticed that there was no sign of cancer. Naturally, the physicians in the 11th century did not ponder whether a spontaneous febrile immune response saved Peregrine; they concluded it was a miracle. The priest’s cancer never recurred, and he lived to the ripe old age of 85. Several centuries later, he was canonized as the patron saint of cancer.

Using the immune system to battle cancer began to gain traction in 1866, when noted German physician, ­Wilhelm Busch, MD, observed that some of his patients with sarcomas had tumor regressions after surviving postoperative wound erysipelas, an infection with a bacterial species of Streptococcus. Intrigued by this phenomenon, he deliberately infected a postoperative sarcoma with pus from another patient with postoperative erysipelas in an attempt to induce tumor regression. He did, but it was minimal and short-lived. Dr. Busch’s attempt at generating a spontaneous cancer-killing immune response was one of the earliest forays into cancer immunotherapy.

The Father of Immunotherapy A physician named William Coley, MD, now regarded as the “Father of Immunotherapy,” took immunotherapy to the next level. Dr. Coley began his career as a young surgeon at New York Memorial Hospital. His search for new ways to treat patients with cancer began after the loss of his very first patient.

A 17-year-old woman who had injured her hand presented with persistent pain and inflammation. Dr. Coley diagnosed her lesion as a sarcoma of the bone and opted to amputate her right arm below the elbow. Despite no evidence of metastases, the young woman died of her disease 2 months after surgery, leaving Dr. Coley shaken by his clinical failure.

Over the past several years, immunotherapy has had a renaissance of sorts, emerging as one of the most active areas in cancer research. This pioneering line of cancer treatment has been around, in one form or another, for centuries.

He spent months pouring through the literature; he discovered the record of an immigrant patient who presented with an egg-sized sarcoma on his left cheek. The tumor was excised twice but recurred after each surgery. The patient was considered terminal. However, a wound after the last surgery resulted in severe erysipelas infection, and the patient developed a very high fever. Little could be done to control the fever, yet after each spike, the tumor shrank and finally disappeared. The patient was discharged 4 months later.

cess. After an initial response to his vaccine, many of his patients died from the infections, as his experimental work predated the development of antibiotics.

Shortly before Dr. Coley’s death in 1936, Coley’s Toxins received an endorsement in the New and Nonofficial Remedies of the American Medical Association, which stated: “Its use as a prophylactic in conjunction with conservative or radical surgery’’ and ‘‘inoperable cases may be quite justified.”

However, the lack of a known mechanism of action for Coley’s Toxins and the risks of deliberately infecting cancer patients with pathogenic bacteria caused oncologists to adopt surgery and radiotherapy as standard treatments early in the 20th century.

Hit and Miss

William Coley, MD

Dr. Coley spent weeks searching the Lower East Side for the patient, eventually finding him. The man told Dr. Coley that he had no trace of cancer and felt fine since his discharge from the hospital, 7 years ago. Energized by this sarcoma patient’s success, Dr. Foley continued to search for more evidence, eventually discovering a number of cases in which patients with cancer went into spontaneous remissions after developing erysipelas infections and high fevers.

In 1891, Dr. Coley began injecting mixtures of live and inactivated Streptococcus pyogenes into his patients’ tumors. He achieved responses in several types of malignancies, including sarcoma, lymphoma, and testicular carcinoma. His further work in immunotherapy resulted in a vaccine called Coley’s Toxins, with which he treated hundreds of patients with cancer, with varying degrees of suc-

Using attenuated bacteria to treat malignancies resurfaced in 1976, when a trial was conducted to test the tuberculosis vaccine Bacille CalmetteGuerin as an agent to prevent the recurrence of nonmuscle invasive bladder cancer. This therapy proved effective and is still used today.

However, although promising from a theoretical standpoint, several misfires occurred, and dedicated research in immunotherapy went into dormancy, as promising combination regimens and targeted therapies were developed. However, the promise of harnessing the immune system’s power to eradicate cancer cells was reinvigorated, and we have seen a decade of promising research.

This year, ASCO recognized immunology pioneer James P. Allison, PhD, awarding him the Society’s Science of Oncology award. Dr. Allison’s research focuses on new drug development that blocks checkpoints or stimulates the immune system. Dr. Allison, and many others in the oncology community, is confident that this line of therapy, which has stirred the interest of clinicians for centuries, will eventually prove be an invaluable tool in our fight against cancer. n

The ASCO Post | OCTOBER 25, 2015

PAGE 110

Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Breast Cancer Compiled by Liz Janetschek

T

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with breast cancer. The trials are investigating cancer risk based on breast density; novel imaging techniques; fasting and chemotherapy; radiosurgery; lymph node dissection; and interpersonal therapy for depression. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

OBSERVATIONAL Study Type: Observational Study Title: Longitudinal Changes in Mammographic Density and Risk of Breast Cancer Study Sponsor and Collaborators: Case Comprehensive Cancer Center, National Cancer Institute Purpose: To study changes in breast density and gathering health information over time to assess breast cancer risk in women with breast cancer and in healthy women Primary Outcome Measures: Within-individual mammographic density (MD) longitudinal change and breast cancer risk, patterns of withinindividual longitudinal change in MD, predictors of across-individual differences in MD change [time frame: cancer cases diagnosed within the last 3 years (2004–2006)] Principal Investigator: Li Li, MD, PhD, and Cheryl Thompson, PhD, Case Medical Center/University Hospitals Seidman Cancer Center/Case Comprehensive Cancer Center; 216844-3944, lili@uhhospitals.org ClinicalTrials.gov Identifier: NCT00445445

PHASE I Study Type: Phase I/interventional/ single-group assignment Study Title: FBnTP Positron Emission Mammography Imaging of Mitochondria Function–Breast Cancer Study Sponsor and Collaborators: Sidney Kimmel Comprehensive

Cancer Center Purpose: To study the capacity of the positron emission tomography imaging agent 18F-fluorobenzyl triphenyl phosphonium (FBnTP) to detect earlystage small breast tumors (eg, DCIS) and differentiate benign from malignant masses with better accuracy than that obtained by existing breast imaging tools Primary Outcome Measures: ­Malignant breast cancer detection [time frame: pretreatment] Principal Investigator: Igal Madar, PhD, Johns Hopkins University; contact John Crandall, 410-502-2186, jcranda1@jhmi.edu ClinicalTrials.gov Identifier: NCT02204462

PHASE I/II Study Type: Phase I/II/interventional/single-group assignment Study Title: A Pilot Study of Shortterm Fasting on Neoadjuvant Chemotherapy in Patients With Newly Diagnosed Breast Cancer (STEFNE Study) Study Sponsor and Collaborators: Western Regional Medical Center Purpose: To study how safe the use of short-term fasting is in breast cancer patients who will receive chemotherapy before undergoing surgery and to examine if the use of short-term fasting will decrease the side effects of chemotherapy and how much a tumor shrinks while receiving chemotherapy Primary Outcome Measures: Evaluate pathologic complete remission rate at the time of surgery or partial pathologic response rate (defined

as residual invasive disease of 1cm) at the time of surgery or at the time of biopsy upon completion of planned chemotherapy [time frame: 4–6 cycles (up to 12 weeks)] Principal Investigator: Jiaxin Niu, MD, PhD, Western Regional Medical Center; contact 623-207-3000, westerntrials@ctca-hope.com ClinicalTrials.gov Identifier: NCT02379585

PHASE II Study Type: Phase II/interventional/ single-group assignment Study Title: A Phase II Study of Stereotactic Radiosurgery Plus HER2 Directed Therapy in HER2-Positive Breast Cancer With Brain Metastasis Study Sponsor and Collaborators: University of Maryland Purpose: To determine if treatment with stereotactic radiosurgery followed by a HER2-directed therapy regimen results in a 6-month distant brain relapse rate of less than 30% Primary Outcome Measures: Relapse rate (primary) [time frame: 12 months] Principal Investigator: Elizabeth Nichols, MD, University of Maryland Baltimore; contact Bahiyyah Jackson, MS, 410-328-7586, bjackson1@umm.edu ClinicalTrials.gov Identifier: NCT01924351

PHASE III Study Type: Phase III/interventional/parallel assignment Study Title: A Randomized Phase III Trial Comparing Axillary Lymph Node Dissection to Axillary Radiation in Breast Cancer Patients (cT13 N1) Who Have Positive Sentinel Lymph Node Disease After Neoadjuvant Chemotherapy Study Sponsor and Collaborators: Alliance for Clinical Trials in Oncology,

National Cancer Institute Purpose: To study axillary lymph node dissection to see how well it works compared to axillary radiation therapy in treating patients with nodepositive breast cancer treated with neoadjuvant chemotherapy followed by surgery Primary Outcome Measures: Invasive breast cancer recurrence-free interval (IBC-RFI) [time frame: up to 5 years after completion of radiation therapy] Principal Investigator: Judy Boughey, MD, Mayo Clinic; see ­ClinicalTrials.gov record for study locations and contacts ClinicalTrials.gov Identifier: NCT01901094

PHASE IV Study Type: Phase IV/interventional/parallel assignment Study Title: Interpersonal Therapy for Depression in Breast Cancer Study Sponsor and Collaborators: New York State Psychiatric Institute Purpose: To compare the efficacy of interpersonal psychotherapy (IPT), problem-solving therapy (PST), and brief supportive psychotherapy (BSP), in improving depressive symptoms, psychosocial functioning, and quality of life among patients with breast cancer and major depressive disorder Primary Outcome Measures: Hamilton Depression Scale (HAMD-17) [time frame: weeks 1, 4, 8, 12, 16, 24, 32] Principal Investigator: Carlos Blanco, MD, PhD, New York State Psychiatric Institute; 646-774-8111, cb255@columbia.edu ClinicalTrials.gov Identifier: NCT01191580 n Editor’s Note: The clinical trials presented here do not represent all the trials listed on ClinicalTrials.gov. For the complete list, go to ClinicalTrials.gov.

October is Breast Cancer Awareness Month

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Announcements

American Cancer Society Awards 2015 Medals of Honor

T

he American Cancer Society has bestowed its highest honor on four individuals and one foundation during the Society’s 2015 Medal of Honor ceremony and celebration dinner in Washington, DC. The Medal of Honor is awarded to those who have made the most valuable contributions and impact in the fight to end cancer through basic research, clinical research, cancer control, or philanthropy.

James P. Allison, PhD Dr. Allison was awarded the American Cancer Society Medal of Honor for Basic Research for his pioneering work on the regulation of immune cell activation and defining immune checkpoint blockade. His research has resulted in major advances in immunotherapy for cancer and the first FDA-approved drug for the treatment of metastatic melanoma. Dr. Allison is a Professor in the Department of Immunology, Division of Basic Science Research at the University of Texas MD Anderson Cancer Center.

Steven A. Rosenberg, MD, PhD

James P. Allison, PhD

The 2015 recipients are James P. Allison, PhD, for Basic Research; Steven A. Rosenberg, MD, PhD, for Basic Research; Jack Cuzick, PhD, for Clinical Research; Sidney Jerome Winawer, MD, for Cancer Control; and The Richard M. Schulze Family Foundation, for Philanthropy.

“Our Medal of Honor recipients truly embody what the American Cancer Society is all about,” said Gary Reedy, CEO of the American Cancer Society. “Each of this year’s recipients has significantly contributed to the advancement and impact of our collective efforts to eliminate cancer as a major health problem.”

Dr. Rosenberg was presented with the Medal of Honor for Basic Research for the development of adoptive immunotherapy that resulted in the first effective immunotherapies for selected patients with advanced cancer. His recent studies of the adoptive transfer of genetically modified lymphocytes have resulted in the regression of metastatic cancer in patients with melanoma, sarcomas, and lymphomas. Dr. Rosenberg is Chief of Surgery at the National Cancer Institute and a Professor of Surgery at the Uniformed Services University of Health Sciences and at the George Washington University School of Medicine and Health Sciences.

Jack Cuzick, PhD Dr. Cuzick was awarded the American Cancer Society Medal of Honor for Clinical Research for his contributions to the field of biostatistics, epidemiolo-

Steven A. Rosenberg, MD, PhD

Jack Cuzick, PhD

gy, and clinical medicine. Over the past 3 decades, Dr. Cuzick has demonstrated consistent leadership in cancer prevention and screening, including chemoprevention and cancer treatment. He is internationally known for advancing the field of breast cancer chemoprevention through his work with tamoxifen and most recently the research that contributed to the introduction of aromatase inhibitors, both for the treatment of breast cancer and as an agent for chemoprevention. He is the codeveloper of a widely used breast cancer risk estimation model and has been a leader in the design and analysis of clinical trials of cancer prevention, early detection, and treatment. Dr. Cuzick is Director of Wolfson Institute of Preventive Medicine and Head of the Centre for Cancer Prevention and John Snow Professor of Epidemiology at Queen Mary, University of London.

Sidney Jerome Winawer, MD Dr. Winawer received the Medal of Honor for Cancer Control in recognition of his lifetime contributions and dedication to advance screening and prevention of colorectal cancer.

Sidney Jerome Winawer, MD

His monumental work has expanded the colorectal cancer knowledge base, documenting the impact of colonoscopy and polyp removal in reducing colorectal cancer incidence and mortality. Dr. Winawer is an attending physician and member with tenure and holds the Paul Sherlock Chair in Medicine at Memorial Sloan Kettering Cancer Center and is also a Professor of Medicine at Weill Cornell Medical School.

The Richard M. Schulze Family Foundation Based in Minneapolis and Naples, Florida, the Richard M. Schulze Family Foundation was awarded the Medal of Honor for Philanthropy for a $7.5 million grant to expand the Hope Lodge in Rochester, Minnesota, and to build the Twin Cities Hope Lodge in Minneapolis. Mr. Schulze is a founder of Best Buy and has been an officer and director since its inception in 1966 and is currently Founder and Chairman Emeritus. He is a trustee of the University of St. Thomas and Chairman of the Board of Governors of the University of St. Thomas Business School. n

Don’t Miss These Important Reports in This Issue of The ASCO Post Jonas A. de Souza on Financial Toxicity and Cancer Care see page 1

Padmanee Sharma, MD, on Nivolumab in Advanced Renal Cell Carcinoma see page 1

Toni Choueiri, MD, on Cabozantinib vs Everolimus in Advanced Renal Cell Carcinoma see page 3

Martin Reck, MD, on Atezolizumab in NSCLC see page 5

Frederic Amant, MD, on Chemotherapy and Radiotherapy in the Second and Third Trimesters of Pregnancy see page 15

Philippe Ruszniewski, MD, on Expanded Treatment Options in Neuroendocrine Tumors see page 16

Visit The ASCO Post online at ASCOPost.com

2 FDA APPROVALS For use both as monotherapy and in combination with paclitaxel

CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal (GE) junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions

Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs) • Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/ tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforations was also increased in patients who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing • Impaired wound healing can occur with antibodies inhibiting the VEGF pathway.

CYRAMZA has not been studied in patients with serious or nonhealing wounds.

CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

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

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome • Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction • Monitor thyroid function during treatment with CYRAMZA. Embryofetal Toxicity • Based on its mechanism of action, CYRAMZA can cause fetal harm when

CYRAMZA® (ramucirumab) PLUS PACLITAXEL SIGNIFICANTLY EXTENDED OVERALL SURVIVAL (OS)1 RAINBOW OS: MEDIAN - MONTHS (95% CI)*1 1.0

CYRAMZA + paclitaxel (8.5, 10.8)

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

9.6

MONTHS

30% INCREASE IN MEDIAN OS

0.6

Hazard Ratio=0.81 (0.68, 0.96); P=0.017

0.4

7.4

0.2

MONTHS

CYRAMZA + paclitaxel Placebo + paclitaxel (6.3, 8.4)

Placebo + paclitaxel

0.0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

78

60

41

24

13

6

1

0

294

241

180

143

109

81

64

47

30

22

13

5

2

0

• The percentage of deaths at the time of analysis was 78% (256 patients) and 78% (260 patients) in the CYRAMZA plus paclitaxel and placebo plus paclitaxel treatment arms, respectively1 The phase III RAINBOW trial evaluated the efficacy and safety of CYRAMZA plus paclitaxel vs placebo plus paclitaxel in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- and platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). All patients were Eastern Cooperative Oncology Group performance status 0 or 1. Prior to enrollment, 97% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease. Twenty-five percent of patients had received anthracycline in combination with platinum/ fluoropyrimidine therapy, while 75% did not. Patients were randomized 1:1 to CYRAMZA 8 mg/kg (n=330) or placebo (n=335) every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle.1,3 CI=confidence interval. *Intent-to-treat (ITT) population. † ITT population.

ORR was defined as complete plus partial response. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2

CYRAMZA PLUS PACLITAXEL ALSO SIGNIFICANTLY DELAYED DISEASE PROGRESSION AND PROVIDED SIGNIFICANTLY GREATER ORR VS PLACEBO PLUS PACLITAXEL (SUPPORTIVE EFFICACY OUTCOME MEASURES)*1 • Median PFS with CYRAMZA plus paclitaxel was 4.4 months (95% CI: 4.2, 5.3) vs 2.9 months (95% CI: 2.8, 3.0) with placebo plus paclitaxel (hazard ratio 0.64 [95% CI: 0.54, 0.75]; P<0.001)1 - The percentage of events at the time of analysis was 85% (279 patients) and 88% (296 patients), respectively • Significantly more patients responded to CYRAMZA combined with paclitaxel (28%; 95% CI: 23, 33) than to placebo plus paclitaxel (16%; 95% CI: 13, 20) (P<0.001)†1,2

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

Most Common Adverse Reactions—Single Agent • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZAtreated patients in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusionrelated reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusionrelated reactions was 0.4%.

Most Common Adverse Reactions—Combination with Paclitaxel • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).

• The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.

• Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).

• Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).

Drug Interactions • No pharmacokinetic interactions were observed between ramucirumab (CYRAMZA) and paclitaxel.

Use in Specific Populations • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm.

Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development.

Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page.

RB HCP ISI 24APR2015 References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 2. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group.

Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. 3. Data on file, Eli Lilly and Company. ONC09302014b.

RB97116

05/2015 PRINTED IN USA

© Lilly USA, LLC 2015. All rights reserved.

CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGE Gastric Cancer CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

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

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

Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients. ®

CYRAMZA (ramucirumab) injection

RB-G HCP BS 29APR2015

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women.

Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks.

Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal.

CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo N=236 N=115 Adverse Reactions (MedDRA)a System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a

MedDRA Version 15.0.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.

In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 CYRAMZA plus Paclitaxel Placebo plus Paclitaxel (N=327) (N=329) Adverse Reactions (MedDRA) System Organ Class All Grades Grade ≥3 All Grades Grade ≥3 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Neutropenia Thrombocytopenia Gastrointestinal Disorders Diarrhea Gastrointestinal hemorrhage events

54 13

41 2

31 6

19 2

32 10

4 4

23 6

2 2

1

7

1

12 2

44 14

6 1

1

5

1

1

6

0

0

7

0

15

6

3

Stomatitis 20 General Disorders and Administration Site Disorders Fatigue/Asthenia 57 Peripheral edema 25 Metabolism and Nutrition Disorders Hypoalbuminemia 11 Renal and Urinary Disorders Proteinuria 17 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 31 Vascular Disorder Hypertension 25 ®

CYRAMZA (ramucirumab) injection

RB-G HCP BS 29APR2015

Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic interactions were observed between ramucirumab and paclitaxel.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.

PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness].

• Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event.

• Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment.

• Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA Additional information can be found at www.CYRAMZAHCP.com.

DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to paclitaxel, refer to the current prescribing information.

CYRAMZA® (ramucirumab) injection

RB-G HCP BS 29APR2015

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2015, Eli Lilly and Company. All rights reserved.

RB-G HCP BS 29APR2015 CYRAMZA® (ramucirumab) injection

RB-G HCP BS 29APR2015

The ASCO Post | OCTOBER 25, 2015

PAGE 116

Patient’s Corner

The Race of My Life

Two bouts of breast cancer have taught me the importance of living for today.

By Louise Cooper, as told to Jo Cavallo

I

’ve lived my adult life by three guiding principles I learned as an adventure racer: to set goals, to determine how to achieve them, and to persevere in the face of adversity. Those standards helped me complete more than 70 marathons and 7 Ironman competitions, and they helped me conquer breast cancer twice.

The first time was 17 years ago, when I was just 44 and found a lump in my left breast. The diagnosis was HER2-positive ductal carcinoma in situ. Because I had early-stage disease and my oncologist was aware of my athleticism and my desire to preserve as much of my upper body muscle mass as possible, he recommended a partial mastectomy (rather than a total mastectomy) and an aggressive course of trastuzumab (Herceptin) plus carboplatin and docetaxel, followed by 6 weeks of daily radiation therapy.

Because trastuzumab was so new in the clinic—the U.S. Food and Drug Administration had approved the drug just a few weeks after my diagnosis— my oncologist wasn’t sure how effective the treatment would be for me.

But 2 years later, there were no signs of Louise Cooper is a marathon runner and elementary school teacher. She lives in West Hills, California.

cancer in my body, and for the next 15 years, I was able to continue with my active lifestyle and my teaching career uninterrupted.

has only reinforced my desire to live each day as fully as possible. I’m determined to do everything I want to do, and if cancer eventually takes my life,

Living a full life takes the same kind of unrelenting determination as conquering cancer: having a plan, executing the plan, and living each day as if it is your last.

—Louise Cooper

Then, in 2014, I was diagnosed with a second breast cancer in the same breast.

This time it was triple-negative disease, and after consulting with my medical team, I decided to have a contralateral prophylactic mastectomy. After the surgery, I had several more rounds of combination carboplatin and docetaxel chemotherapy. Today, I am once again running marathons and working out daily, although not at the level I was able to achieve before this second cancer.

Making a Contribution to Research As someone who has never been on the sidelines of life, having cancer

I’ll know that I left nothing undone and will have no regrets.

Cancer has also given me the desire to give back. I’ve been so fortunate to have an oncology team that not only took great care of my medical needs, but gave me a sense of connection as well, and I’m hoping I can do the same for other women diagnosed with breast cancer.

Earlier in 2015, I joined the “Share the Journey: Mind, Body, and Wellness” clinical study (sharethejourneyapp.org [see article in The ASCO Post, September 10]), which is investigating the symptoms many women experience after breast cancer treatment,

Patient Guides Available Through ASCO University Bookstore

why these symptoms vary over time, and what can be done to improve them. It is my great wish that my contribution to this important study will help improve the lives of all breast cancer survivors.

Soon after I joined Share the Journey, two of my friends were diagnosed with the disease, and I immediately sent them the link to the study so they, too, could get involved and stay informed.

On a personal level, participating in the study also helps me feel less alone and gives me a sense of connection with researchers doing such important work in breast cancer.

Lessons Learned Being a two-time cancer survivor has not derailed my enthusiasm for life or diminished the joy and focus I get from leading an active lifestyle.

I applied that same laser-like focus I learned from years of sports competitions to overcome breast cancer, and it is what I use now to give me back a sense of control when I’m feeling anxious about the future.

Living a full life takes the same kind of unrelenting determination as conquering cancer: having a plan, executing the plan, and living each day as if it is your last. n

The ASCO Post

Wants to Hear From You

• ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

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

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/ survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

www.ASCOPost.com

Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

ASCOPost.com | OCTOBER 25, 2015

PAGE 117

In the News Gastrointestinal Oncology

Important Caveats to Consider Concerning Low-Dose Daily Aspirin for the Primary Prevention of Colorectal Cancer

By Charlotte Bath

T

he use of low-dose aspirin by most adults aged 50 to 59 for the primary prevention of colorectal cancer is now included in the U.S. Preventive Services Task Force (USPSTF) updated draft recommendation statement, “Aspirin to Prevent Cardiovascular Disease and Cancer.”1 The release of the statement in September was widely reported by major media, including The New York Times2 and The Washington Post,3 which pointed out the statement marked the first time the USPSTF had recommended daily aspirin to prevent colorectal cancer and that it sparked diverse reactions. These reactions ranged from support and excitement about another option for colorectal cancer prevention to caution about the potential harms of aspirin use and overemphasis of the role of aspirin in preventing colorectal cancer.

“I have major concerns that the message will be, ‘I take aspirin, so I don’t need to be screened,’” said David Johnson, MD, a member of the U.S. Multi-Society Task Force on Colorectal Cancer, who was quoted in The New York Times.2 Elaborating on this and other caveats to the USPSTF draft recommendations, Dr. Johnson, Professor of Medicine and Chief of Gastroenterology at Eastern Virginia Medical School, Norfolk, and Past President of the American College of Gastroenterology, told The ASCO Post that it is “really important not to take [the USPSTF

recommendation] out of context.”

“This does not subrogate the appropriate need for colonoscopy for screening, which is the best test for colon cancer prevention because we remove premalignant polyps,” Dr. Johnson stated. The recommendation concerning aspirin “doesn’t decrease the message that patients still need screening

increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. Those aged 60 to 69 who have a 10% or greater 10-year risk of cardiovascular disease, and particularly those who meet the other criteria, may also benefit from daily low-dose aspirin, but the decision to do so should

I have major concerns that the message will be, ‘I take aspirin, so I don’t need to be screened.’ … It is really important not to take [the USPSTF recommendation] out of context.

—David Johnson, MD

by colonoscopy for true prevention of colon cancer.” But taken out of context, “the danger would be that patients may shy away from colonoscopy,” Dr. ­Johnson explained.

Update of Previous Recommendations The draft recommendations advise daily low-dose aspirin (75 to 81 mg/d) for the primary prevention of cardiovascular disease and colorectal cancer in adults aged 50 to 59 who have not been diagnosed with cardiovascular disease, but have a 10% or greater 10-year risk of cardiovascular disease, are not at

be made on an individual basis. The evidence was insufficient for the U ­ SPSTF to recommend daily aspirin use for adults younger than 50 or older than 70.

An explanatory document noted that the task force “found that people at increased risk of cardiovascular disease who take aspirin for at least 10 years can also reduce the likelihood of developing colorectal cancer. However, they found no direct evidence that people who are at increased risk for colorectal cancer but not cardiovascular disease would benefit overall from taking aspirin.”4 To update its 2007 recommendation concerning aspirin and nonsteroi-

dal anti-inflammatory drugs (NSAIDs) to prevent colorectal cancer and the 2009 recommendation on aspirin to prevent cardiovascular disease events, the ­USPSTF reviewed four additional studies of aspirin and cardiovascular disease and several additional analyses of colorectal cancer follow-up data.

“The USPSTF also relied on reviews of all-cause mortality and total cancer incidence and a comprehensive review of harms. The USPSTF then used a microstimulation model to systematically estimate the balance of benefits and harms,” according to the draft document.

“The evidence supports what the recommendation is,” Dr. Johnson said.

“There are clearly a number of caveats that I think need to be registered with that recommendation, however.”

In addition to the caveat about aspirin use not supplanting colonoscopy, Dr. Johnson cited concerns about the target population, risk stratification, and the potential harms of aspirin use, particularly when combined with NSAIDs.

May Be ‘Timeline Bias’ The USPSTF recommendation “is focused on a very specific age range, which to me seems somewhat nonsensical. And there may be a timeline bias that the risk of cancer is potentially pushed back, not necessarily decreased overall, because of the limited focus on continued on page 120

Expect Questions From Patients About Daily Aspirin to Prevent Colorectal Cancer

By Charlotte Bath

U

pdating previous recommendations, the U.S. Preventive Services Task Force now recommends lowdose aspirin for the primary prevention of colorectal cancer among most adults age 50 to 59. This a draft recommendation, but it has generated major media coverage noting that this is the first time the USPSTF has recommended aspirin to prevent colorectal cancer.

In an interview with The ASCO Post, David Johnson, MD, a member of the U.S. Multi-Society Task Force on Colorectal Cancer, expressed concern that some patients may extract part of that information and just start taking as-

pirin, without considering the potential harms. Dr. Johnson is Professor of Medicine and Chief of Gastroenterology at Eastern Virginia Medical School, Norfolk, and Past President of the American College of Gastroenterology.

Potential harms associated with aspirin use include increased risk of gastrointestinal bleeding and hemorrhagic stroke. The Task Force acknowledged these potential harms, determining that they vary with individual risk but are small in adults aged 59 and younger and small to moderate in adults ages 60 to 69. Dr. Johnson noted that patients may have

other risk factors they may or may not be aware of and may be taking other over-the counter nonsteroidal antiinflammatory drugs (NSAIDs) that could increase the risk of bleeding.

‘May Not Be Quite So Simple’ “Unfortunately, sometimes patients take a part of the information because they want something simple.

And it may not be quite so simple,” Dr. Johnson said. “It may be they need to get screened—not just take a pill and prevent a disease.”

To guard against oversimplification, “patients and health-care pro-

viders—not just physicians—should communicate well and discuss anything related to a health issue, especially when it comes to something as critical as the prevalent disease of colon cancer in this country, “ Dr. Johnson advised. “I am for anything that will decrease colon cancer,” Dr. Johnson affirmed. He added that a riskbenefit assessment would be a good starting point.

The USPSTF updated draft recommendation statement, “Aspirin to Prevent Cardiovascular Disease and Cancer,” is available at www.uspreventiveservicestaskforce.org. n

When multiple myeloma relapses

INDICATION Kyprolis® (carfilzomib) for Injection is a proteasome inhibitor that is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.

IMPORTANT SAFETY INFORMATION Cardiac Toxicities: New onset or worsening of pre-existing cardiac

failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration.

Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/ risk assessment.

Adequate hydration is required prior to each dose in Cycle 1. Monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.

Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities may be at greater risk for cardiac complications.

until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.

Dyspnea: Dyspnea was reported in patients treated with Kyprolis.

Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Hypertension: Hypertension, including hypertensive crisis and

hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Venous Thrombosis: Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. Thromboprophylaxis is recommended and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Acute Renal Failure: Cases of acute renal failure and renal

Infusion Reactions: Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.

Tumor Lysis Syndrome: Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving Kyprolis.

Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold Kyprolis until TLS is resolved.

Thrombocytopenia: Kyprolis causes thrombocytopenia with

insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred in patients receiving Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy.

This risk was greater in patients with a baseline reduced estimated creatinine clearance. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS),

acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some events have been fatal.

In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in patients treated with Kyprolis. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for PAH

recovery to baseline platelet count usually by the start of the next cycle.

Thrombocytopenia was reported in patients receiving Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure,

including fatal cases, have been reported during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS): Cases of TTP/HUS including fatal outcome

have occurred in patients receiving Kyprolis. Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected.

If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, KYPROLIS, and KYPROLIS logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2015 Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary, Thousand Oaks, CA TROPIC-KYPR-103559 August 2015 Printed in USA

Ne w

RESPOND

In dic at

ion

with the power of significantly improved progression-free survival (PFS)

Posterior Reversible Encephalopathy Syndrome (PRES):

Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

The KYPROLIS regimen significantly improved PFS in patients with relapsed multiple myeloma1

Embryo-fetal Toxicity: Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.

In the ASPIRE study of KYPROLIS + lenalidomide + low-dose dexamethasone (KRd) vs lenalidomide + low-dose dexamethasone (Rd), the KYPROLIS regimen delivered improved efficacy with a safety profile comparable to Rd.1,2*

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis and the potential hazard to the fetus if Kyprolis is used during pregnancy.

26.3 months median progression-free

ADVERSE REACTIONS The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.

References: 1. KYPROLIS [prescribing information]. Thousand Oaks, CA: Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary; 2015. 2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al; for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

N Engl J Med. 2015;372(2):142-152.

Please see Brief Summary of full Prescribing Information on adjacent pages.

survival with the KYPROLIS regimen vs 17.6 months with Rd, a 49% improvement over Rd (P value [two-sided] 0.0001)1

Find out more at www.kyprolis.com/hcp *ASPIRE was a global, multicenter, open-label, randomized phase 3 pivotal trial evaluating KYPROLIS in patients with relapsed multiple myeloma. 792 patients were randomized in a 1:1 ratio (396 patients to KRd, 396 to Rd). Patients received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity.1,2 The primary endpoint was progression-free survival.

Secondary endpoints included overall survival, overall response rate (partial response or better), duration of response, and safety.2

The ASCO Post | OCTOBER 25, 2015

PAGE 120

In the News Aspirin and Colorectal Cancer continued from page 117

the ages that they target in this recommendation,” Dr. Johnson said.

“It doesn’t seem very helpful to target for a very narrow age range when patient life expectancy is far greater than what it used to be, “ Dr. Johnson added. “The risk for colon cancer in the average risk

individual by the age of 85 is around 5.5% for males and females both. Then targeted risks go up with a variety of other factors, such as family history, smoking, and obesity,” he added.

Dr. Johnson referenced a study conducted at the Indiana University Medical Center in Indianapolis showing that the five factors most commonly associ-

ated with colorectal cancer in the published literature—age, sex, cigarette smoking, body fat, and a family history of colorectal cancer—can be used to stratify risk for colorectal cancer.5

Risk-Benefit Assessment as Starting Point “I am for anything that will decrease

colon cancer,” Dr. Johnson stressed but added that the starting point should be a risk-benefit assessment.

The Task Force did note that aspirin use in adults has potential harms,B:16.75” increasing the risk for gastrointestinalT:16.25” bleeding and hemorrhagic stroke. TheseS:14.625” harms vary with individual risk but are small in adults aged 59 and younger and

(carfilzomib) forintravenous injection, foruse intravenous use Brief of Hepatic ToxicityFailure and Hepatic Failure KYPROLIS® KYPROLIS (carfilzomib)® for injection, for Brief Summary of Summary Hepatic Toxicity and Hepatic Prescribing Information.

Prescribing Information.

Cases of hepatic failure, fatal cases, have(< been (< 1%) in patients Cases of hepatic failure, including fatal including cases, have been reported 1%)reported in patients see thepackage KYPROLIS insert for full prescribing information.

Please see the Please KYPROLIS insertpackage for full prescribing information. receiving Kyprolis.

Kyprolis can cause increased serum transaminases. receiving Kyprolis.

Kyprolis can cause increased serum transaminases.

Monitor liver Monitor liver INDICATIONS enzymes regularly.

Reduce or as withhold dose as appropriate.

INDICATIONS enzymes regularly.

Reduce or withhold dose appropriate.

Kyprolis inwith combination withand lenalidomide and dexamethasone indicated for theThrombotic Thrombocytopenic Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) Kyprolis in combination lenalidomide dexamethasone is indicated foristhe Purpura/Hemolytic Uremic Syndrome (TTP/HUS) treatment patientsmultiple with relapsed multiple who one havetoreceived treatment of patients withofrelapsed myeloma who myeloma have received three one to three Cases of TTP/HUS, including fatal outcome, have been reported inreceived patients who received Cases of TTP/HUS, including fatal outcome, have been reported in patients who prior lines of therapy. prior lines of therapy.

Kyprolis.

Monitor for signs and symptoms Discontinue of TTP/HUS.Kyprolis Discontinue Kyprolis if TTP/ Kyprolis. Monitor for signs and symptoms of TTP/HUS. if TTP/ WARNINGS AND PRECAUTIONS HUS is evaluate. suspected Ifand diagnosisisofexcluded, TTP/HUS is excluded, WARNINGS AND PRECAUTIONS HUS is suspected and theevaluate. diagnosisIfofthe TTP/HUS Kyprolis may Kyprolis may be restarted.

The safetyKyprolis of reinitiating Kyprolis therapy in patients previously experiencing be restarted. The safety of reinitiating therapy in patients previously experiencing Cardiac Toxicities Cardiac Toxicities TTP/HUS TTP/HUS is not known. is not known.

New onsetoforpre-existing worsening of pre-existing failure (e.g., congestive New onset or worsening cardiac failure cardiac (e.g., congestive heart failure, heart failure, Posterior Reversible Encephalopathy Syndrome (PRES) Posterior Reversible Encephalopathy Syndrome (PRES) pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial myocardial ischemia, and myocardial infarction including a day in patients receiving of PRES havein been reported in patients receiving Kyprolis. formally known ischemia, and myocardial infarction including fatalities withinfatalities a day inwithin patients receiving Cases of PRESCases have been reported patients receiving Kyprolis.

PRES, formallyPRES, known Kyprolis.

Withhold Kyprolis Gradeadverse 3 or 4 cardiac events until recovery, as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), can present with seizure, Kyprolis. Withhold Kyprolis for Grade 3 or for 4 cardiac events adverse until recovery, as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), can present with seizure, and consider whether to restart Kyprolis 1 dose level based on a benefit/risk headache, lethargy, confusion, blindness, altered consciousness, and consider whether to restart Kyprolis at 1 dose level at reduction basedreduction on a benefit/risk headache, lethargy, confusion, blindness, altered consciousness, and other visualand andother visual and assessment.

Adequately hydrate alltopatients prior to receiving Kyprolis. neurologicalalong disturbances, along with Perform hypertension.

Perform diagnostic neuroradiological assessment. Adequately hydrate all patients prior receiving Kyprolis. neurological disturbances, with hypertension. diagnostic neuroradiological (MRI) at the onset of visual orsymptoms. neurological symptoms.Kyprolis Discontinue Kyprolis if imaging (MRI)imaging at the onset of visual or neurological Discontinue if Monitor patientsoffor evidence of volume overload, especially at risk for cardiac Monitor all patients for all evidence volume overload, especially patients at risk patients for cardiac PRES is evaluate. suspected The and safety evaluate.

The safetyKyprolis of reinitiating Kyprolis therapy in patients PRES is suspected and of reinitiating therapy in patients failure.

Adjust total fluid intake as clinically appropriate.

Patients ≥ 75 years, with New failure. Adjust total fluid intake as clinically appropriate. Patients ≥ 75 years, with New previouslyPRES experiencing PRES is not known. previously experiencing is not known.

York Heart Association and IVrecent heart myocardial failure, recent myocardial York Heart Association Class III and IVClass heartIIIfailure, infarction, and infarction, and conduction abnormalities may be at greater risk for cardiac complications.

Embryo-fetal Toxicity conduction abnormalities may be at greater risk for cardiac complications.

Embryo-fetal Toxicity Acute Renal Failure Acute Renal Failure

Kyprolis cause fetal harm whentoadministered to a pregnant woman Kyprolis can cause fetal can harm when administered a pregnant woman based on its based on its mechanism of action findings in animals.

There are nowell-controlled adequate and well-controlled mechanism of action and findings inand animals.

There are no adequate and of acute renal failure in have occurred in patients receiving Kyprolis. Renal Cases of acute Cases renal failure have occurred patients receiving Kyprolis.

Renal studies in pregnant women using Kyprolis. studies in pregnant women using Kyprolis. insufficiency events (renal impairment, acuterenal renalfailure) failure,occurred renal failure) occurred insufficiency adverse events adverse (renal impairment, acute renal failure, in approximately patients incontrolled a randomized trial.

Acute renal failureFemales was Females ofpotential reproductive should be potential advised ofhazard the potential hazard in approximately 8% patients in 8% a randomized trial.controlled Acute renal failure was of reproductive shouldpotential be advised of the to the fetus andto the fetus and reported more frequently patients with advanced relapsed multiple and refractory multiple to avoid becoming whilewith being treated with Kyprolis.

If this drug is used during reported more frequently in patients withinadvanced relapsed and refractory to avoid becoming pregnant whilepregnant being treated Kyprolis.

If this drug is used during who received Kyprolis monotherapy.

This risk was greater if the patient becomes while taking Kyprolis, advise myeloma who myeloma received Kyprolis monotherapy.

This risk was greater in patients within patients with pregnancy, or ifpregnancy, the patientorbecomes pregnant whilepregnant taking Kyprolis, advise the patient of the patient of a baseline reduced estimated creatinine clearance.

Monitor with renalregular function with regular the potential hazard to the fetus. a baseline reduced estimated creatinine clearance.

Monitor renal function the potential hazard to the fetus. of the serum creatinine and/or estimated creatinine clearance.

Reduce or measurement ofmeasurement the serum creatinine and/or estimated creatinine clearance.

Reduce or ADVERSE REACTIONS ADVERSE REACTIONS withhold Kyprolis dose as appropriate. withhold Kyprolis dose as appropriate.

The following adverse have been discussed andthe canWarning be found the WarningK The following adverse reactions have reactions been discussed above and can above be found Tumor Lysis Syndrome (TLS) Tumor Lysis Syndrome (TLS) de Precautions section of the package insert. cardiac They include cardiac and Precautionsand section of the package insert.

They include toxicities, acutetoxicities, kidney acute kidney a of TLS, havein been reported patients who received injury, TLS, Pulmonary toxicity, pulmonarydyspnea, hypertension, dyspnea,venous hypertension, venous Cases of TLS, Cases including fatal including outcomes,fatal haveoutcomes, been reported patients whoinreceived injury, TLS, Pulmonary toxicity, pulmonary hypertension, hypertension, b Kyprolis.

Patientsmyeloma with multiple andburden a highare tumor burdenrisk are at greater thromboses, risk thromboses, infusion reactions, thrombocytopenia, toxicity and hepatic failure, c Kyprolis. Patients with multiple and amyeloma high tumor at greater infusion reactions, thrombocytopenia, hepatic toxicityhepatic and hepatic failure, forpatients TLS. Ensure patients arebefore well hydrated before administration of Kyprolis. Consider and PRES. for TLS. Ensure are well hydrated administration of Kyprolis. Consider TTP/HUS and TTP/HUS PRES. d uricdrugs acid lowering drugs in patients risk for TLS. Monitoroffor evidence uric acid lowering in patients at risk for TLS.atMonitor for evidence TLS during of TLS during Trials Safety Experience Clinical Trials Clinical Safety Experience treatment and manage promptly.

Withold Kyprolis until TLS is resolved. treatment and manage promptly.

Withold Kyprolis until TLS is resolved. e Because clinical trials under are conducted under widely varying conditions, adverse reaction Because clinical trials are conducted widely varying conditions, adverse reaction Pulmonary Toxicity Pulmonary Toxicity in theofclinical ofbe a drug cannot be directly rates observed rates in theobserved clinical trials a drug trials cannot directly compared withcompared rates in thewith rates in the N another and may not reflect the rates observed in medical practice. p Acute Respiratory Distress Syndrome acute respiratory failure, and acuteclinical diffusetrials ofclinical anothertrials drug,ofand may drug, not reflect the rates observed in medical practice.

Acute Respiratory Distress Syndrome (ARDS), acute(ARDS), respiratory failure, and acute diffuse infiltrative pulmonary such asand pneumonitis lung of disease, some of infiltrative pulmonary disease such asdisease pneumonitis interstitial and lunginterstitial disease, some The safety of Kyprolis inwith combination withand lenalidomide and dexamethasone (KRd) was G The safety of Kyprolis in combination lenalidomide dexamethasone (KRd) was which fatal, in have than 1% of patients receiving Kyprolis. In the which were fatal, havewere occurred lessoccurred than 1%inofless patients receiving Kyprolis.

In the inrandomized an open-label randomized study patientsmultiple with relapsed multiple myeloma. d evaluated in anevaluated open-label study in patients withinrelapsed myeloma. event ofpulmonary drug-induced pulmonary toxicity, discontinue Kyprolis. event of drug-induced toxicity, discontinue Kyprolis.

The median number of cycles wasthe 22KRd cycles forand the14 KRd armfor and 14 cycles for h The median number of cycles initiated was 22initiated cycles for arm cycles Pulmonary Hypertension (PAH) the Rd arm. the Rd arm.

Pulmonary Hypertension (PAH) L Deaths due to adverse events 30 days dose of therapy Cases of PAH(~1%) was reported (~1%) in patients treated with KYPROLIS , <1% experiencing Deaths due to adverse events within 30 dayswithin of the last doseof ofthe anylast therapy in any the KRd armin the KRd arm Cases of PAH was reported in patients treated with KYPROLIS , <1% experiencing vs.

Rd arm was 27/392 (7%) patients vs.

27/389 (7%) patients in the Rd arm.

The most Grade 3 or greater PAH..

Evaluate with cardiac imaging and/or other tests as indicated.

In vs.

Rd arm was 27/392 (7%) patients vs.

27/389 (7%) patients in the Rd arm.

The most Grade 3 or greater PAH.. Evaluate with cardiac imaging and/or other tests as indicated. In of deaths occurring patients 10 (3%) vs. 7 (2%), infection 9 the discontinue event of PAH, discontinue Kyprolisor until resolved or returned to baseline.

Perform a causecommon common of deathscause occurring in patients (%) in cardiac 10(%) (3%)cardiac vs. 7 (2%), infection 9 the event of PAH, Kyprolis until resolved returned to baseline.

Perform a (2%) vs. 10 (3%),vs.renal (0%)and vs. other 1 (< 1%), andevents other adverse events 9 (2%) vs. 10 (3%). benefit/risk assessment when considering restarting Kyprolis.

(2%) vs. 10 (3%), renal 0 (0%) 1 (<01%), adverse 9 (2%) vs.

10 (3%). benefit/risk assessment when considering restarting Kyprolis. events in were reported vs. 54% of KRd patients theRd KRd arm vs. Rd Serious adverseSerious events adverse were reported 60% vs. 54%inof60% patients in the arminvs.

Dyspnea Dyspnea The most common the KRd arm. The mostarm. common serious adverseserious events adverse reportedevents in the reported KRd arminverses the arm Rd verses the Rd arm were pneumonia vs. 11%), tractvs. infection vs. 1.5%), pyrexia arm were pneumonia (14% vs. 11%),(14% respiratory tractrespiratory infection (4% 1.5%),(4% pyrexia Dyspnea(28%) was reported (28%) in patients treated with Kyprolis, with 4% of cases being Dyspnea was reported in patients treated with Kyprolis, 4% of cases being (4%pulmonary vs. 2%), and pulmonary (3% vs. 2%). Discontinuation due to any adverse (4% vs. 2%), and embolism (3% embolism vs. 2%). Discontinuation due to any adverse GradeEvaluate 3 or greater.

Evaluate dyspnea to exclude cardiopulmonary conditions including Grade 3 or greater. dyspnea to exclude cardiopulmonary conditions including occurred in 26% the25% KRdinarm the Rd events arm. Adverse leading to in 26% in the KRd arminvs. the vs.

Rd 25% arm. in Adverse leading events to failure and pulmonary syndromes.

Stop Kyprolis Grade 3until or 4 dyspneaevent untiloccurredevent cardiac failure cardiac and pulmonary syndromes.

Stop Kyprolis for Grade 3 or for 4 dyspnea of Kyprolis occurred in 12% of patients. discontinuationdiscontinuation of Kyprolis occurred in 12% of patients. resolved or returned to baseline.

Performassessment a benefit/risk assessment when considering resolved or returned to baseline.

Perform a benefit/risk when considering restarting Kyprolis. restarting Kyprolis.

Common Adverse (≥ 10% the KRd Arm) Occurring Common Adverse Events (≥ 10% inEvents the KRd Arm)inOccurring in Cycles 1–12 in Cycles 1–12 (Combination Therapy) (Combination Therapy)

Hypertension Hypertension

KRd Arm Rd Arm KRd Arm Rd Arm Hypertension, includingcrisis hypertensive crisis andemergency, hypertensive emergency, Hypertension, including hypertensive and hypertensive some of whichsome of which System Organ Class (N = 392) (N = 392) (N = 389) System Organ Class (N = 389) has been observed with Kyprolis. pressure were fatal, has were been fatal, observed with Kyprolis.

Monitor blood Monitor pressure blood regularly in all regularly in all patients. Ifcannot hypertension cannot controlled, be adequately controlled, withhold Kyprolis and evaluate. Preferred Term Preferred Term patients. If hypertension be adequately withhold Kyprolis and evaluate.

Grade Grade ≥ Grade ≥ Grade 3 Any Grade Any Grade3 ≥Any Grade 3 ≥Any Grade 3 Performassessment a benefit/risk assessment when considering restarting Kyprolis.

Perform a benefit/risk when considering restarting Kyprolis.

Venous Thrombosis Venous Thrombosis

Blood System and Lymphatic System Disorders Blood and Lymphatic Disorders

138 (35%) 53 (14%)

53 (33%) (14%) 127

127(12%) (33%) 47

47 (12%)

124(27%) (32%) 104

104(30%) (27%) 115

115(23%) (30%) 89

89 (23%)

100 (26%) 58 (15%)

58(19%) (15%) 75

75(10%) (19%) 39

39 (10%)

115 (29%) 7 (2%)

(2%) 1057 (27%)

105 (27%) 12 (3%)

680(17%)

0 53 (14%)

53 (14%) 1 (0%)

1 (0%)

Infusion reactions, including life-threatening have occurred in patients receiving Infusion reactions, including life-threatening reactions, havereactions, occurred in patients receiving Nausea (15%) (0%) Nausea 60 (15%) 160(0%) 391(10%) Kyprolis.

Symptoms include fever, chills, arthralgia, Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facialmyalgia, flushing,facial facialflushing, edema, facial edema, General Disorders and Administration Site Conditions General Disorders and Administration Site Conditions vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. reactions can occurfollowing immediately or up to administration 24 hours after administration These reactionsThese can occur immediately or upfollowing to 24 hours after Fatigue 109(5%) (28%) 21(27%) (5%) Fatigue 109 (28%) 21 104 of Kyprolis. with Pre-medicate with dexamethasone to reduceand the severity incidence of Kyprolis. Pre-medicate dexamethasone to reduce the incidence ofand severity of Pyrexia 93 (24%) 5 (1%) Pyrexia 93 (24%) 5 (1%) 64 (17%) infusion reactions Inform patients of the risk and symptoms of an infusion reaction and to infusion reactions Inform patients of the risk and symptoms of an infusion reaction and to contact a physicianif immediately of an infusion contact a physician immediately symptoms ofifansymptoms infusion reaction occur.reaction occur.

(16%) (1%) Edema PeripheralEdema Peripheral 63 (16%) 263(1%) 572(15%)

39 (10%) 3 (1%)

3 (1%)

104 (27%) 20 (5%)

57 (15%) 2 (1%)

2 (1%)

Thrombocytopenia Thrombocytopenia

Anemia

Anemia

138 (35%)

Venous thromboembolic events, deep venous Venous thromboembolic events, including deepincluding venous thrombosis andthrombosis pulmonaryand pulmonary Neutropenia 124 (32%) have been observed with Kyprolis.

In thestudy, combination study, the incidenceNeutropenia embolism, haveembolism, been observed with Kyprolis.

In the combination the incidence of venous thromboembolic events in the was first 13% 12 cycles was vs. 6% in the Kyprolis of venous thromboembolic events in the first 12 cycles vs. 6% in 13% the Kyprolis Thrombocytopenia Thrombocytopenia 100 (26%) combination control armWith respectively.

Kyprolisthe monotherapy, combination arm and controlarm armand respectively.

Kyprolis With monotherapy, incidence the incidence Disorders GastrointestinalGastrointestinal Disorders of venous thromboembolic was 2%. Thromboprophylaxis is recommended and of venous thromboembolic events was 2%.events Thromboprophylaxis is recommended and based onpatient an individual patient assessment. should be basedshould on anbe individual assessment.

Diarrhea Diarrhea 115 (29%) Infusion Reactions Infusion Reactions

Constipation

Constipation

64 (17%) 1 (0%)

P

T K si re 12 (3%) a

D

K a a 20 (5%) in 1 (0%)

53 (14%)

53(3%) (14%) 11

(3%) 4611(12%)

46 (12%) 7 (2%)

7 (2%)

Cases of thrombocytopenia caninoccur (40%) in patients receiving Cases of thrombocytopenia can occur (40%) patients receiving Kyprolis, with Kyprolis, platelet with platelet Infections and Infestations Infections and Infestations observed 8 and 15 of eachwith 28-day cycle, to with recovery to baseline nadirs observednadirs between Day 8between and DayDay 15 of eachDay 28-day cycle, recovery baseline Upper Infection Upper Respiratory TractRespiratory Infection Tract85 (22%) plateletoccurring count usually occurring by the of the next cycle.

Monitor platelet count usually by the start of the nextstart cycle.

Monitor platelet counts platelet counts frequently during Kyprolis.

Reduce or as withhold dose as appropriate. Nasopharyngitis Nasopharyngitis frequently during treatment with treatment Kyprolis. with Reduce or withhold dose appropriate.

63 (16%)

(22%) 785(2%)

(2%) 527(13%)

52 (13%) 3 (1%)

3 (1%)

630(16%)

0 43 (11%)

43 0(11%)

0

Asthenia

Asthenia

68 (17%)

K de

U

P

K p

F b ri

ASCOPost.com | OCTOBER 25, 2015

In the News

small to moderate in adults aged 60 to 69, the USPSTF determined.

The assumption that the risk for harm is small “again creates a bit of a consternation for me as I look at what patients may take out of context. Because this assumes that patients don’t have any other risk factors for bleeding that they may or may not know about,

B:16.75” T:16.25” S:14.625”

Bronchitis

Bronchitis

Pneumonia

Pneumonia

a

a

and that they are not taking any other over-the-counter nonsteroidal antiinflammatory agents,” Dr. Johnson said.

He cited a recent study using data from 10,280 patients selected from the Danish Cancer Registry and 102,800 controls.

This analysis found that while long-term use of low-dose aspirin and nonaspirin NSAIDs was associated with a substan-

54 (14%)

(14%) 554(1%)

(1%) 395(10%)

39 (10%) 2 (1%)

54 (14%)

54(9%) (14%) 35

(9%) 4335(11%)

43(7%) (11%) 27

and Nutrition Disorders Metabolism andMetabolism Nutrition Disorders Hypokalemia

Hypokalemia

78 (20%)

78(6%) (20%) 22

22(9%) (6%) 35

35(3%) (9%) 12

Hypocalcemia

Hypocalcemia

55 (14%)

55(3%) (14%) 10

(3%) 3910(10%)

39 (10%) 5 (1%)

43 (11%)

43(5%) (11%) 18

18(9%) (5%) 33

33(4%) (9%) 15

(22%) 388(1%)

(1%) 733(19%)

73 (19%) 3 (1%)

(11%) 743(2%)

(2%) 377(10%)

37 (10%) 4 (1%)

(16%) 663(2%)

(2%) 506(13%)

50 (13%) 8 (2%)

Hyperglycemia Hyperglycemia

and Connective and Connective Tissue DisordersTissue Disorders gMusculoskeletalMusculoskeletal

,

d

PAGE 121

Muscle Spasms Muscle Spasms

88 (22%)

Psychiatric Disorders Psychiatric Disorders Insomnia

Insomnia

63 (16%)

Respiratory, Thoracic, and Mediastinal Disorders Respiratory, Thoracic, and Mediastinal Disorders Cough

Cough

85 (22%)

(22%) 185(0%)

(0%) 461(12%)

46 0(12%)

Dyspneac

Dyspneac

70 (18%)

(18%) 970(2%)

(2%) 589(15%)

58 (15%) 6 (2%)

45 (12%)

(12%) 545(1%)

(1%) 535(14%)

53 (14%) 5 (1%)

EmbolicEvents, and Thrombotic49Events, (13%) Embolic and Thrombotic Venousd Venousd

49(4%) (13%) 16

16(6%) (4%) 22

(6%) 922(2%)

41(3%) (11%) 12

12(4%) (3%) 15

(4%) 415(1%)

Skin andTissue Subcutaneous Tissue Skin and Subcutaneous Disorders Disorders Rash

Rash

Vascular Disorders Vascular Disorders

Hypertensione

Hypertensione

41 (11%)

during pregnancy, if the patient becomes while taking Kyprolis, advise the during pregnancy, or if the patientorbecomes pregnant whilepregnant taking Kyprolis, advise the 2 (1%) patient ofhazard the potential hazard to the fetus. patient of the potential to the fetus.

27 (7%)

Lactation

There is no information regardingofthe presence of Kyprolis human milk, the effects There is no information regarding the presence Kyprolis in human milk,inthe effects (3%) the breastfed infant,on ormilk the effects on milk production.

The developmental and health on12the breastfedoninfant, or the effects production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for benefits 5 (1%) of breastfeeding should be considered along with the mother’s clinical need for Kyprolis andadverse any potential effects oninfant the breastfed infant from Kyprolis or from Kyprolis and any potential effectsadverse on the breastfed from Kyprolis or from (4%) the underlying maternal condition. the15underlying maternal condition.

3 (1%) can cause Kyprolis cause fetal harm whentoadministered to pregnant Kyprolis fetal can harm when administered pregnant women Advisewomen femalesAdvise females reproductive use effectivemeasures contraception measures to prevent pregnancy of reproductiveofpotential to usepotential effectivetocontraception to prevent pregnancy during withfor Kyprolis for atfollowing least 2 weeks following completion of therapy. during treatment with treatment Kyprolis and at leastand 2 weeks completion of therapy.

4 (1%)

Pediatric Use Pediatric Use safety andofeffectiveness of Kyprolis in pediatric patients have not been established.

The safety andThe effectiveness Kyprolis in pediatric patients have not been established.

8 (2%)

Geriatric Use Geriatric Use 392 patients treated in with Kyprolis inwith combination withand lenalidomide and Of 392 patientsOf treated with Kyprolis combination lenalidomide 0 dexamethasone, 185 patients (47%) ≥ 65 years of age and 43 patients dexamethasone, 185 patients (47%) were ≥ 65 yearswere of age and 43 patients (11%) were (11%) were ≥75No years of age.

No overall differences inwere effectiveness observed ≥75 years of age. overall differences in effectiveness observed were between these between these 6 (2%) and younger patients. of The incidence of serious events was 50% and younger patients.

The incidence serious adverse events adverse was 50% in patients ≤ 65in patients ≤ 65 years age, 70% patients 65age, to 74and years ofin age, and 74% patients ≥ 75 years of age. years of age, 70% in of patients 65 toin74 years of 74% patients ≥ 75inyears of age.

5 (1%)

Joseph A. Sparano, MD, on the TAILORx Study and Low Recurrence Scores in Breast Cancer see page 18

B:11.25”

S:10”

T:10.875”

B:11.25”

S:10”

T:10.875”

difference 2%) between the two arms werethrombocytopenia, neutropenia, thrombocytopenia, difference (≥ 2%) between(≥the two arms were neutropenia, of chills,renal hypotension, renalthrombocytopenia insufficiency, thrombocytopenia and lymphopenia Acute onset of Acute chills, onset hypotension, insufficiency, and lymphopenia hypokalemia, and hypophosphatemia. hypokalemia, and hypophosphatemia. hasfollowing been reported following a dose of 200 mg of Kyprolis administed in error. has been reported a dose of 200 mg of Kyprolis administed in error.

Laboratory Abnormalities Laboratory Abnormalities Thereantidote is no specific antidote for KyprolisInoverdosage. the event overdose, the patient There is no specific for Kyprolis overdosage. the event of In overdose, theofpatient m should specifically be monitored, the adverse in the adverse reaction section. should be monitored, forspecifically the adversefor reactions in thereactions adverse reaction section.

Grade Abnormalities 3–4 Laboratory( Abnormalities ( ≥1-12 10%) in Cycles 1-12 Grade 3–4 Laboratory ≥ 10%) in Cycles DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION

KRd (N = 392)

KRd Rd (N = 392) (N = 389)

182 (46%)

182 (46%) 119 (31%)

withintravenous both oral and intravenous (IV) fluids.with Premedicate with dexamethasone prior to with both oral and (IV) fluids. Premedicate dexamethasone prior to 119 (31%)

Decreased Absolute Decreased Absolute Neutrophil CountNeutrophil Count152 (39%)

152 (39%) 140 (36%)

140 (36%) at baseline.

Administer over 10-minuteDo IVnot infusion. Do not surface area at surface baseline.area Administer Kyprolis over aKyprolis 10-minute IVainfusion.

Laboratory Abnormality Laboratory Abnormality

Don’t Miss These Important Reports in This Issue of The ASCO Post

Noadjustment starting dose adjustment is required patientsmild, with moderate, baseline mild, moderate, or severe No starting dose is required in patients withinbaseline or severe renal or patients on chronic dialysis based on a phase 2 pharmacokinetic and renal impairment or impairment patients on chronic dialysis based on a phase 2 pharmacokinetic and 9 (2%) safety trialThe of Kyprolis.

The pharmacokinetics Kyprolis was not influenced by the safety trial of Kyprolis. pharmacokinetics of Kyprolis wasofnot influenced by the degree of impairment, baseline renal impairment, whenreceiving patients were receiving dialysis. degree of baseline renal including whenincluding patients were dialysis.

Administer KYPROLIS after the dialysis procedure.

Administer KYPROLIS after the dialysis procedure.

4 (1%)

Safety patients New York Heart Association and IV Safety of patients withofNew Yorkwith Heart Association Class III and IVClass heartIIIfailure orheart failure or No relevant new clinically relevantin ARs in the later treatment cycles in the 274recent (70%)myocardial No new clinically ARs emerged theemerged later treatment cycles in the 274 (70%) recent myocardial infarction (within 3has to not 6 months) has not been evaluated. infarction (within 3 to 6 months) been evaluated. patients the KRd armtreatment who received treatment beyond Cycle 12. patients in the KRd arminwho received beyond Cycle 12.

OVERDOSE OVERDOSE Gradeadverse 3 and higher adverse reactionsduring that occurred during Cycles 1-12 with a substantial Grade 3 and higher reactions that occurred Cycles 1-12 with a substantial

Decreased Lymphocytes Decreased Lymphocytes

continued on page 122

Renal Impairment Renal Impairment

Hepatic Impairment Hepatic Impairment = Kyprolis, and low-doseRd dexamethasone; Rdand = lenalidomide and low-dose KRd = Kyprolis, KRd lenalidomide, andlenalidomide, low-dose dexamethasone; = lenalidomide low-dose dexamethasone dexamethasone y The safety, efficacy and pharmacokinetics of not Kyprolis have not been evaluated in patients The safety, efficacy and pharmacokinetics of Kyprolis have been evaluated in patients a Pneumonia terms of pneumonia, bronchopneumonia Pneumonia includes preferredincludes terms ofpreferred pneumonia, bronchopneumonia with baseline hepaticPatients impairment.

Patients withlaboratory the following laboratory with baseline hepatic impairment. with the following values were values were b Peripheral NEC includes preferred underneuropathies HLT peripheral Peripheral neuropathies NECneuropathies includes preferred terms under HLT terms peripheral NECneuropathies NEC fromclinical the Kyprolis clinical trials: ≥ 3of× normal upper limit of normal (ULN) excluded from excluded the Kyprolis trials: ALT/AST ≥ 3 ×ALT/AST upper limit (ULN) c Dyspnea of dyspnea, dyspnea exertional Dyspnea includes preferredincludes terms ofpreferred dyspnea,terms dyspnea exertional bilirubin ≥and 2 × bilirubin ULN. ≥ 2 × ULN. d Embolicevents, and thrombotic events,preferred venous include terms MedDRA SMQ narrowand scope Embolic and thrombotic venous include terms inpreferred MedDRA SMQinnarrow scope of embolicevents, and thrombotic search of embolicsearch and thrombotic venous. events, venous.

Cardiac Impairment Cardiac Impairment e Hypertension terms hypertensive of hypertension, hypertensive crisis, hypertensive emergency Hypertension includes preferredincludes terms ofpreferred hypertension, crisis, hypertensive emergency

(Combination Therapy) (Combination Therapy)

“I do endoscopies for a living. I see 20-year-olds come in with nonsteroidal anti-inflammatory agent–related bleeding.

So bleeding risk is across all ages. It may be stratified and higher in certain ages because of other cofactors, but clearly there is still an implicit risk of harm, potentially in all ages,” Dr. Johnson said.

“The decision to take medicines always needs to be balanced with complete understanding, and when you go

Lactation

ContraceptionContraception

System Disorders Nervous SystemNervous Disorders b b Peripheral Neuropathies NEC 43 (11%) Peripheral Neuropathies NEC

tial reduction in colorectal cancer, the potential use of aspirin and NSAIDs for preventing colorectal cancer “is limited by the risk for gastrointestinal bleeding and, for most nonaspirin NSAIDs, cardiovascular risks. These potential harms will need to be balanced against the chemoprevention benefits that our results indicate,” the authors noted.6

Rd (N = 389) Adequately hydrate alltopatients prior to the andadministration following the administration Adequately hydrate all patients prior and following of Kyprolis of Kyprolis

administering Kyprolis.

Calculatedose the using Kyprolis using the patient’s administering Kyprolis.

Calculate the Kyprolis the dose patient’s acutal body acutal body

Decreased Phosphorus Decreased Phosphorus

122 (31%)

122 (31%) 106 (27%)

as athe bolus.

Flush IV line withor normal saline orinjection 5% dextrose injection administer as aadminister bolus. Flush IV line withthe normal saline 5% dextrose 106 (27%)

Decreased Platelets Decreased Platelets

101 (26%)

101 (26%) 59 (15%)

59 (15%) administer as another infusion with other medicines. Thromboprophylaxis is recommend for administer as an infusion with medicines.

Thromboprophylaxis is recommend for

Ugo Pastorino, MD, on Smoking Cessation and Mortality Reduction see page 25

immediately and administration. after Kyprolis administration.

Do notwith mix or Kyprolis with or immediately before and afterbefore Kyprolis Do not mix Kyprolis

Decreased Total Decreased Total White Blood CellWhite CountBlood Cell Count 97 (25%)

97 (25%) 71 (18%)

patientswith being with theofcombination of Kyprolis,and lenalidomide and dexamethasone. patients being treated thetreated combination Kyprolis, lenalidomide dexamethasone.

71 (18%)

Decreased Hemoglobin Decreased Hemoglobin

58 (15%)

58 (15%) 68 (18%)

68 (18%)

Decreased Potassium Decreased Potassium

41 (11%)

41 (11%) 23 (6%)

23 (6%) product can be found at www.kyprolis.com or 1-877-669-9121. product labeling can belabeling found at www.kyprolis.com or 1-877-669-9121.

Consider antiviral in treated patientswith being treated with Kyprolis.

Consider antiviral prophylaxis in prophylaxis patients being Kyprolis.

The riskprovided information here is not comprehensive.

The FDA-approved The risk information hereprovided is not comprehensive.

The FDA-approved

KRdlenalidomide, = KYPROLIS, and low-doseRd dexamethasone; Rdand = lenalidomide KRd = KYPROLIS, andlenalidomide, low-dose dexamethasone; = lenalidomide low-dose and low-dose This product, its production, and/or its use may be covered or more US Patents, This product, its production, and/or its use may be covered by one or moreby USone Patents, dexamethasone dexamethasone including Patent Nos. 7,232,818; 7,417,042; 7,491,704; 7,737,112; 8,129,346; including US Patent Nos.US 7,232,818; 7,417,042; 7,491,704; 7,737,112; 8,129,346;

Post-marketing Post-marketing Experience Experience

8,207,125; 8,207,126; andwell 8,207,297 well asorother patents or patents pending.

8,207,125; 8,207,126; 8,207,127; and8,207,127; 8,207,297 as as otheraspatents patents pending.

following adverse were in the post-marketing experience with The following The adverse reactions were reactions reported in thereported post-marketing experience with Kyprolis.

Because these reactions are reported voluntarily fromofauncertain population of uncertain Kyprolis. Because these reactions are reported voluntarily from a population size, itpossible is not always possible to reliably estimate their frequency or establish a causal ize, it is not always to reliably estimate their frequency or establish a causal to drug exposure:TTP/HUS, dehydration, elationship to relationship drug exposure: dehydration, TLSTTP/HUS, including TLS fatal including outcomes,fatal outcomes, and PRES. and PRES.

David Stewart, MD, on the Effects of Drug Approval Delays see page 30

DRUG INTERACTIONS DRUG INTERACTIONS

Kyprolis is primarily viaepoxide peptidase and epoxide hydrolase activities, and as Kyprolis is primarily metabolized viametabolized peptidase and hydrolase activities, and as a result, the pharmacokinetic profile of Kyprolis unlikelyby to concomitant be affected by concomitant a result, the pharmacokinetic profile of Kyprolis is unlikely to beis affected cytochrome inhibitors Kyprolis and inducers. administration administration of cytochrome of P450 inhibitorsP450 and inducers. is notKyprolis expectedistonot expected to influence exposure nfluence exposure of other drugs. of other drugs.

USE IN SPECIFIC POPULATIONS USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy

Kyprolis cause fetalare harm.

There areand nowell-controlled adequate and well-controlled studies in Kyprolis may cause fetalmay harm.

There no adequate studies in pregnant women using Kyprolis. pregnant women using Kyprolis.

Females ofpotential reproductive potential should be advised to avoid becoming Females of reproductive should be advised to avoid becoming pregnant whilepregnant while being treated with Kyprolis.

Consider benefits and risks Kyprolis and possible being treated with Kyprolis.

Consider the benefits andtherisks of Kyprolis andofpossible risks to the fetus when prescribing Kyproliswoman. to a pregnant woman.

If Kyprolis is used isks to the fetus when prescribing Kyprolis to a pregnant If Kyprolis is used

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | OCTOBER 25, 2015

PAGE 122

Announcements

UC Davis Granted $15.5 Million to Build World’s First Total-Body PET Scanner

A

University of California, Davis research team has been awarded $15.5 million to build the world’s first total-body positron emission tomography (PET) scanner, which could fundamentally change the way cancers are tracked and treated.

The Transformative Research Award, part of the National Institutes of Health High-Risk, High-Reward Program, supports bold and untested ideas that have the potential to be paradigm-shifting. This award is one of eight given in the transformative research category in 2015. The 5-year grant, administered by the National Cancer Institute, will fund the EXPLORER project, led by Simon Cherry, PhD, Distinguished Professor of Biomedical Engineering, and Ramsey Badawi, PhD, Professor of Radiology.

Limitations of Current Scanning PET scans are widely used to diagnose and track a variety of diseases, including cancer, because they show how organs and tissues are functioning in the body (in contrast to magnetic resonance imaging or computed tomography scans, which mostly show anatomy). The EXPLORER project

Aspirin and Colorectal Cancer continued from page 117

to simulation modeling, there is a lot of danger in misapplication or misunderstanding as patients are left to their own accord, when they start seeing recommendations from a national body such as the U.S. Preventive Services Task Force,” Dr. Johnson stated.

More Is Not Better The USPSTF draft statement on aspirin to prevent cardiovascular disease and colorectal cancer noted that a dose of about 75 mg/d, used in many of the studies the Task Force looked at, seems as effective as higher doses, but that a pragmatic approach is an 81mg dose, which is the most commonly prescribed dose for baby aspirin in the United States.

Might some people take higher doses, thinking that would offer a greater level of protection? “Sometimes that

would address shortcomings of the current scanning technology, which requires more time and exposes the patient to more radiation because scans are done in 20-cm segments.

“The vision of the EXPLORER project is to solve two fundamental limitations of PET as it is currently practiced,” said Dr. Cherry, who is Codirector of the Biomedical Technology Program at the UC Davis Comprehensive Cancer Center. “The first is to allow us to see the entire body all at once. The second huge advantage is that we’re collecting almost the entire available signal, which means we can acquire the images much faster or at a much lower radiation dose. That’s going to have some profound implications for how we use PET scanning in medicine and medical science.”

Huge Advantages Drs. Cherry and Badawi predict that by seeing the entire body simultaneously, their scanner could drop the radiation dose by a factor of 40 or decrease scanning time from 20 minutes to just 30 seconds. A quicker scan also could reduce the incidence of images blurred by patient movement.

The technology would have implications in diagnostics, treatment, and is the patient’s perspective—a little is good; more is better. And it is hard to contain that,” Dr. Johnson said, without a discussion between the patient and health-care provider about the risks and benefits of aspirin use, both in general and for the individual patient.

Still Just a Draft The draft recommendation for the use of aspirin for the primary prevention of colorectal cancer is not only a first for the USPSTF but runs counter to recommendations from other medical organizations. “No organizations recommend aspirin use for the primary prevention of colorectal cancer in average-risk adults,” according to the USPSTF draft recommendation statement. “The American Cancer Society recommends against the use of aspirin and other NSAIDs as a colorectal cancer prevention strategy.

The American Gastroenterological

There are many questions that we couldn’t possibly ask before—and now we will be able to ask them.… It’s going to give us a tool that will allow us to see things we’ve never seen before.

—Ramsey Badawi, PhD

drug development. With whole-body PET, physicians could diagnose a disease and then follow its trajectory in a way never before possible, affecting how patients are treated. This approach reflects the current trend in medicine to develop systems-based treatments and more individualized care.

Additionally, pharmaceutical companies could use the scanner to show how drugs and compounds are transported through the body and determine whether a drug is targeting the disease or whether it goes to other organs.

“There are many questions that we couldn’t possibly ask before—and now we will be able to ask them,” Dr. Badawi said. “This is not just a big instrumentation grant. It’s going to

give us a tool that will allow us to see things we’ve never seen before.”

After additional studies, the researchers are hoping their technology will lead to new discoveries of the human body and even launch a whole diagnostic field.

The project is a consortium led by UC Davis that also involves University of Pennsylvania and Lawrence Berkeley National Laboratory researchers.

Fundamental research for the ­E XPLORER project was made possible by the UC Davis Research Investments in the Sciences and Engineering program, designed to launch large-scale interdisciplinary research activity at the university. Additional support was provided by the National Cancer Institute. n

Association and the National Comprehensive Cancer Network limit their recommendations to patients who are at increased risk for colorectal cancer.”

The USPSTF draft recommendation statement was open for public comments from September 15 to October 12. The final recommendations will be published in a peer-reviewed journal, but the date of publication will depend on the volume and complexity of comments received and other work process factors. n

2. Rabin RC: In a first, aspirin is recommended to fight a form of cancer. The New York Times. September 14, 2015.

3. Dennis B: Expert panel: An aspirin a day can help keep heart attacks—and cancer—away. The Washington Post.

September 14, 2015.

4. U.S. Preventive Services Task Force: Understanding task force draft recommendations: Aspirin to prevent cardiovascular disease and cancer. Available at www.uspreventiveservicestaskforce.org.

Accessed October 9, 2015.

5. Imperiale TF, Monahan PO, Stump TE, et al: Derivation and validation of a scoring system to stratify risk for advanced colorectal neoplasia in asymptomatic adults: A cross-sectional study.

Ann Intern Med 163:339-346, 2015.

6. Friis S, Riis AH, Erichsen R, et al: Low-dose aspirin or nonsteroidal antiinflammatory drug use and colorectal cancer risk. Ann Intern Med 163:347355, 2015.

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

References 1. U.S. Preventive Services Task Force: Aspirin to prevent cardiovascular disease and cancer. Draft Recommendation Statement. Available at www.uspreventiveservicestaskforce.org. Accessed October 9, 2015.

MANY PEOPLE DIAGNOSED WITH SQUAMOUS NSCLC:

STILL WAITING FOR NEW TREATMENT OPTIONS TO EVOLVE1

EVERY ADVANCE MATTERS In 2012, there were an estimated 450,000 cases of squamous NSCLC worldwide.*2,3 Unfortunately, despite decades of research, the median overall survival for squamous NSCLC remains at approximately 8 to 10 months.4,5 Lilly Oncology is committed to finding treatment advances for people living with lung cancer.

VISIT SQUAMOUSNSCLC.COM TO LEARN MORE.

* Worldwide prevalence of squamous NSCLC based on World Health Organization/GLOBOCAN estimates of worldwide lung cancer prevalence and distribution of histology as reported by the American Cancer Society.

References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed February 16, 2015. To view the most recent and complete version of the guidelines, go online to http://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. 2. From Ferlay J., Soerjomataram I, Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 3. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/ non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed February 16, 2015. 4. Hoang T, Dahlberg SE, Schiller JH, et al. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594.

Lung Cancer. 2013;81(1):47-52. 5. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277-1280.

MARCH 2015

GLOONC00009a

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In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER Patients Whose Treatment Included Bevacizumab Were More Likely to Experience Toxicity but Less Likely to Be Hospitalized A study among patients with advanced non–small cell lung cancer (NSCLC) treated with carboplatinpaclitaxel or carboplatin-paclitaxel-bevacizumab (Avastin) found that those receiving the triplet were more likely to experience a toxicity event but less likely to be hospitalized within 180 days after the start of chemotherapy. “Findings here confirm the need for adherence to clinical recommendations for judicious use of carboplatin-paclitaxel-bevacizumab but provide reassurance regarding the relative risk for hospitalization,” researchers reported in the Journal of Oncology Practice.

The study involved 1,109 patients with stages IIIB-IV NSCLC aged ≥ 21 years diagnosed between 2005 and 2010 and treated with first-line carboplatin-paclitaxel or carboplatinpaclitaxel-bevacizumab at four health maintenance organizations. Followup continued through December 31, 2011. The researchers, affiliated with those four health maintenance organizations and Fred Hutchinson Cancer Research Center in Seattle, used data about patient and tumor characteristics and hospital and ambulatory encounters in the 180 days after chemotherapy initiation to evaluate the association between carboplatin-paclitaxel and carboplatin-paclitaxel-bevacizumab

and toxicities and hospitalizations.

“Describing the patterns of toxicity profiles and hospitalizations associated with bevacizumab use in a community setting is important because it directly addresses the need for more clinically relevant information regarding the potential balance of benefits and harms for an expensive drug that may confer only limited improvements in survival,” the authors noted.

Most patients received carboplatinpaclitaxel, 911 (82%) vs 198 (18%) who received carboplatin-paclitaxelbevacizumab. “Patients who received carboplatin-paclitaxel-bevacizumab were younger and were more likely to have had stage IV disease and well- or moderately differentiated tumors,” the researchers observed.

Toxicity and Hospitalization Approximately 57% of the carboplatin-paclitaxel-bevacizumab patients and 53% of the carboplatin-paclitaxel patients had evidence of any toxicity event (P = .40). Patients treated with carboplatin-paclitaxel-bevacizumab “had significantly more bleeding, proteinuria, and GI perforation events (all P < .05),” the investigators found. The finding of significantly more toxicity events among patients receiving carboplatinpaclitaxel-bevacizumab was “consistent with earlier randomized clinical trials,” the authors noted.

Overall, 34% of patients receiving carboplatin-paclitaxel vs 19% of patients receiving carboplatin-paclitaxelbevacizumab had at least one hospitalization (P < .001). “Both unadjusted

© David Sipress/The New Yorker Collection/www.cartoonbank.com

and adjusted models showed that patients who received carboplatin-paclitaxel-bevacizumab were less likely than patients who received carboplatin-paclitaxel to experience a hospital-related event after the initiation of chemotherapy,” the researchers wrote.

The unadjusted odds ratio associated with the likelihood of patients who received carboplatin-paclitaxelbevacizumab having a hospitalization was 0.46 (95% confidence interval [CI], 0.32–0.67). Using multivariable and propensity score–adjusted models, the odds ratio for patients who received carboplatin-paclitaxel-bevacizumab being hospitalized was 0.48 (95% CI, 0.32–0.71). Patients receiving carboplatin-paclitaxel-bevacizumab also had fewer total hospitalizations (rate ratio, 0.62; 95% CI, 0.47–0.82) and hospital days (rate ratio, 0.53; 95% CI, 0.47–0.60) than patients who received carboplatin-paclitaxel.

With these findings, “we rejected the null hypothesis that in the presence of a higher toxicity burden, the likelihood of a hospitalization after the initiation of bevacizumab would increase after the adjustment for observable factors, including age and comorbidity status,” the authors stated. “To our knowledge, this is the first study outside of a clinical trial setting to examine these outcomes in patients with NSCLC.”

Clinical Implications The findings of this study “have international implications, building on analyses of toxicities and costs recently reported for targeted cancer therapies,” according to an accompanying editorial

by Terhi T. Hermanson, MD, PhD, of Helsinki University Hospital, Finland, and three colleagues from the United States. “Whereas toxicities associated with carboplatin-paclitaxel-bevacizumab may be relatively constant from country to country, therapy-related hospitalizations will differ because of variations both between and within health systems. Although this study is directed toward oncologists and decision makers in the United States, other audiences will benefit from it.”

The editorial continued: “The authors have made a terrific beginning in analyzing the impact of a new cancer regimen for NSCLC in a community setting in the United States. Updates are essential as experience with this regimen matures internationally and as new NSCLC regimens are introduced.

For the time being, caveat emptor to clinicians who choose to administer carboplatin-paclitaxel-bevacizumab therapy to patients with NSCLC; toxicities are significant with this regimen, even among younger patients with few comorbid illnesses.”

Carroll NM, et al: J Oncol Pract 11:356-362, 2015.

Hermanson TT, et al: J Oncol Pract 11:363-364, 2015.

RENAL CELL CARCINOMA Patient Characteristics Differ in Some Clinical Trials From Real-World Population Patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors in real-world clinical practice tend to be older and sicker than the patients enrolled in pivotal clinical trials of these agents. In addition, patients with metastatic renal cell carcinoma treated with the mTOR inhibitor temsirolimus (Torisel) in the real-world setting also were older than those in the pivotal clinical trial but were more likely to have favorable-disease risk factors. Applying clinical trial results to dissimilar patient populations could result in harm, according to a study in the Journal of Oncology Practice.

“Clinical research with more inclusive eligibility criteria is needed to appropriately guide real-world practice,” concluded Aaron P. Mitchell, MD, of Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina, and colleagues.

Comparing Patients Investigators from Duke Clinical Research Institute and ACORN Research, Memphis, Tennessee, conducted a cohort study to compare baseline characteristics of patients with metastatic renal cell carcinoma in phase III clinical trials of new targeted therapies with 438 patients in a retrospective registry composed of academic (Duke) and community (ACORN Network) practices. Applying the eligibility criteria from the phase III clinical trials, the researchers determined that 39% of registry patients would have been excluded from the clinical trial testing the agent they received as first-line treatment in the real-world practice setting.

The agents most commonly used as first-line therapy for patients in

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In the Literature

the registry study were the tyrosine kinase inhibitors sunitinib (Sutent) (289 patients), sorafenib (Nexavar) (59 patients), and pazopanib (Votrient; 31 patients) and the mTOR inhibitor temsirolimus (59 patients).

Data were abstracted from the published results of phase III clinical trials for these four agents.

contrast, we were able to compare patients with cancer receiving the same treatments within and outside of clinical trials. This higher level of granularity allowed us to demonstrate that concerns regarding trial generalizability are borne out in clinical practice, in that the targeted therapies for metastatic renal cell carcinoma are commonly used in

patients not represented in the landmark trials,” the researchers wrote.

“The question of external validity— or generalizability—is increasingly important in the era of targeted therapies,” the authors observed. “These newer agents are more easily tolerated than the cytotoxic chemotherapeutics they are replacing, allowing for treatment of

patients with more comorbidities and advanced disease and increasing the need to study such patients.” n Mitchell AP, et al: J Oncol Pract. September 1, 2015 (early release online).

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

Differences in Study Populations Registry patients receiving the tyrosine kinase inhibitors were older than the clinical trial participants by an average of 4.1 years and “significantly less likely” to have favorable-risk disease by Memorial Sloan Kettering Cancer Center (MSKCC) criteria, 30.1% vs 43.8% (P < .001) for clinical trial patients.

Registry patients were more likely to have poor-risk disease by MSKCC criteria, 7.4% vs 2.9% (P < .001), and to have impaired performance status (Eastern Cooperative Oncology Group > 1), 11.1% vs 0.6% (P < .001).

Overall survival was better for patients receiving sunitinib in clinical trials, 26.4 months vs 21.3 months for registry patients, but registry patients receiving sorafenib had better overall survival, 30.1 months vs 19.3 months for trial participants. Median overall survival was 22.9 months for trial participants receiving pazopanib and had not been reached for registry patients.

Among patients receiving temsirolimus, patients from the registry were older than the clinical trial participants by an average of 7.8 years; more likely to have favorable-risk disease, 16.9% vs 0% (P < .001) for clinical trial patients; and less likely to have poor-risk disease, 10.2% vs 69.4% (P < .001). Further, in regard to performance status, 11.9% of registry patients were impaired vs 80.4% of trial participants (P < .001).

“Our findings suggest that temsirolimus is being used in practice to treat disease of lower risk than that in which it has been studied,” the authors noted. “Interestingly, overall survival was shorter for patients receiving temsirolimus (4.8 months) [outside of a clinical trial] than for corresponding trial participants (10.9 months), despite the more favorable MSKCC risk and performance status of these patients.” The authors called these “the most intriguing results of our survival analysis.”

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External Validity The authors noted that their analysis builds on studies comparing “patients with cancer treated in clinical trials vs those excluded from clinical trials who received different treatments; in

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The ASCO Post | OCTOBER 25, 2015

PAGE 126

Art of Oncology What Do You Say When She Is No Longer Living With Cancer?

by Martee L. Hensley, MD, MSc

The ASCO Post is pleased to reproduce installments of the “Art of Oncology” as published previously in the Journal of Clinical Oncology ( JCO). These articles focus on the experience of suffering from cancer or of caring for people diagnosed with cancer, and they include narratives, topical essays, historical vignettes, poems, and photographic essays.

To read more, visit http://jco. ascopubs.org/ and search “Art of Oncology.” For information on how you can submit your own essay for consideration in JCO’s Art of Oncology, visit http:// jco.ascopubs.org/site/ifc/ determine-my-article-ty pe. xhtml#art-of-oncology

T

oday, I held the hand of a 37-year-old woman who I knew was dying. Yesterday, we had spoken of second-line chemotherapy, weighing the risks against the chance that it might slow the malevolent progression of her sarcoma. Today, I entered her room knowing that I had to change my story, revise the plan, darken the prognosis, look in her eyes, hold her hand, probably cry. In the past 24 hours, the urine had stopped flowing and the jaundice had arrived.

Her body had made that awful transition from living with cancer to dying of it. I entered the room, heavy with the burden of knowing too much.

“How do you do what you do?” People ask me this all of the time at dinner parties or school pick-up. There is no party-ready answer. It is no different than trying to explain the pathophysiology of multisystem organ failure to a layperson; trying to explain how oncologists willingly care for people

Martee L. Hensley, MD, MSc, is a medical oncologist on the Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center, and Professor of Medicine at Weill Cornell Medical College, in New York.

who die is just too complicated. But, sometimes, a student or a fellow is candid and courageous enough to ask me, truly seeking an answer—how do you tell a patient that she is dying?

First, sit down. Rearrange the furniture if you need to. Be on eye level. Make a physical connection: hold a hand or touch the bed. Doing so says that you are courageous enough to share her suffering for a little while. Second, invite her support into this intimate space: ask her mother to be at the foot of the bed and let her sit down, call dad on the mobile phone and put him on speaker.

Next, set an agenda for the conversation (I want to talk about what the labs are telling us is happening to your body, about what choices we have now about what to do for your cancer, and about what might happen in the coming weeks... Is that okay with you?). Read their faces, check for resistance, for fear, for anxiety, for trust. Then talk. Talk about how the tests are showing that the cancer isn’t allowing her organs to work properly, then talk about how the chemotherapy might hasten the damage, might do more harm than good.

Talk about how her days are likely to be stronger and safer and more gratifying without the adverse effects and risks of chemotherapy. Introduce the concept of home hospice by saying that it is a route to having skilled nursing support at home, with the added benefit of emotional and spiritual support for her and for her family.

Answer all of her questions honestly, patiently, compassionately, truthfully. Ask her mom and dad to voice their questions. Answer them, even if it is territory that you have covered many times before. (What about a clinical trial? What about the oral chemotherapy I read about? Those are the relatively easy ones: “Unfortunately, there are still limits to what medicine can do for advanced cancers; the chance that the oral chemotherapy will control the disease is low, and the risks when the bowels are blocked like this are too high.”) Listen to the hard questions; don’t deflect them (How

long do I have? Why is this happening to me?). For the “how long” question, I check to see that she is truly seeking an answer to that question. I admit that I cannot give an exact time; I reassure her that we will keep her from suffering. If she does want my estimate of a time frame, then I do my best: I say that, although I could be wrong, I would expect her time is “probably measured in weeks, not months.”

When this answer makes her cry, I hold her hand tighter and acknowledge how awful this truth is. I do my best with the “why” question. I tell her again that we don’t know why any single individual gets a cancer, nor why the same cancer may be indolent in one and relentless in another. I remind her that nothing she has done in her life caused the cancer. I acknowledge

My patient breaks the silence and says “It’s okay, thank you, doctor, it’s okay,” as she blinks a tear, squeezes my hand. I clasp her hand in both of mine and meet her eyes. I echo her “yes, it’s okay.” But it is not. It is not okay that her body won’t even let me try to bring her sarcoma under control for a little longer. It is not okay for her young and beautiful life to stop unfolding. It is not okay for parents to outlive their children. My tears are coming now, too, and she offers me one of her tissues—the patient taking care of the doctor for a moment. I stand up and smile gently. I tell her that I will always be her doctor and that my care and concern for her will never stop.

She nods and smiles gently back, and I can tell that it is okay for me to end today’s visit. I walk outside the room

This is our work. Some days, it is inordinately sad, but, strangely, it is not depressing.... It is good, hard work, and, every day, I know that I am privileged to do it.

—Martee L. Hensley, MD, MSc

how very unsatisfying my answer is. I say that I am sorry.

I don’t know how long this conversation takes. On the days when this is the necessary task, one attends not to the time, only to the patient. When all of the most difficult items on the agenda have been addressed, I turn the conversation back to the things we can do for her right now: arrange for the case manager to discuss the logistics of home hospice, order what hardware they would like at home (eg, hospital bed, bedside commode, shower chair), adjust the pain medication dosing, make arrangements for the home patient-controlled analgesia. Ask again for questions or concerns, first from her, then from her family.

Hold still and listen.

and stop at the sink to wash my hands.

Her mother comes up behind me, and, frankly, I brace to absorb the displaced anger or witness her raw despondency.

But she just says, “Thank you, Doctor, thank you.” And, right then, my heart breaks for her.

This is our work. Some days, it is inordinately sad, but, strangely, it is not depressing. What I say at dinner parties is that there is an odd and deep satisfaction in it. We are willing to have these conversations, witness the suffering, share the journey, again and again, patient by patient, day after day.

It is humane work that makes a difference in human lives. It is good, hard work, and, every day, I know that I am privileged to do it. n

To read more of the Art of Oncology, visit http://jcoascopubs.org and search Art of Oncology.

ASCOPost.com | OCTOBER 25, 2015

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Announcements

Mayo Clinic Receives Federal Grant to Fund Clinical Test of Triple-Negative Breast Cancer Vaccine

R

esearchers on Mayo Clinic’s Florida campus have been awarded a $13.3 million, 5-year federal grant to test a vaccine designed to prevent the recurrence of triple-negative breast cancer.

This Breakthrough Award from the U.S. Department of Defense’s Breast Cancer Research Program will fund a national, phase II clinical trial testing the ability of a folate receptor alpha vaccine to prevent recurrence of this aggressive cancer following initial treatment. The trial will enroll 280 patients at multiple clinical sites and is expected to begin in 2016.

cer if it begins to reemerge in these patients,” he said.

The grant is a collaborative effort among Mayo Clinic’s clinicians, clinical researchers, and basic science research-

ers, said Edith Perez, MD, a breast cancer researcher at the Mayo Clinic Cancer Center in Florida. Dr. Perez is a partner and Principal Investigator on the grant, along with Dr. Knutson. n

Disclosure: Mayo Clinic and Dr. Knutson have a financial interest in the technology referenced in this Announcement. TapImmune Inc has a license for the vaccine and will supply it for the trial.

Success in Phase I Trial A 22-patient phase I clinical trial, previously conducted by the grant’s principal investigator, Keith Knutson, PhD, Associate Professor in the Department of Immunology, found the vaccine was safe. It did not induce autoimmunity, as some vaccines can. The vaccine was designed by Dr. Knutson and initially tested by researchers at Mayo Clinic’s Minnesota campus for safety and its ability to stimulate the immune system.

2015 RTA Recipients Photo by © ASCO/Zach Boyden-Holmes 2015

Opportunities for Medical Students and Residents from Underrepresented Populations

Keith Knutson, PhD

It exploits the need of triple-negative breast cancer to take in folic acid to grow, said Dr. Knutson. Because of that need, these tumors overproduce the folate receptor alpha, which latches on to folic acid in the tumor’s microenvironment. Evidence shows some patients naturally produce an immune response to parts of these receptors, “but the cancer is much too strong for what is typically a weak immune response,” said Dr. Knutson.

The vaccine is designed to boost the immune system to rapidly react to the presence of the receptor on cancer cells early in the course of tumor recurrence. “We believe this vaccine will provide a much more robust and sustained immune response to these receptors, which will then improve the body’s ability to directly or indirectly kill the tumor by cutting off access to the folate it needs to respond to can-

The Conquer Cancer Foundation of ASCO is working to increase access to quality cancer care for underserved communities by inviting medical students and residents from underrepresented populations in medicine to consider a career in oncology.

We encourage you to pass along this information to individuals who might be interested.

MEDICAL STUDENT ROTATION Provides financial support for U.S. medical students from underrepresented populations in medicine to complete a clinical or clinical research oncology rotation.

For eligibility criteria and to apply visit: ConquerCancerFoundation.org/MSR

RESIDENT TRAVEL AWARD Provides financial support for residents from underrepresented populations in medicine to attend the ASCO Annual Meeting where they will have an opportunity to meet oncologists and learn more about career options in oncology.

For eligibility criteria and to apply visit: ConquerCancerFoundation.org/RTA Applications Close: December 7, 2015, 11:59 EST Recipients will be announced in March 2016.

“This program was one of the most enriching programs that I’ve been able to participate in.”

- Armando Villanueva 2012 MSR Recipient

The ASCO Post | OCTOBER 25, 2015

PAGE 128

In Memoriam

Noted Integrative Oncology Specialist Mitchell L. Gaynor, MD, Dies at 59

By Ronald Piana Southwestern Medical School in Dallas, he was a clinical fellow in hematology-oncology at the New York Hospital–Cornell Medical Center.

He has held the position of Director of Medical Oncology at the Strang Cancer Prevention Center and also Medical Director of Oncology at the Weill Cornell Medical College Center for Complementary and Integrative Medicine. Dr. Gaynor was also a member of ASCO. Mitchell L. Gaynor, MD

I

ntegrative oncology had a long road to acceptance by the mainstream medical community; the field is now widely accepted for its healthful benefits, especially in assuaging the more troublesome side effects of cancer treatments. Many well-known oncologists have adapted integrative oncology into their clinical practice, such as Mitchell L. Gaynor, MD, a talented and persuasive advocate for the field. Dr. Gaynor died on September 15. The cause of death was reported as suicide.

Dr. Gaynor was born in rural Hale Center, Texas, on June 5, 1956, the son of Dr. J. Irvin Gaynor, a dentist, and the former Elaine Shure. The family relocated to the suburban town of Plainview, New York, when Dr. Gaynor was in elementary school.

He graduated from Plainview High School in 1974.

After receiving his medical degree from the University of Texas

Early Interest in Integrative Oncology In 1987, when Dr. Gaynor was a postdoctoral fellow at Rockefeller University in New York, he became interested in the emerging field of integrative oncology. At that time, research at the university was being conducted on nutrient-gene interactions and the immune system.

However, an even earlier experience might also have had a latent formative effect on his attraction to alternative medicine. When he was 9 years old, his mother died of breast cancer, and he would often remark on how impressed he was that a person with a terminal disease could have equanimity and inner peace in the presence of significant physical suffering and illness.

In 1991, Dr. Gaynor had another pivotal career episode. While at New York Hospital, he was caring for a refugee Tibetan monk named Odsal who had a very rare cardiac condition.

Dr. Gaynor’s eyebrow-raising diagnosis was that because the monk was separated from his spiritual homeland, he was suffering from a broken heart. A practitioner of meditation, he schooled the monk in his own style of meditation, and they quickly became friends. The monk reciprocated by bringing a traditional Tibetan metal singing bowl to Dr. Gaynor’s Manhattan apartment.

He was known to move outside of the mainstream comfort zone. Most of the nutritional supplements and alternative treatments that Dr. Gaynor recommended were aimed at fortifying a patient’s immune system and targeted what he determined were the root causes of disease. During a 2013 interview, he said, “I was amazed at the fact that we really ‘are what we eat,’ and that with the best medical training in the world, nobody in medical school had ever taught me this.”

The Sound of Healing A published author, Dr. Gaynor, recalled his unlikely friendship with Odsal in his book, The Healing Power of Sound. He wrote, We removed our shoes and settled ourselves cross-legged on the living room floor. Odsal took out a small wooden baton and moved it lightly around the rim of the bowl, in much the same way you might trace the lip of a wineglass with your finger. I could feel the vibration physically resonating through my body, touching my core in such a way

 In Memoriam

Mitchell L. Gaynor, MD June 5, 1956 – September 15, 2015 

that I felt harmony in the universe.…

I immediately intuited that playing the bowls would change my life, and the lives of many of my patients.

Something of a Renaissance man, Dr. Gaynor joined up with the son of one of his patients to produce a record titled, “Change Your Mind.” After it was featured on The Dr. Oz Show, the record topped Billboard Magazine’s new age charts. The duo recorded two other successful records.

Dr. Gaynor was the author of the recent book, The Gene Therapy Plan, which combined nutritional recipes and medical research to help fight cancer. At the time of his death, Dr. Gaynor was promoting the book, which was said to provide a revolutionary approach to reversing gene damage associated with aging, cancer, obesity, and diabetes and to prevent future gene deterioration with specific alternative health programs. He was also the author of five other books, many of them focused on the environment’s effect on an individual’s health and geared for a general readership.

Dr. Gaynor served on advisory boards for Healthy Living Magazine and the Sass Foundation for Medical Research and was a member of the editorial board of the journal Integrative Cancer Therapies.

Dr. Gaynor’s marriage ended in divorce; he is survived by two sons, Eric and David, and a brother, Dr. Richard Gaynor. n

ASCOPost.com | OCTOBER 25, 2015

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Announcements

Joann B. Sweasy, PhD, Named Associate Director for Basic Sciences at Yale Cancer Center

J

oann B. Sweasy, PhD, has been named Associate Director for Basic Sciences for Yale Cancer Center. In this role, Dr. Sweasy will be a member of Yale Cancer Center’s senior leadership team, and will help enhance the cancer research environment for scientists engaged in fundamental cancer research across Yale University. She will also lead the intramural grant program

at Yale Cancer Center, including the pilot-awards and the American Cancer Society award.

Dr. Sweasy takes over the position from Daniel DiMaio, MD, PhD, who will remain Deputy Director of Yale Cancer Center, and will continue to oversee the Center’s scientific endeavors and provide support to Dr. Sweasy.

Dr. Sweasy is Professor and Vice

Joann B. Sweasy, PhD

Chair of Therapeutic Radiology at Yale University School of Medicine.

She is also Professor in the Department of Genetics at Yale, and an Adjunct Professor of Microbiology and Molecular Genetics at the University of Vermont. She has held a Donaghue Investigator Award and a Junior Faculty Scholar Award from the American Cancer Society. n

Constantinos G. Hadjipanayis, MD, PhD, Joins Mount Sinai Beth Israel, Tisch Cancer Institute

R

enowned surgical neuro-oncologist Constantinos (Costas) G. Hadjipanayis, MD, PhD, has been named Professor and Chair of the Department of Neurosurgery at Mount Sinai Beth Israel. He has also been appointed as Director of Neurosurgical Oncology for the Mount Sinai Health System and Director of the Brain Tumor Nanotechnology Laboratory in the Tisch Cancer Institute.

Both as a neurosurgeon and a National Institutes of Health–funded scientist, Dr. H ­ adjipanayis is recognized as a neuro-oncology pioneer, leading cooperative group- and industry-sponsored clinical trials for patients with malignant brain tumors. He was the first in the

Constantinos G. Hadjipanayis, MD, PhD

United States to perform fluorescenceguided surgery for malignant gliomas with the use of a 5-aminolevulinic acid (5-ALA) drug called Gliolan, which can light up otherwise invisible brain tumors in the operating room. His laboratory

developed a unique trial for brain tumors using magnetic nanoparticle therapeutic agents that can target brain tumor cells and can also be seen by magnetic resonance imaging.

Dr. Hadjipanayis’ interests include surgery and experimental therapeutics for malignant brain tumors, neuroendoscopy for pituitary tumors, and colloid cysts. In addition, he performs microsurgery and radiosurgery for tumors of the skull base and spinal cord.

Prior to joining Mount Sinai, Dr. Hadjipanayis was an Associate Professor in the Department of Neurosurgery at Emory University School of Medicine, Chief of Neurosurgery at Emory University Hospital Midtown,

and Director of the Winship Brain Tumor Center of Emory. He was also the President of the Georgia Neurosurgical Society and the Southeastern Brain Tumor Foundation.

Dr. Hadjipanayis received his medical degree from Jefferson Medical College. He completed his internship and residency in neurosurgery at the University of Pittsburgh School of Medicine, simultaneously obtaining his doctorate in the Department of Molecular Genetics and Biochemistry. He pursued further advanced training in awake craniotomy techniques and intraoperative cortical/subcortical mapping at the University of California, San Francisco. n

Edward M. Schaeffer, MD, PhD, Joins the Lurie Cancer Center

E

dward (Ted) M. Schaeffer, MD, PhD, an internationally recognized physician-scientist with expertise in urologic oncology, will join the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Dr. Schaeffer has been named Chair of the Department of Urology at the Feinberg School of Medicine and Northwestern Memorial Hospital, effective December 1, 2015.

A respected clinician with expertise in open, laparoscopic, and robotic treatments of urologic malignancies, Dr. Schaeffer is currently Director of

the Prostate Cancer Program, Director of International Urology, and Codirector of the Prostate Cancer Multidisciplinary Clinic at Johns Hopkins Medicine. He is an active member of the James Buchanan Brady Urological Institute and the Sidney Kimmel Comprehensive Cancer Center, where he participates in multidisciplinary approaches to the treatment of genitourinary cancers. Dr. Schaeffer is the R. Christian B. Evensen Professor of Urology, Oncology, and Pathology at the Johns Hopkins School of Medicine, and Founder and Chief Medical

Officer of the Prostate Cancer Foundation of Norway.

Dr. Schaeffer’s discoveries have greatly advanced the basic scientific understanding of prostate cancer and

Edward M. Schaeffer, MD, PhD

clinical care pathways. His research emphasizes at-risk populations, diagnosis, treatment outcomes, and the molecular biology of lethal prostate cancer.

Dr. Schaeffer’s laboratory, which has had funding by the National Institutes of Health, the Howard Hughes Medical Institute, the U.S. Department of Defense, and the Prostate Cancer Foundation, specifically focuses on the molecular biology of locally aggressive prostate cancers and the impact of race on the biology of prostate cancer. n

Send Your News to The ASCO Post The ASCO Post encourages readers to send news of new appointments, awards, and other milestones relevant to their career in oncology. News should include a high-resolution photo of the individual(s) named in the announcement. Send copy and photo to editor@ASCOPost.com.

All submissions will be considered for publication.

The ASCO Post | OCTOBER 25, 2015

PAGE 130

Perspective Jonas A. de Souza, MD continued from page 1

finances. As cancer drugs now routinely cost over $10,000 a month, these cost conversations between oncologists and their patients are becoming increasingly common.

The term “financial toxicity”1,2 has been used to describe the objective financial consequences of cancer, as well as the subjective financial concerns that come along with expensive health care.

For example, according to the Family Reach Foundation Annual Report, 59% of their grants to help patients who have cancer with their expenses were for those in need of housing (mortgage and rent) support.3 In addition, more than an impact on our patients’ bank accounts, financial toxicity has been linked to differences in health-related quality of life,4-6 compliance,7 and, most recently, survival.8

Thinking Outside the Box Given this crippling rise in the cost of cancer therapies, and the negative impact it is having on our patients, physicians need to be prepared to participate in discussions about costs. ASCO has made costs a priority research area through its Value in Cancer Care Task Force. Before that, in 2009, ASCO published a guidance statement urging oncologists to discuss the cost of care with their patients.9 ASCO argues that considering the factors of a patient’s welfare outside of a pure therapeutic approach is a tenant of ethical medical care.

The reality is that the pressures on a busy oncologist may not permit him or her to know all of the details associated with the costs of cancer care; costs may differ dramatically by insurance provider and plan, therapeutic modality chosen, and site of cancer care. As the ASCO report highlights, physicians are not trained on how to discuss costs with their patients and, as a result, generally feel uncomfortable with these discussions.

Therefore, to make strides in addressing financial toxicity and enacting real change, it is important for all of us to start to think outside the box.

We propose two ideas to tackle the financial toxicity problem from the

patient’s point of view.

First, we propose that instead of talking about the financial consequences in terms of out-of-pocket costs, we talk about the impact that costs of care (including loss of income and disability) will have on patients’ health-related quality of life. Oncologists are well versed in discussing the physical side effects of cancer and its therapies. Pain, alopecia, neuropathy, and vomiting are all documented in clinical trials, addressed in practice, and considered in therapeutic decisions for patients. Let us consider the impact of costs on a patient’s quality of life a side effect.

The instruments and methods to do so have already been developed.5,6,10 For instance, Zafar et al4 measured financial

Last, let us share this knowledge among ourselves and with our patients.

Let us develop mechanisms to share and increase our knowledge about this side effect. In this regard, our group has developed an online registry (www. costofcancercare.org), which has the potential not only to better understand the impact of financial toxicity on patients, but also to learn what yields to financial toxicity in different cancers and therapies. This registry is built upon a validated patient-reported outcome measure10 and aims to collect information on a patient’s condition, healthrelated quality of life, and treatment approach.

Our goal is to collect data to empower physicians to answer that question

Let us consider financial toxicity as any other side effect and discuss its impact on patients’ quality of life. The timing to do so is now.

—Jonas A. de Souza, MD

toxicity by “the difficulty with living on their income” and “whether their insurance changed.” We also developed a patient-reported outcome, the comprehensive score for financial toxicity (COST),10 to measure financial toxicity. Both studies showed that higher financial toxicity correlates with worse quality of life.6 Let us not make the cost discussions with patients all about the money and about something we were not trained to do. But rather, let us focus on how the financial consequences of these therapies may impact our patients’ health-related quality of life.

The second proposal is to let us learn and share data about financial toxicity.

Document whenever your patient cannot take a medication because of costs.

Document when a patient on treatment declares bankruptcy. Document when a patient reports changes in his/her daily life due to financial concerns. Just like any side effect, documentation of financial toxicity is the key to understanding it.

about how much a determined therapy would cost a patient with financial toxicity data. The day we will have enough data to say that ipilimumab (Yervoy) and nivolumab (Opdivo) cause grade 3 or 4 diarrhea in 9% of patients with melanoma,11 grade 3 or 4 fatigue in 4%, and a hypothetical grade 3 financial toxicity in 20% will soon come to reality.

Closing Thoughts We should acknowledge that we are not trained for discussing costs with our patients, and, as physicians, we may never be. However, improving patients’ understanding of their financial toxicity is paramount to making informed decisions about their cancer treatment.

Patients should be given the support mechanisms to address this side effect or, at the very least, should be notified about it. A valid alternative is to do what we do best: Let us consider financial toxicity as any other side effect and discuss its impact on patients’ quality of life. The timing to do so is now. n

Disclosure: Dr. de Souza reported no potential conflicts of interest.

References 1. Ratain MJ: Biomarkers and clinical care. Presented at the AAAS/FDLI Colloquium, Personalized Medicine in an Era of Health Care Reform, Washington, DC, October 27, 2009. Available at https://costofcancercare-sites.uchicago .edu/sites/costofcancercare.uchicago .edu/files/uploads/Ratain.pdf. Accessed August 18, 2015.

2. Ubel PA, Abernethy AP, Zafar SY: Full disclosure—Out-of-pocket costs as side effects. N Engl J Med 369:1484-1486, 2013.

3. Family Reach: Financials. Available at http://familyreach.org/financials/. Accessed August 18, 2015.

4. Zafar SY, McNeil RB, Thomas CM, et al: Population-based assessment of cancer survivors’ financial burden and quality of life: A prospective cohort study. J Oncol Pract 11:145-150, 2015.

5. Fenn KM, Evans SB, McCorkle R, et al: Impact of financial burden of cancer on survivors’ quality of life. J Oncol Pract 10:332-338, 2014.

6. De Souza JA, Wroblewski K, Yap BJ, et al: Grading financial toxicity based upon its impact on health-related quality of life.

2015 ASCO Annual Meeting. Abstract 6618. Presented May 29, 2015.

7. Neugut AI, Subar M, Wilde ET, et al: Association between prescription copayment amount and compliance with adjuvant hormonal therapy in women with early-stage breast cancer. J Clin Oncol 29:2534-2542, 2011.

8. Bansal A, Ramsey SD, Fedorenko CR, et al: Financial insolvency as a risk factor for mortality among patients with cancer. 2015 ASCO Annual Meeting. Abstract 6509. Presented May 29, 2015.

9. Schnipper LE: ASCO Task Force on the Cost of Cancer Care. J Oncol Pract 5:218-219, 2009.

10. de Souza JA, Yap BJ, Hlubocky FJ, et al: The development of a financial toxicity patient-reported outcome in cancer: The COST measure. Cancer 120:32453253, 2014.

11. Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23-34, 2015.

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