TAP Vol 6 Issue 21

Managing Prostate Cancer

15, 20, 30

| Mammography Screening at What Age?

82, 148

| ASCO Guideline Update: NSCLC

87

VOLUME 6, ISSUE 21

NOVEMBER 25, 2015

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

NCCN Annual Congress: Hematologic Malignancies

Does Low-Dose Radiation Cause Leukemia?

Chronic Myelogenous Leukemia: What Drug for Which Patient?

By Caroline Helwick

T

reatment of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors is “the golden child success story of targeted treatment,” Jerald P. Radich, MD, of the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance, Seattle, Washington, told attendees at the National Comprehensive Cancer Network (NCCN) 10th Annual Congress on Hematologic Malignancies. “I don’t know of any other story showing the power of knowing the actual target of the agent and the agent affecting its biology. These things have made a huge impact on overall survival,” he added.

Game Changers Tyrosine kinase inhibitors have had a huge impact on overall survival of patients with CML. The trick for clinicians, Dr. Radich suggested, is choosing the most appropriate agent for a given patient. “This question drives clinical care,” he added.

Eight years after treatment initiation with imatinib

(Gleevec) in the landmark IRIS trial, approximately half of study subjects remained on the drug. Treatment has been associated with a complete cytogenetic response rate of 83%, transformation-free survival of 92%, and overall Jerald P. Radich, MD survival of 85%,1 he noted.

“No matter how you slice it, these patients have done fantastically well,” Dr. Radich observed. “This therapy has greatly decreased progression to accelerated phase and blast crisis.”

Use of the second-generation tyrosine kinase inhibitors, nilotinib (Tasigna) and dasatinib (Sprycel), as first-line treatment has produced higher rates of major molecular and complete cytogenetic responses. continued on page 6

Perspective

5-Year Results of GEC-ESTRO Trial of Accelerated Partial-Breast Irradiation vs Whole-Breast Irradiation: Is There Any Impact?

By Jay R. Harris, MD

T

here is a strong rationale for the use of accelerated partial-breast irradiation: The large majority of inbreast recurrences are at or near the primary site, limiting the radiation dose to the primary site has the potential to decrease side effects, and treatment can be delivered over a shorter period (typically about 1 week). Accelerated partial-breast irradiation can be performed by a variety of techniques, including external-beam (conformal or

intensity-modulated) radiation therapy, interstitial multicatheter brachytherapy, intracavitary brachytherapy, or intraoperative radiation, typically at the time of resection of the primary tumor.

In the United States, external-beam radiotherapy is the most frequent technique for accelerated partialbreast irradiation. Most U.S. radiation oncologists are not skilled in the use of interstitial brachytherapy.

The 5-year results of the European GEC-ESTRO I don’t believe that the available trial comparing accelerated partial-breast irradiation data establish accelerated and whole-breast irradiapartial-breast irradiation as equivalent tion have been reported by Strnad et al1 and are sumto whole-breast irradiation. Mature marized in this issue of The 10-year results are needed.

ASCO Post (see page 68).

—Jay R. Harris, MD The results are encourag-

By Robert Peter Gale MD, PhD, DSc(hc), FACP, FRSM, and F. Owen Hoffman, PhD

D

ata from A-bomb survivors, persons with ankylosing spondylitis and neoplasms treated with radiation therapy, and many other sources show a strong association between exposure to ionizing radiation (particles or electromagnetic waves with sufficient energy to cause an ionization such as photons and gamma rays) and an increase in the risk of developing leukemia.

In A-bomb survivors, the relative risks of continued on page 156

Dr. Gale is Visiting Professor of Haematology, Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, United Kingdom; and Dr. Hoffman is President and Director, Oak Ridge Center for Risk Analysis, Oak Ridge, Tennessee.

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

MORE IN THIS ISSUE Oncology Meetings Coverage Breast Cancer Symposium ��������������������� 3–5 NCCN Hematologic Congress ������������6–14 ASTRO Annual Meeting �� 15, 20, 22–27 European Cancer Congress ��������������������������� 30–32, 37–40 Inherited Colorectal Cancers Group ��������������������������������� 44–46 On Heme Malignancies: Drs. David Williams, Michael Williams, and Vincent Rajkumar �������������������������������������49 Direct From ASCO ��������������������������� 75–78 Joseph V. Simone on QOPI® ��������������������79 ACS Update on Breast Screening ��� 82–86

continued on page 69

Visit The ASCO Post booth at ASH (booth 1125) and SABCS (booth T2)

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PAGE 3

Breast Cancer Symposium Targeted Therapy

Neratinib Improves Disease-Free Survival in Early-Stage HER2-Positive Breast Cancer

By Chase Doyle and Caroline Helwick

P

atients with early-stage HER2positive breast cancer who received neratinib as extended adjuvant therapy demonstrated improved invasive disease–free survival, with an absolute benefit of 2.3% at 2 years.1 However, these results of the ExteNET trial, previously presented at the 2015 ASCO Annual Meeting, are only part of the story. According to secondary data introduced at the 2015 Breast Cancer Symposium, certain subsets derived even greater benefits,2 including those with hormone receptor–positive disease and those pretreated with trastuzumab (Herceptin) sequentially.

“ExteNET is the first study to show a statistically significant improvement in invasive disease–free survival in the intent-to-treat population,” said Arlene Chan, MD, of the Breast Cancer Re-

At the time of the study design, there was no protocol-mandated antidiarrheal prophylaxis put in place, but currently three studies have shown that an intensive loperamide prophylactic regimen can successfully reduce the rates of grade 3 diarrhea to 0% to 17%.

—Arlene Chan, MD

search Centre, Western Australia, and Curtin University in Perth. “Furthermore, in the centrally confirmed HER2positive cohort, we are now seeing absolute benefits on the order of 4.1% to 8.6%, depending on the subset.”

The positive results, however, were not met with total enthusiasm by a number of listeners, who considered the toxicity of the drug to far outweigh the benefit.

Neratinib is an oral tyrosine kinase inhibitor of HER1, 2, and 4. In xeno-

grafts, neratinib produced dose-dependent and sustained tumor growth regression,3 and in a phase II trial, responses were observed in 24% of patients previously treated with trastuzumab and 56% of trastuzumab-naive patients; 16-week progression-free survival rates were 59% and 78%, respectively.4

ExteNET Trial Details The ExteNet trial is an international, multicenter study that enrolled 2,840 patients with locally defined, HER2positive disease who had been pretreated with adjuvant trastuzumab and chemotherapy. In addition, the estrogenreceptor status of the primary tumor was required for inclusion in the study.

Patients were randomly assigned on a 1:1 basis to receive either neratinib at continued on page 4

EXPERT POINT OF VIEW

D

iscussant Clifford Hudis, MD, Chief of Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York, highlighted neratinib’s benefits while also advocating caution in interpreting the results due to incomplete data, the serious side effect of diarrhea, and

recurrence risk by 33%, Dr. Modi highlighted that ExteNET’s positive findings were discordant from the ALTTO and HERA trials. In HERA, overall survival was the same whether patients received 1 or 2 years of trastuzumab (Herceptin)—approximately 87% at 9 years. In ALTTO,

There are confirmed data from only 60% of the population. We have to watch this study and be careful about overinterpretation.

—Clifford Hudis, MD

the potentially game-changing outcomes of the adjuvant trial testing pertuzumab (Perjeta).

In addition, Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, who discussed the study at the 2015 ASCO Annual Meeting, and Richard Gelber, PhD, Professor of Biostatistics at Harvard Medical School, Boston, put the ExteNET trial results into context with other studies in HER2-positive patients.

Noting that neratinib reduced the

the addition of lapatinib (Tykerb) to trastuzumab did not improve survival over trastuzumab alone (approximately 95% at 4 years).

Words of Caution “There are confirmed HER2 data from only 60% of the population,” noted Dr. ­Hudis. “We have to watch this study and be careful about overinterpretation.”

Whether neratinib is “ready to be the new standard of care” is up for de-

bate, concluded Dr. Modi.

“On the one hand, I’d say yes, the absolute disease-free survival is real. These results are similar to what we saw with the 2-year data of the original adjuvant trastuzumab trials,” she pointed out.

“But on the other hand, we have no overall survival data, and this is something we did have with the trastuzumab trials.”

Shanu Modi, MD

What About Pertuzumab?

Dr. Modi also questioned the appropriate population for this drug.

Pertuzumab is an option in the neoadjuvant setting for high-risk patients, and it is unknown whether neratinib’s benefit would persist in this group. In patients with low-risk disease, it could be difficult to justify the toxicity for a small potential benefit, she said.

“Preoperative studies for pertuzumab … showed a near doubling of the pathologic complete response rate,” added Dr. Hudis. “Accelerated approval that was granted to pertuzumab is just the beginning. If converted to full approval, it would raise a number of questions that would be challenges to the ExteNET trial results going forward.”

Richard Gelber, PhD

‘A Fatal Limitation’ Following the initial presentation at the ASCO Annual Meeting, Dr. Gelber took a more absolute stance.

“I hypothesize that the short followup, which Dr. Chan acknowledged as a limitation of the study, is a fatal limitation,” he said. “I consider these results nonactionable. The early results of ALTTO showed an even larger advantage than we saw here. The curves separated early and came together later. Follow-up of ExteNET is much too short to take action.” n Disclosure: Drs. Hudis and Modi reported no potential conflicts of interest.

Dr. Gelber is the senior independent statistician for the HERA, ALTTO, and APHINITY clinical trials, for which his institution received research funds from Roche and GSK.

The ASCO Post | NOVEMBER 25, 2015

PAGE 4

Breast Cancer Symposium Supportive Care

APF530 Superior to Ondansetron in Preventing Chemotherapy-Induced Nausea or Vomiting

By Chase Doyle

A

s part of a three-drug regimen, APF530 (extended-release formulation of granisetron) has become the first 5-HT3 (5-hydroxytryptamine) receptor antagonist to demonstrate superiority over the standard of care for delayed nausea and vomiting after highly emetogenic chemotherapy. According to the results of the MAGIC trial, presented at the 2015 Breast Cancer Symposium, APF530, administered with fosaprepitant (Emend) and dexamethasone, provided superior complete response in delayed-phase chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy vs a standard-of-care regimen of ondansetron with fosaprepitant plus dexamethasone.1 “The APF530 regimen was associ-

ated with a clinical benefit over the ondansetron regimen in nausea control, rescue medication use, and patient satisfaction,” said Ian D. Schnadig, MD, of Compass Oncology, US Oncology Research, Tualatin, Oregon. “It is significant that both arms of the study had a three-drug prophylactic regimen, which has not been previously evaluated in phase III trials in this high-risk patient group.”

“Results presented here indicate that not all 5-HT3 receptor antagonists are equally effective in the setting of delayed-phase chemotherapy-induced nausea and vomiting due to highly emetogenic chemotherapy,” Dr. Schnadig added.

Although APF530 has been previously tested in randomized tri-

Neratinib in Breast Cancer

tor–positive subset, patients receiving 1 year of neratinib derived a 49% risk reduction of an invasive event, translating into a 4.2% absolute benefit.

Distant recurrences were reduced in all patients receiving neratinib, with a 1.4% difference between patients receiving neratinib and placebo.

“In the centrally confirmed HER2positive cohort, to date, approximately 60% of patients have been evaluated,” said Dr. Chan. “Approximately 86% of patients were centrally confirmed as having HER2-positive disease.” For patients with centrally confirmed HER2-positive disease, a sustained, statistically significant benefit (hazard ratio = 0.51) was observed in those receiving neratinib.

“In terms of invasive disease, I want to draw your attention to the magnitude of benefit in the distant metastatic disease,” said Dr. Chan. “In the centrally

continued from page 3

240 mg/d for 12 months or placebo.

ExteNet’s primary analysis was the invasive disease–free survival for all patients treated who had completed 2 years of follow-up.

The primary endpoint, reported at the 2015 ASCO Annual Meeting, was met in the intent-to-treat population, showing improved invasive disease– free survival for patients receiving neratinib (93.9%) vs placebo (91.6%).1

Additional Data At the 2015 Breast Cancer Symposium, Dr. Chan presented further data, showing that disease-free survival in the ductal carcinoma in situ subset was also significantly improved, with a hazard ratio of 0.63 and a 2.9% absolute benefit.

Also, in the predefined hormone recep-

Neratinib in HER2-Positive Breast Cancer ■■ The phase III ExteNET trial evaluated 1 year of treatment with the tyrosine kinase inhibitor neratinib, following chemotherapy and trastuzumab, in patients with early-stage HER2-positive breast cancer.

■■ The study met its primary endpoint, showing improved invasive disease– free survival with neratinib, which translated to an absolute benefit of 2.3% at 2 years.

■■ In the predefined, hormone receptor–positive subset, patients receiving neratinib derived an even greater benefit, with a 49% risk reduction of an invasive event (2.2% absolute benefit).

■■ Grade 3 diarrhea was a problem for nearly 40% of patients treated with neratinib, but intensive prophylaxis with loperamide reduced the frequency of this side effect.

The APF530 regimen was associated with a clinical benefit over the ondansetron regimen in nausea control, rescue medication use, and patient satisfaction.

—Ian D. Schnadig, MD

als—demonstrating noninferiority to palonosetron in various settings—the MAGIC trial is the first three-drug vs three-drug regimen efficacy trial, based on current antiemetic guideline–recommended treatment, comparing the efficacy and safety of APF530 in preventing chemotherapy-induced nausea confirmed HER2-positive population, there was a 4.1% absolute difference in the number of patients developing metastatic disease.”

Patients who were both centrally confirmed HER2-positive and hormone receptor–positive derived a significant absolute benefit of 8.6% at 2 years (hazard ratio = 0.25) for invasive disease–free survival, remarked Dr. Chan, although only 765 patients have been evaluated to date.

Further analysis showed superiority in the neratinib arm as well for patients who had received prior trastuzumab sequentially and for patients with both premenopausal and postmenopausal status.

Adverse Events Despite these significant benefits, Dr. Chan acknowledged neratinib’s safety concerns. The predominant side effect was diarrhea, with up to 40% of patients experiencing a grade 3 event.

“We’re very cognizant that this is a side effect that we need to address,” admitted Dr. Chan. “It’s noteworthy that at the time of the study design, there was no protocol-mandated antidiarrheal prophylaxis put in place. Only 1.4% of patients were actually hospitalized for this side effect,” she added, “and there was no difference in other adverse events between neratinib and placebo groups.”

Dr. Chan suggested that loperamide might provide a solution to this side effect. “Currently, three studies have shown that an intensive loperamide

and vomiting after highly emetogenic chemotherapy with ondansetron.

MAGIC Trial The MAGIC trial is a prospective, randomized, placebo-controlled, double-dummy, double-blind, multicenter continued on page 5

prophylactic regimen can successfully reduce the rates of grade 3 diarrhea to 0% to 17%,” she indicated. “With a mandatory, intensive loperamide program in the first 30 days of neratinib, we’re confident that we can reduce this side effect very significantly,” Dr. Chan concluded. n

Disclosure: Dr. Chan has consulted for Pfizer; has been on the speakers bureau for Pierre Fabre, Amgen, and Novartis; and has received travel funds from Pierre Fabre.

References 1. Chan A, Delaloge S, Holmes FA, et al: Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). 2015 ASCO Annual Meeting. Abstract 508. Presented June 1, 2015.

2. Chan A, Martin M, Von Minckwitz G, et al: Invasive disease-free survival benefit following neratinib as extended adjuvant therapy in centrally confirmed HER2-positive early-stage breast cancer: The ExteNet phase III randomized placebo-controlled trial. 2015 Breast Cancer Symposium. Abstract 117. Presented September 25, 2015.

3. Rabindran SK, Discafani CM, Rosfjord EC, et al: Antitumor activity of HKI272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64:3958-3965, 2004.

4. Burstein HJ, Sun Y, Dirix LY, et al: Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 28:1301-1307, 2010.

ASCOPost.com | NOVEMBER 25, 2015

PAGE 5

Breast Cancer Symposium APF530 vs Ondansetron continued from page 4

trial conducted in the United States. Researchers stratified 942 patients based on planned receipt of cisplatin (yes or no) before randomization to one of two arms.

In the ondansetron arm, patients received ondansetron (0.15 mg/kg IV), fosaprepitant (150 mg IV), dexamethasone (12 mg IV), and placebo subcutaneous injection. In the APF530 arm, patients received fosaprepitant (150 mg IV), dexamethasone (12 mg IV), and APF530 (500-mg subcutaneous injection).

The study’s primary endpoint was the proportion of patients achieving a complete response, which was defined as no emetic episodes (vomit or retch) and no rescue medication use during the delayed-onset phase of chemotherapy-induced nausea and vomiting, occurring 24 to 120 hours following administration of highly emetogenic chemotherapy agents.

Demographics were balanced between the treatment arms, Dr. Schnadig noted, with the majority of patients being female. The most common chemotherapy regimens in both treatment arms were AC-based (anthracycline-cyclophosphamide) regimens, representing almost two-thirds of patients.

Primary Endpoint Met As Dr. Schnadig reported, the study met its primary endpoint. “The percentage of patients who achieved a complete response was significantly higher in the APF530 group than the ondansetron

group (64.7% vs 56.6%, P = .014),” he said. “Complete response rates were 8.0% higher in the APF530 arm, equating to a 14.2% relative improvement.”

In addition, for those patients receiving cisplatin, the results were even more impressive. “Within the cisplatin stratum,” he added, “complete response rates were 10.6% higher in the APF530 arm compared to the ondansetron arm, equating to a 19.4% relative improvement and indicating a meaningful clinical benefit in this particularly difficultto-treat patient population.”

The following trends favoring APF530 over ondansetron were also observed: • The percentage of patients who achieved complete control, defined as complete response plus no more than mild nausea during the delayed-onset phase, favored APF530 (P = .022); • Overall-phase complete response rates were 58.4% and 52.9% in the APF530 and ondansetron arms, respectively; Rates of no emetic episodes were 82.2% and 79.2% in the APF530 and ondansetron arms, respectively.

EXPERT POINT OF VIEW

D

iscussant Clifford Hudis, MD, Chief, Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York, highlighted the obvious clinical advantages of APF530 over the current standard of care. “If this drug were simply the same in price and availability, why wouldn’t you use it?

It’s more convenient. It’s a little more effective, and it’s one less thing for all of us in our practice to think about,” he stated.

Dr. Hudis continued: “This indeed is the first and only 5-HT3 receptor antagonist with superiority in a three-drug vs three-drug regimen. It has superior delayed-phase activity. So the question is: What are the next steps for this unapproved agent?” n Disclosure: Dr. Hudis reported no potential conflicts of interest.

According to Dr. Schnadig, a significantly greater proportion of patients in the APF530 arm did not require rescue medication in the delayed phase vs ondansetron (P = .013). Patient-reported satisfaction with nausea and vomiting control was also significantly better with APF530 vs ondansetron in the delayed phase (P = .040), and the proportion of patients with treatment failure was numerically higher across the entire treatment period with ondansetron (P = .095).

APF530 was generally well tolerated, Dr. Schnadig noted, with no new

Clinical Benefit of APF530 vs Standard of Care ■■ APF530 provided superior complete response (no emetic episodes and no rescue medication use) in delayed-phase chemotherapy-induced nausea or vomiting following highly emetogenic chemotherapy.

■■ The APF530 regimen was associated with a clinical benefit over the ondansetron regimen in nausea control, rescue medication use, and patient satisfaction.

safety signals identified. The most common treatment-emergent adverse events were injection-site reactions, which were generally mild or moderate.

“Symptom management in patients receiving cancer treatment represents a significant unmet medical need,” concluded Dr. Schnadig, “and the results of this study represent another step forward in this important clinical space.” n

Disclosure: Research support for this study was provided by Heron Therapeutics. Dr. Schnadig is employed by Compass Oncology and reported relationships with Heron, Tesaro, and McKesson.

Reference 1. Schnadig ID, Agajanian R, Dakhil SR, et al: Phase III study of APF530 versus ondansetron with a neurokinin 1 antagonist + corticosteroid in preventing highly emetogenic chemotherapy-induced nausea and vomiting: MAGIC trial. 2015 Breast Cancer Symposium. Abstract 68. Presented September 25, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Vratislav Strnad, MD, on Accelerated Partial-Breast vs Whole-Breast Irradiation see page 68

Kevin C. Oeffinger, MD, on the ACS Guideline Update on Breast Cancer Screening see page 82

Gregory A. Masters, MD, on the ASCO Clinical Practice Guideline Update for Stage IV NSCLC see page 87

Heather A. Wakelee, MD, on Keeping Up With Updated Guidelines see page 90

Brian I. Rini, MD, FACP, on Nivolumab and Cabozantinib in Metastatic Renal Cell Carcinoma see page 95

Jyothirmai Gubili, MS, on Graviola see page 100

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | NOVEMBER 25, 2015

PAGE 6

NCCN Annual Congress: Hematologic Malignancies Hematology

Chronic Myelogenous ­Leukemia continued from page 1

However, he indicated, overall survival is “curiously” no better.

The fact that the agents are essentially equivalent gives clinicians excellent options both for initial treatment and treatment after switching for patients with suboptimal responses.

Accuracy of Early Predictions “At 12 months, you can pick out patients who will do great, and others for whom you need to consider Plan B,” he continued. In IRIS, event-free survival at 12 months was approximately 90% for patients with BCR-ABL/ABL ratio ≤ 0.1%, compared with approximately 50% for those > 10%.

However, predictions are accurate by 3 months, based on the achievement of a molecular response, or not, he added. In patients with BCR-ABL/ABL < 9.8%, overall survival has been reported at 93%, compared with 57% for those with levels > 9.8%.2 “After 3 months of initiating treatment, you can get a pretty good idea about who will do well and who won’t,” said Dr. Radich.

This time cutoff is more nuanced under certain conditions. “A poor response at 3 months is different for the person who takes the drug daily, vs the patient having toxicity and taking treatment breaks,” he noted. He cautioned that adherence to treatment, by patient report, is unreliable.

Although European guidelines suggest waiting 6 months before switching treatment, those of the NCCN, which Dr. Radich coauthored, accept the 3-month mark. There is not much data for switching at either time point, he acknowledged, “so why wait?”

“Trials show that progression to accelerated phase and blast crisis usually occurs soon after starting treatment, so if you wait from 3 months to 6 months, you will lose some patients to this,” he maintained.

Can Mutations Drive Second-Line Treatment?

Approximately half of patients who progress or become resistant to tyrosine kinase inhibitors have BCR-ABL kinase domain mutations, and the available tyrosine kinase inhibitors target them differently.

“In the clinic, you will find patients with mutations who should respond to a drug but don’t, and some who should not respond, but do,” Dr. Radich said.

In general, however, mutation analysis can guide second-line treatment, and

the NCCN recommends the following steps for particular mutation subsets: • T3151: Consider ponatinib [Iclusig], omacetaxine [Synribo], stem cell transplant, or a clinical trial • Y253H, E255K/V, or F359V/C/I: Consider dasatinib or a clinical trial • F317L/V/I/C, T315A, or V299L: Consider nilotinib or a clinical trial • E255K/V, F317L/V/I/C, F359V/ C/I, T315A, or Y253H: Consider bosutinib [Bosulif] or a clinical trial “But remember, in the second-line setting, you are not as likely to cure patients,” he pointed out. Complete cytogenetic responses are observed in only about 50% of patients in this setting.

“Most of us think resistance may be forever. It’s time to start HLA typing (finding a donor takes about 4 months) and having the conversation about transplant,” Dr. Radich advised. “If the patient responds well, then follow him [or her]. If not, move to transplant.”

When should the patient on secondline therapy be switched to a different drug? Several studies suggest that the optimal time is 3 to 4 months after starting the second-line agent, especially in patients lacking a complete cytogenetic response, he said.

Treatment Selection Based on Toxicity For front-line therapy, the NCCN maintains there is no real difference in first- vs second-generation tyrosine kinase inhibitors in terms of efficacy or toxicity, although toxicity profiles do differ. Some toxicities are common to the tyrosine kinase inhibitor class, whereas others are unique to the drug, and this can help guide treatment selection among patients with underlying comorbidities.

Common side effects of tyrosine kinase inhibitors are myelosuppression, increased transaminase levels, and change in electrolytes. Particular

to imatinib are edema/fluid retention, myalgia, hypophosphatemia, and gastrointestinal side effects. The most concerning toxicity with dasatinib is pulmonary arterial hypertension; this tyrosine kinase inhibitor is also associated with pleural/pericardial effusions and bleeding risk.

As for other agents, nilotinib can increase the risk of cardiovascular events and is associated with increased pancreatic enzymes, indirect hyperbilirubinemia, hyperglycemia, and QT prolonga-

consider treatment discontinuation in robust responders but continuing treatment when response is merely “good.” Patients with poor responses should be considered for transplant.

Key Messages Dr. Radich summed up his talk regarding CML treatment with several key messages (see sidebar). He emphasized that although the NCCN Guidelines are “generic,” patients are clearly not generic, and their situations

After 3 months of initiating treatment, you can get a pretty good idea about who will do well and who won’t.

—Jerald P. Radich, MD

tion. With bosutinib, diarrhea, nausea, emesis, and rash are seen. Ponatinib is associated with thrombotic events and can also increase pancreatic enzymes, hypertension, and skin toxicity.

Discontinuing Treatment in Robust Responders Some patients will continue to do well after treatment discontinuation, Dr. Radich noted. Studies have shown that among patients who are polymerase chain reaction–negative for several years and discontinue treatment, approximately 65% will relapse, usually within the first 3 months, but almost 40% will remain negative for BRC-ABL mutation for 2 to 3 years.3 Fortunately, patients who relapse and restart treatment usually return to a complete molecular remission.

“We don’t know the long-term consequences of this practice; therefore, these patients should be on a clinical trial,” he emphasized. With unopposed BCR-ABL activity, major clones may be downgraded, but minor clones may lie dormant and eventually create resistance, he said.

Dr. Radich suggested that clinicians

Clinical Pearls in CML Management ■■ As front-line therapy, second-generation tyrosine kinase inhibitors produce greater responses than imatinib, but this has not translated into long-term efficacy (ie, survival benefit). Second-generation agents are somewhat more toxic, especially in terms of cardiovascular risk.

■■ The cost of first- vs second-generation tyrosine kinase inhibitors is similar at this point, but the upcoming availability of a generic tyrosine kinase inhibitor will probably change this.

■■ Patients not achieving a strong response on first-line tyrosine kinase inhibitor should be considered for a therapeutic switch at 3 months.

■■ The choice of second-line tyrosine kinase inhibitor can be based on specific mutational and toxicity profiles.

■■ Some patients can discontinue treatment—but this is best done as part of a clinical trial.

dictate individualized treatment. Second-generation agents, for example, may be preferred for the 30-year-old who wants to have children and does not want continuous treatment. These agents are more likely to produce a complete molecular response, which is required for treatment discontinuation. However, for the 70-year-old with some heart disease, disease control (and hopefully increased survival), without undue cardiac toxicity, may be the treatment goal, and for this patient, imatinib should be sufficient.

Finally, he added, “If the patient looks like chronic phase, but ‘smells like’ accelerated phase/blast crisis,” a second-generation agent is better.

“Your clinical judgment trumps everything else.” n

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

References 1. Deininger M, O’Brien SG, Guilhot F, et al: International randomized study of interferon vs STI571 (IRIS) 8-year follow up: Sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib. 2009 ASH Annual Meeting. Abstract 1126. Presented December 5, 2009.

2. Marin D, Ibrahim AR, Lucas C, et al: Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 30:232-238, 2012.

3. Rousselot P, Charbonnier A, ConyMakhoul P, et al: Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol 32:424-430, 2014.

Please visit www.OPDIVO.com for more information.

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OPDIVO® and the related logo are trademarks of Bristol-Myers Squibb Company. ©2015 Bristol-Myers Squibb Company. All rights reserved. Printed in USA. 1506US15BR00117-06-01 06/15

The ASCO Post | NOVEMBER 25, 2015

PAGE 8

NCCN Annual Congress: Hematologic Malignancies Targeted Therapy

Genomics Now Driving Treatment of Waldenström’s Macroglobulinemia

By Caroline Helwick

T

he treatment of Waldenström’s macroglobulinemia has been greatly impacted by an understanding of its genomics, according to Steven P. Treon, MD, PhD, of Dana-Farber/ Brigham and Women’s Cancer Center and Massachusetts General Hospital Cancer Center, Boston. Dr. Treon brought listeners up to date on this lymphoma subtype at the 2015 Annual Congress on Hematologic Malignancies, sponsored by the National Comprehensive Cancer Network (NCCN).1 “Waldenström’s macroglobulinemia is a disease where I can see 20 patients in a day, and no 2 will present the same.

There is a lot of diversity in presentation,” noted Dr. Treon.

For example, although Waldenström’s macroglobulinemia is a lymphoma, it rarely presents with adenopathy or splenomegaly (20%), but these features are common at relapse (60%). “This factors into our treatment,” he added.

For most patients, disease is centered in the bone marrow, which can lead to cytopenias. For others, morbidity stems from immunoglobulin M (IgM) production: hyperviscosity syndrome, IgM neuropathy, cryoglobulinemia, and cold agglutinemia.

Waldenström’s macroglobulinemia has a strong familial predisposition (20%–25%) and is common among those of Ashkenazi Jewish ancestry (20%) but rare among African Americans (< 5%). It can begin as a prodrome of IgM monoclonal gammopathy of undetermined significance, with likely progression to Waldenström’s macroglobulinemia.

“Thankfully, with new treatments, overall survival has been improving,” noted Dr. Treon. A recent analysis of the SEER database, for which Dr. Treon was senior author, documented median overall survival of 8 years.2

Getting a Handle on the Genomics “The future is optimistic, because we finally have a handle on the genomics,” Dr. Treon said. A somatic mutation in the MYD88 gene, MYD88L265P, is identified in more than 90% of patients and in more than 50% of patients with IgM monoclonal gammopathy of undetermined significance. “It is an early oncogenic driver of this disease,” he remarked.

The identification of MYD88 L265P has made it easier to discern Waldenström’s

macroglobulinemia from other conditions that secrete IgM, including marginal zone lymphoma and chronic lymphocytic leukemia. MYD88 testing by polymerase chain reaction is, therefore, essential in the workup of suspected cases.

The second most common mutation involves the CXCR4 gene, which plays a pivotal role in trafficking cells toward the bone marrow. The WHIM-like CXCR4 C–tail mutation (CXCR4WHIM) occurs in 30% to 40% of patients with Waldenström’s macroglobulinemia, usually in association with MYD88L265P. Unlike the “almost singular nature” of MYD88 mutations, more than 40 types of mutations affect the CXCR4 gene, largely nonsense and frameshift mutations, which are associated with a high disease burden and increased serum IgM levels. “The patient

However, patients with symptomatic hyperviscosity; moderate/severe peripheral neuropathy; and symptomatic cryoglobulins, cold agglutinins, autoimmune-related events, and amyloid should be considered for treatment.

Plasmapheresis is a good initial intervention for certain subsets of patients: those with symptomatic hyperviscosity, severe cryoglobulinemia, and cold agglutinemia (with blood warmers); rapidly progressing IgM-associated neuropathy (but not chronic IgM neuropathy); IgM > 4,000 mg/dL (prerituximab [Rituxan]); and progressive renal failure due to IgM pathology (but not due to other causes).

“IgM is a bulky molecule and is mostly in the bloodstream, so plasmapheresis is effective in rapidly bringing

Patients had a robust benefit after ibrutinib, with rapid responses, rapid reduction of IgM, and improvements in hemoglobulinemia. Genomics are playing a major role in helping us predict who will benefit from ibrutinib.

—Steven P. Treon, MD, PhD

with hyperviscosity crisis is likely to have one of the CXCR4 mutations,” Dr. Treon indicated.

CXCR4 mutation, however, is not a marker for worse overall survival, but lack of the MYD88 mutation is. Patients with wild-type MYD88 disease had more than a 10-fold increased risk of dying, according to a 2014 study led by Dr. Treon.3 The discovery of the MYD88 mutation also led to an understanding of the signaling pathways that foster this tumor. Two key pathways are triggered as a result of this aberration—one involves the protein IRAK and the other involves Bruton’s tyrosine kinase. Both pathways ultimately result in activation of nuclear factor kappa B (NF-kB), a growth and survival factor. Knowledge of this pathway has opened the door for targeted treatment with the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Observation, Plasmapheresis Since the disease is largely indolent, most patients with Waldenström’s macroglobulinemia do not require immediate treatment. “In fact, 30% to 40% are simply followed,” Dr. Treon said.

down IgM levels,” he indicated. “In addition, in the setting of rituximab, IgM can rise rapidly. In these patients, plasmapheresis can get that IgM level down before they end up with hyperviscosity crisis.” However, Dr. Treon added, “plasmapheresis should be regarded as a temporary supportive measure, not definitive treatment.”

Optimizing Rituximab Rituximab is an important drug in Waldenström’s macroglobulinemia, since almost all patients express CD20.

Single-agent rituximab produces responses in 20% to 40%, but since time to disease progression is short, the drug should not be used alone as the initial intervention.

Rituximab can also induce an IgM flare. A rise of IgM above 4,000 mg/ dL can trigger a hyperviscosity crisis and worsen symptoms of neuropathy, cryoglobulinemia, and cold agglutinins.

In this situation, rituximab should be avoided and plasmapheresis considered.

Approximately 15% of patients will develop intolerance to rituximab in the form of infusion reactions, usually toward the end of induction. These patients can

be switched to ofatumumab (Arzerra; a 300-mg test dose is recommended).

Rituximab combinations should increase the rates of complete and very good partial responses, and thus prolong the time to disease progression. Such drugs have included cyclophosphamide, nucleoside analogs, proteasome inhibitors, and bendamustine (Treanda).

Clinicians should avoid using rituximab in combination with doxorubicin and vincristine, since these drugs do not appear to impact response rates or progression-free survival. Nucleoside analogs have fallen out of favor for Waldenström’s macroglobulinemia, because they increase the risk of transformation and negatively impact stem cell collection.

The most acceptable three drug-regimen is cyclophosphamide, dexamethasone, and rituximab (CDR), said Dr. Treon. However, there is interest in substituting bendamustine for cyclophosphamide, based on the study by Rummel and colleagues of bendamustine/ rituximab, vs R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone).4 In the subset of patients with Waldenström’s macroglobulinemia, a median progression-free survival was 69.5 months in the bendamustine/rituximab arm, vs 28.1 in the R-CHOP arm (P = .0033).

Proteasome Inhibitors and Maintenance Therapy Proteasome inhibitors have become a mainstay of treatment, and the combination of bortezomib (Velcade)/dexamethasone/rituximab has been associated with progression-free survival beyond 4 years. Dr. Treon and colleagues are currently evaluating carfilzomib (Kyprolis)/lenalidomide (Revlimid)/dexamethasone; early results are promising. The second- and third-generation proteasome inhibitors could be an important component of treatment in Waldenström’s macroglobulinemia, since they are less likely than bortezomib to produce neuropathy, he pointed out.

Maintenance therapy appears to prolong remission and even survival in Waldenström’s macroglobulinemia; however, clinicians should watch for worsening of hypogammaglobulinemia and recurring sinobronchial infections with maintenance rituximab. These infections can be difficult to control with antibiotcontinued on page 10

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 | NOVEMBER 25, 2015

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NCCN Annual Congress: Hematologic Malignancies

LARGE TRIM: 8.125” BLEED:8.5”

Waldenström’s Macroglobulinemia continued from page 8

ics. Intravenous immunoglobulin can be given to severely affected patients.

Treatment With Ibrutinib Taking advantage of Bruton’s tyrosine kinase as an important factor in

Waldenström’s macroglobulinemia, ibrutinib is emerging as a targeted therapy in relapsed/refractory disease. In a study reported this year by Dr. Treon and his team, 91% of patients responded; major responses were seen in 73%, and very good partial responses or better were seen in 16%, with ibrutinib at 420 mg/d.5

SMALLaTRIM:7.875” had robust

“Patients benefit after SAFETY:6.875” ibrutinib, with rapid responses, rapid reduction of IgM, and improvements in hemoglobulinemia. Genomics are playing a major role in helping us predict who will benefit from ibrutinib,” he noted.

In the updated analysis, 69% of patients were free of disease progression

at 2 years, and 95% were alive, after a median of two prior therapies. Major responses in his study were completely absent among patients lacking mutations in both MYD88 and CXCR4 but were observed in 91.7% of patients with mutated MYD88 and wild-type CXCR4 and in 61.9% in patients with mutations in both genes.

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 | NOVEMBER 25, 2015

PAGE 11

NCCN Annual Congress: Hematologic Malignancies LARGE TRIM: 8.125” BLEED:8.5”

Based on this study, ibrutinib received Breakthrough Therapy designation from the U.S. Food and Drug Administration for Waldenström’s macroglobulinemia and is included in the NCCN Guidelines for untreated and previously treated patients. n Disclosure: Dr. Treon reported no potential conflicts of interest.

SMALL TRIM:7.875”

References 1. Treon SP: SAFETY:6.875” Advances in Waldenström macroglobulinemia. 2015 NCCN Annual Congress: Hematologic MalignanciesTM. Presented October 17, 2015.

2. Castillo JJ, Olszewski AJ, Kanan S, et al: Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: An analysis of the Surveil-

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.

lance, Epidemiology and End Results database. Br J Haematol 169:81-89, 2015.

3. Treon SP, Cao Y, Xu L, et al: Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 123:2791-2796, 2014.

4. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab

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]

versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:1203-1210, 2013.

5. Treon SP, Tripsas CK, Meid K, et al: Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med 372:1430-1440, 2015.

The ASCO Post | NOVEMBER 25, 2015

PAGE 12

Announcements LARGE TRIM: 8.125” BLEED:8.5”

Antoni Ribas, MD, PhD, Receives NCI Outstanding Investigator Award SMALL TRIM:7.875”

U

CLA Jonsson Comprehensive Cancer Center member ­A ntoni Ribas, MD, PhD, has received a National Cancer Institute (NCI) Outstanding Investigator Award of $4.2 million in recognition of his research conducted in the development

SAFETY:6.875”

of new immunotherapies that utilize the human body’s own natural defenses to fight cancer.

Projects of Unusual Potential The NCI Outstanding Investigator Award supports investigators with

outstanding records of productivity in cancer research by providing extended funding stability and encouraging investigators to continue or embark on projects of unusual potential in cancer research.

Dr. Ribas’ recent clinical research Antoni Ribas, MD, PhD

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

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]

With the NCI award, Dr. Ribas and colleagues hope to build upon his prior work and develop new and innovative bench-to-beside-andback research studies, with the goal of developing patient-centric advances in cancer immunotherapy for melanoma.

“I am extremely grateful to receive this generous recognition of my research by the National Cancer Institute,” Dr. Ribas said. “Immunotherapy provides some patients with advanced cancer a realistic chance at long-term survival. But currently, it only benefits a subset of patients.

With this award, my research group will study why some patients benefit and many others do not, and this knowledge will hopefully lead to the testing of new combination treatments to provide benefit to more patients.”

The Outstanding Investigator Award will provide Dr. Ribas up to $600,000 in direct costs per year for 7 years, allowing substantial time for his laboratory to take greater risks and be more adventurous in its ­research. n 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.

Looking Ahead 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)]

led to the approval of pembrolizu­ mab (Keytruda) for the treatment of advanced melanoma. Pembrolizumab is the first-in-class programmed cell death protein 1 (PD-1)-blocking immunotherapy approved by the U.S Food & Drug Administration (FDA).

As part of the largest phase I study in the history of oncology, Dr. Ribas was principal investigator leading a clinical trial that enrolled more than 600 patients with metastatic melanoma. Because so many of the patients in the early testing showed significant long-lasting responses, the investigation was continued and the FDA granted the drug Breakthrough Therapy status, allowing it to be fast-tracked for approval in ­October 2014.

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]

ASCOPost.com | NOVEMBER 25, 2015

PAGE 13

NCCN Annual Congress: Hematologic Malignancies Novel Therapies

Changing the Outlook for Chronic Lymphocytic Leukemia

By Caroline Helwick

S

mall-molecule inhibitors, especially ibrutinib (Imbruvica) and idelalisib (Zydelig), have greatly changed the outlook for patients with chronic lymphocytic leukemia. William G. Wierda, MD, PhD, Professor and Center Medical Director in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, discussed the optimal use of these agents and previewed others that are poised to further impact the treatment of chronic lymphocytic leukemia (CLL), at the National Comprehensive Cancer Network’s 10th Annual Congress on Hematologic Malignancies, held in San Francisco.

The Bruton’s tyrosine kinase inhibitor brutinib, the PI3 kinase inhibitor idelalisib, and others in development (including Syk inhibitors) target B-cell receptor signaling in CLL. The hypothesis is that CLL cells receive stimulation from their micro-environment through the B-cell receptor and other surface receptors.

When this signal for activation is blocked with the small-molecule signaling inhibitors, the cells undergo apoptosis and die.

dard of care, and for relapsed patients who might otherwise receive rituximab, idelalisib (given with rituximab) is indicated. For patients with Richter’s transformation, intensive chemoimmunotherapy and stem cell transplant are the first options, with planning for allogeneic stem-cell transplant if possible.

“For Richter’s, we use intensive chemoimmunotherapy and try to get the patient to transplant. There is no standard-of-care regimen. This patient ultimately needs transplant,” he indicated.

Ibrutinib Data In long-term follow-up of the phase II PCYC-1102/1103 trial of ibrutinib

features, including Bcl-6 abnormalities, complex karyotype, and refractoriness to fludarabine. In a multivariable survival analysis of patients from MD Anderson, hazard ratios (HRs) were significant for fludarabine refractoriness (HR = 6.4) and complex karyotype (HR = 5.7).2 The emergence of activating mutations has been observed in some patients with progressive disease, “but mutations are not the whole story” in the development of resistance, he added.

Toxicities that are not uncommon with ibrutinib include neutropenia and thrombocytopenia which are likely more disease-related; the nonhematologic toxicities to watch for are atrial fibrillation

[CLL] patients lacking del(17p) or del(11q) are doing exceptionally well on ibrutinib, with 90% progression-free at 30 months.

—William G. Wierda, MD, PhD

Standards of Care, for Now Dr. Wierda first reminded listeners about the standards of care for certain CLL patient populations, summarizing the key points.

For untreated patients without an indication for treatment—even those deemed to have high-risk disease—observation is recommended. “For patients with high-risk features, we are tempted to start treatment, but we really should not,” he said. “Even for patients with 17p deletion, we can identify a subgroup of those who have a relatively indolent course who can probably go for years without needing treatment.”

In initiating first-line therapy, clinicians should evaluate patients based on age and chromosome abnormalities found with fluorescence in situ hybridization (FISH). For patients who are young and fit, chemoimmunotherapy is the standard of care, and FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) is the model regimen. For the elderly (> 65 years), data support the use of chlorambucil (Leukeran) plus an anti-CD20 monoclonal antibody; bendamustine (Treanda) plus rituximab can be used for fit elderly patients able to tolerate chemoimmunotherapy.

For patients with del(17p), first-line ibrutinib is the standard of care.

In the salvage setting, for patients with active disease, ibrutinib is stan-

monotherapy in treatment-naive patients (n = 31) and those with relapsed/refractory disease (n = 101), response rates have reached 90%.1 Owing to the durability of these responses, median progression-free survival has not been reached in either group, except for relapsed/refractory patients with del(17p), whose estimated median progression-free survival was 28 months. Overall survival at 30 months was 97% for treatment-naive and 80% for relapsed/refractory groups (66% for patients with 17p deletion), and estimated median survival has not been reached.

“Patients lacking del(17p) or del(11q) are doing exceptionally well on ibrutinib, with 90% progression-free at 30 months,” Dr. Wierda noted.

Results of the large, randomized phase III RESONATE-2 trial will be presented at the 2015 American Society of Hematology Annual Meeting in December. RESONATE-2 treated patients aged 65 and older with front-line chlorambucil or ibrutinib.

Positive results are expected for ibrutinib (as indicated by press release), perhaps paving the way for the label to be expanded into upfront use, Dr. Wierda said.

Long-term follow-up data indicate that after approximately 30 months of treatment, ibrutinib-treated patients begin to show an increase in disease progression on ibrutinib as well as several associated

and severe bleeding; each occurs in about 5% of ibrutinib recipients. Dr. Wierda cautioned against using this drug in patients taking warfarin. Age and number of prior treatments have been associated with discontinuation due to toxicity.

Ibrutinib is being evaluated in combination with other agents, but no such regimen has yet appeared to be impressive, he said.

“Personally, I am excited about combining ibrutinib with venetoclax— drugs that seem to have complementary mechanisms of action,” he commented.

Venetoclax is an investigational oral Bcl-2 inhibitor with potent monotherapy activity. It has produced complete remissions in patients with relapsed/ refractory CLL and del(17p), including complete responses that are negative for minimal residual disease (see below).

A number of other Bruton’s tyrosine kinase inhibitors are in development in this setting, including ACP-196, BGB3111, and ONO-4059.

Idelalisib The PI3 kinase inhibitor idelalisib is approved for relapsed CLL in patients appropriate for rituximab monotherapy, based on improved overall survival (in all risk categories) compared to rituximab monotherapy. Median progres-

sion-free survival was reported at 19.4 months for idelalisib plus rituximab, vs 7.3 months for rituximab alone.3 Idelalisib plus rituximab was similarly effective in patients who were IGHV gene–mutated vs nonmutated and those with and without del(17p).

The regimen also demonstrated efficacy in relapsed CLL with del(17p) and del(11q).

Toxicities include elevated liver function tests (which usually occur early and are typically not treatment-limiting) and gastrointestinal side effects (eg, colitis). Pneumonitis, which can be treatment-limiting, can also occur.

“Depending on the severity of the [liver function test] elevation, you can reduce the dose, hold the drug, and continue when the patient improves,” he advised. “As for colitis, some patients develop this early, and it is not necessarily treatment-limiting. You can usually get them through this by holding the drug and restarting at a lower dose. If it’s colitis that occurs after about 6 months of treatment, in my experience this is more severe, can be more difficult to manage, and may be treatment-limiting.”

Other PI3 kinase inhibitors in clinical trials include duvelisib, AMG319, TGR-1202, GS-9820, and SAR245408, which are being studied alone and in combination with a number of drugs, such as ofatumumab (Arzerra), obinutuzumab (Gazyva), ibrutinib, and pembrolizumab (Keytruda).

“There are fewer ongoing novel combination trials with idelalisib than with ibrutinib, but there are a number of strategies,” he added. “As with ibrutinib, it is difficult at this point to identify a clear combination that will be a significant advance yet [over idelalisib plus rituximab].”

Venetoclax The Bcl-2 inhibitor venetoclax is in phase III trials. In a study of 78 CLL patients reported last year by Seymour et al, responses were observed in 77% of patients, including complete responses in 23%.4 Response rates were consistent across subgroups with del(17p), fludarabine refractoriness, and IGHV-unmutated disease.

Dr. Wierda explained that the Bcl-2 family of proteins regulates apoptosis.

Bcl-2, in particular, is overexpressed in CLL and makes cells resistant to apoptosis. By inhibiting Bcl-2 with venetocontinued on page 14

The ASCO Post | NOVEMBER 25, 2015

PAGE 14

NCCN Annual Congress: Hematologic Malignancies Chronic Lymphocytic ­Leukemia continued from page 13

clax, antiapoptotic activity is downregulated and apoptosis is promoted.

Venetoclax has high specificity for Bcl-2 and, unlike a previous, more toxic compound, has much lower specificity for Bcl-XL, meaning less risk for thrombocytopenia, the limiting factor with its predecessor. A dose-escalation scheme also helps to avoid tumor lysis syndrome, which was also previously observed.

“The strategy is to initiate venetoclax at a low dose—20 mg/d—and doseescalate weekly up to the target dose of 400 mg/d by week 5,” he said. With 400 mg/d or higher, median progressionfree survival for fludarabine-refractory and/or del(17p) patients was not reached in the Seymour study.

In a 49-patient study that evaluated venetoclax plus rituximab, the response rate was 88%, with 31% complete responses and activity in the high-risk

population with minimal residual disease in the bone marrow.5 Registration studies, as well as venetoclax combination studies, are now in progress.

CLL Treatment Directions According to Dr. Wierda, future treatment directions for clnical trials will focus on the following areas: • Early intervention in untreated, high-risk patients, including first-line therapy according to mutation status: (1) For fit, IGHV-mutated, chemoimmunotherapy-eligible patients, FCR with maintenance or transplant for minimal residual disease; (2) for fit, IGHV-unmutated and elderly patients, a B-cell receptor inhibitor with or without a Bcl2 inhibitor (delaying exposure to chemotherapy and utilizing nonchemotherapy options to achieve deep, durable remissions) • Second-line therapy for active disease: Expanding options for consolidation

strategies, including consolidation for persistent disease on a Bruton’s tyrosine kinase inhibitor (first-line and later), “pushing patients into remission with additional agents” • Use of effective new agents in Richter’s transformation • Evaluation of novel treatment approaches, including immunomodulating agents (checkpoint inhibitors and others), chimeric antigen receptor (CAR)-modified T cells, and other cellular therapies n

Disclosure: For Dr. Wierda’s disclosure, see online version of this article on ASCOPost.com.

References 1. O’Brien SM, Furman RR, Coutre SE, et al: Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/ small lymphocytic leukemia including deletion 17b disease. 2014 ASCO Annual Meeting. Abstract 7014. Presented June 3, 2014.

2. Thompson PA, Wierda W, Ferra-

joli, A et al: Complex karyotype, rather than del(17p), is associated with inferior outcomes in relapsed or refractory CLL patients treated with ibrutinib-based regimens. 2014 ASH Annual Meeting. Abstract 22. Presented December 6, 2014.

3. Shaman JP, Coutre S, Furman R, et al: Second interim analysis of a phase 3 study of idelalisib plus rituximab for relapsed chronic lymphocytic leukemia. 2014 ASH Annual Meeting. Abstract 330. Presented December 8, 2014.

4. Seymour JF, Davids MS, Pagel JM, et al: ABT-199 (GDC-0199) in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. 2014 European Hematology Association Annual Meeting. Abstract S702. Haematologica 99(suppl 1), 2014.

5. Roberts AW, Ma S, Brander D, et al: Determination of recommended phase 2 dose of ABT-199 (GDC-0199) combined with rituximab in patients with relapsed/ refractory chronic lymphocytic leukemia.

2014 ASH Annual Meeting. Abstract 325.

Presented December 8, 2014.

JADPRO Live at APSHO Conference Third Annual JADPRO Live at APSHO Conference Attracts Over 700 Advanced Practitioners in Hematology-Oncology

O

ver 700 nurse practitioners, physician assistants, pharmacists, clinical nurse specialists, and other oncology health-care professionals were convened in Phoenix, Arizona, earlier this month to participate in JADPRO Live at ­APSHO (Advanced Practitioner Society in Hematology and Oncology), the third annual such conference focusing on the unique educational and professional needs of the advanced practitioner in hematology and oncology.

First launched in 2014 as a live meeting version of the Journal of the Advanced Practitioner in Oncology ( JADPRO), participation has more than doubled from the first event, re-

inforcing the need for specialized education for advanced practitioners who care for patients with cancer.

“Advanced practitioners in oncology are highly educated and skilled practitioners, including nurse practitioners, physician assistants, pharmacists and nurses with advanced degrees who, together with oncologists and hematologists, provide complex care to cancer patients. In most states, advanced practitioners can independently prescribe cancer therapeutics and supportive care medications. These professionals perform a number of procedures necessary for diagnosis and treatment of cancer patients, manage dose modifications,

In most states, advanced practitioners can independently prescribe cancer therapeutics and supportive care medications. These professionals perform a number of procedures necessary for diagnosis and treatment of cancer patients.

—Sandra E. Kurtin, RN, MS, AOCN®, ANP-C

side effects of treatments, and provide patient education—all areas key to providing high-quality cancer care,” according to Sandra E. Kurtin, RN, MS, AOCN®, ANP-C, Co-Chair of the ­APSHO Education Committee.

Academy of Physician Assistants.

“APSHO and JADPRO provide the resources we need to support the advanced practitioner audience and to

Certification for Five Types of Continuing Education Credit Conference participants received access to 20 sessions across the 4 days from November 5 to 8. Preconference workshops included a hands-on procedural skills session that reinforces how to perform a bone marrow biopsy, a primer on immunotherapy in oncology, and managing common comorbidities in cancer patients.

This year’s educational activity was certified for five different types of continuing education credit/contact hours to allow learners to meet various licensure requirements: ACCME (Accreditation Council for Continuing Medical Education), ANCC (American Nurses Credentialing Center Commission on Accreditation), ACPE (Accreditation Council for Pharmacy Education), AANP (American Association of Nurse Practitioners), and AAPA (American

Pamela Hallquist Viale, RN, MS, CNS, ANP

provide a level of educational opportunities targeted to stimulate and add to our clinical and practical knowledge base,” explained Pamela Hallquist Viale, RN, MS, CNS, ANP, Editorin-Chief of JADPRO and a Founding Board Member of APSHO. “Our educational offerings focus on the collaborative practice model.”

Watch future issues of The ASCO Post for news reports from JADPRO Live at APSHO, or visit www.APSHO.org.

See photos from JADPRO Live at APSHO on page 80 in this issue. n­

ASCOPost.com | NOVEMBER 25, 2015

PAGE 15

ASTRO Annual Meeting Genitourinary Cancer

Genomic Test Identifies Patients With Prostate Cancer in Need of Intensified Salvage Therapy

By Alice Goodman

P

rostate cancer has been slow to catch up with breast cancer in terms of using biomarkers, but a new study represents progress in this regard.

A genomic classifier called Decipher® provides important information that can be used to make treatment decisions for men with prostate cancer and a rising prostate-specific antigen (PSA) after radical prostatectomy. The genomic classifier was able to distinguish between low-risk and high-risk men in this setting who received salvage radiation therapy (with or without hormonal therapy). Results were presented at the 2015 ASTRO Annual Meeting.1 “With current standard practice,

cancer. Genomic Prostate Score (GPS) is used prior to treatment, whereas Decipher is performed after surgical resection. The third test, Prolaris, can be used before or after surgery.

The Decipher test, which analyzes a small tissue sample obtained during prostatectomy, has been approved by Medicare for reimbursement. Dr. Den said he uses it routinely in his clinical practice and that it is being adopted across the country.

In an interview with The ASCO Post, Dr. Den explained that the Decipher platform uses a chip with 1.4 million markers containing coding and noncoding genes. The genomic classifier

Three RNA-based genomic platforms are currently commercially available for use in patients with prostate

■■ The assay analyzes prostatectomy tissue to create a score that signifies either low or high risk, regardless of the PSA level.

■■ Men at low risk according to the assay can safely delay salvage radiation, whereas those at high risk should have more intensified therapy.

■■ Tests such as this one will enable more individualized decision-making for men with prostate cancer and a rising PSA post prostatectomy.

score is derived based on 22 markers that are involved in different parts of the metastatic pathway; Prolaris and GPS use a polymerase chain reaction approach looking at amplification of 31 and 12 genes, respectively.

“We have shown that there is predictive value in the set of 22 classifier genes. However, the Decipher platform also provides a view of the genome beyond the classifier genes, that may help inform future studies,” he noted.

Study Details

Risk Classification

The retrospective study included 170 men treated with salvage radiation therapy at three different institutions: Thomas Jefferson, Duke University, and the Mayo Clinic. This was a multi-institutional and multiethnic cohort.

The median age of study patients was 61 years (range, 39–75 years). About 42% were Gleason 7 (3+4) and 24.7% were Gleason 7 (4+3). More than 30% of men were African American, who typically are not well represented in

Regardless of the PSA level, the study showed that in patients classified as low-risk by the genomic classifier score, there was no difference in the cumulative incidence of metastasis whether or not they had salvage radiation; in these patients, the rate of metastasis at 10 years was < 10%. In contrast, high-risk men who received early salvage radiation had a 15% cumulative incidence of metastasis at 10 years, whereas those treated with late salvage therapy had a 33% cumulative

—Robert Den, MD

Genomic Platforms

■■ A genomic assay called Decipher, based on 22 markers, can distinguish between patients at low risk and high risk for the development of metastasis after radical prostatectomy.

clinical trials. About 20% were on concurrent hormone therapy as part of their salvage treatment. Eighty percent had clear surgical margins following prostatectomy.

Salvage radiotherapy was defined as radiotherapy given if the PSA level was > 0.2 ng/mL or after salvage androgendeprivation therapy. Early salvage radiation therapy was defined as given when the PSA level was 0.2–1 ng/mL, and late salvage radiation therapy was defined as given when the PSA level was >1 ng/mL. The primary endpoint was the development of regional or distant metastasis, as documented on CT and/or bone scan. Biochemical failure was not used as a surrogate marker for metastatic disease.

Dr. Den and colleagues compared the genomic classifier with two different nomograms based on clinicopathologic features (Briganti and CAPRA-S); they found that Decipher was the most significant prognostic factor for the development of clinical metastases.

Our study shows that you can identify high-risk men based on genomic classifier score who should get intensified therapy, while men identified as low-risk can safely defer further treatment. many patients are both over- and undertreated. Our study shows that you can identify high-risk men based on a genomic classifier score who should get intensified therapy, while men identified as low-risk can safely defer further treatment,” said Robert Den, MD, of the Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia.

“Patients with a low genomic classifier score have an excellent prognosis with salvage radiotherapy and may avoid concurrent hormonal therapy. This group can safely delay salvage radiotherapy, whereas those with a high genomic classifier score are at significant risk of metastatic disease and may benefit from intensified systemic therapy. Integration of a genomic classifier into clinical practice can impact on decision-making for these men in the postprostatectomy setting,” Dr. Den said.

Predicting Metastasis After Radical Prostatectomy

incidence of metastasis at this time point.

The study was not without limitations. It was a retrospective analysis and did not allow for analysis of cancerspecific mortality.

‘The Wave of the Future’ ASTRO Incoming President David Beyer, MD, of the Cancer Centers of Northern Arizona in Sedona, hailed these results as “the wave of the future.”

David Beyer, MD

He continued: “This is an important study. I don’t know which of the genomic tests will turn out to be best, but in any event, we will be using tests like this to determine who needs intensified treatment and who doesn’t. The standard of care will be some type of test that will allow us to personalize management of prostate cancer.” n

Disclosure: Dr. Den received an unrestricted grant from GenomeDx, the supporter of this study. Dr. Beyer reported no potential conflicts of interest.

Reference 1. Den RB, Choeurng V, Howard L, et al: Validation of a genomic classifier for prediction of metastasis following postoperative salvage radiation therapy. 2015 ASTRO Annual Meeting. Abstract 306.

Presented October 21, 2015.

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 | NOVEMBER 25, 2015

PAGE 18

Announcements

Preston Robert Tisch Brain Tumor Center at Duke Receives $7 Million Outstanding Investigator Award

T

he Preston Robert Tisch Brain Tumor Center at Duke has received nearly $7 million in funding under the National Cancer Institute’s (NCI) Outstanding Investiga-

tor Award program for work on two novel immunotherapy approaches to treat brain tumors. The award recognizes the work of principal investigator Darell Bigner, MD, PhD, Direc-

tor of the Preston Robert Tisch Brain Tumor Center at the Duke Cancer Institute. Dr. Bigner and the other 42 recipients nationwide were selected for “providing significant contributions

toward understanding cancer and de-B:16.75” veloping applications that may leadT:16.25” to a breakthrough in biomedical, be-S:14.625” havioral, or clinical cancer research,” according to the NCI.

(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 | NOVEMBER 25, 2015

Announcements

The funding supports additional animal and human studies for two separate immunotherapies—one using a modified poliovirus, and another using a bacterial immunotoxin to attack glioblastoma tumors—that are already showing promise in early clinical trials. New studies will combine each of the immunotherapies

B:16.75” T:16.25” S:14.625”

Bronchitis

Bronchitis

Pneumonia

Pneumonia

a

a

with a checkpoint inhibitor.

“This is extremely important support for our work, and we are excited to move forward with the studies,” Dr. Bigner said.

Preclinical Studies Underway Dr. Bigner said animal studies are already underway, and clinical trials

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

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

Hyperglycemia Hyperglycemia

35(3%) (9%) 12

and Connective and Connective Tissue DisordersTissue Disorders gMusculoskeletalMusculoskeletal

,

d

PAGE 19

Muscle Spasms Muscle Spasms

88 (22%)

(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%)

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%)

27 (7%)

Lactation

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.

Renal Impairment Renal Impairment 5 (1%)

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%)

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

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%)

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.

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

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.

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following adverse were in the post-marketing experience with The following The adverse reactions were reactions reported in thereported post-marketing experience with Kyprolis.

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DRUG INTERACTIONS DRUG INTERACTIONS

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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

B:11.25”

182 (46%)

Decreased Absolute Decreased Absolute Neutrophil CountNeutrophil Count152 (39%)

Decreased Lymphocytes Decreased Lymphocytes

S:10”

DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION

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KRd (N = 392)

Duke’s poliovirus therapy is currently in a phase I study. The therapy uses deactivated poliovirus, which is predisposed to selectively attach to tumor cells and not healthy cells. After surgically injecting the modified virus into the brain tumor, the immune system goes to work, attacking the virusinfused tumor.

The second brain tumor therapy uses a toxin from the Pseudomonas bacterium and an immune system single fragment chain antibody, which are paired in a therapy that works in much the same way as the poliovirus approach. The antibody component selectively binds to brain tumor cells, while the toxin then kills those cells.

“We believe that by adding the checkpoint inhibitors, we will get even better results than we have seen using the poliovirus and the immunotoxin alone,” Dr. Bigner said.

In addition to Dr. Bigner, the research team includes Annick Desjardins, MD; Xuhui Bao; Vidya Chandramohan, PhD; Allan H. Friedman, MD; Henry S. Friedman, MD; Matthias Gromeier, MD; Smita Nair, PhD; John H. Sampson, MD, PhD; and Gordana Vlahovic, MD. n S:10”

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

Darell Bigner, MD, PhD

T:10.875”

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

(Combination Therapy) (Combination Therapy)

“We’ve actually begun the animal studies and are learning that the checkpoint inhibitors do exactly as hoped— they accentuate the effects of the immunotherapies,” Dr. Bigner said.

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.

ContraceptionContraception

System Disorders Nervous SystemNervous Disorders b b Peripheral Neuropathies NEC 43 (11%) Peripheral Neuropathies NEC

could launch within 2 years with the new funding. The preclinical work will focus on determining how well the checkpoint inhibitors provide a response when combined with the immunotherapies. The early studies will also identify which checkpoint inhibitors work best in the combination ­approach.

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

The ASCO Post | NOVEMBER 25, 2015

PAGE 20

ASTRO Annual Meeting Genitourinary Oncology

Hypofractionated Radiotherapy Makes Inroads as Primary Treatment of Prostate Cancer

By Alice Goodman

S

everal studies presented at the 2015 ASTRO Annual Meeting explored the use of hypofractionation (delivering higher doses of radiation in fewer fractions) in the treatment of patients with prostate cancer. These studies found comparable outcomes in terms of efficacy and adverse events. Although attractive from an economic point of view and from the patient convenience perspective, hypofractionation has not yet become the standard of care. The supportive evidence is mounting, however, and hypofractionation is gaining ground.

Intermediate- and High-Risk Patients Five-year follow-up of the randomized phase III HYPRO trial showed that the rates of relapse-free survival for hypofractionated radiation therapy vs conventional fractionated radiotherapy

were comparable in both men with intermediate- and high-risk prostate cancer (80% vs 77%, respectively).1 Acute toxicity was similar, with slightly higher gastrointestinal toxicity in the hypofractionated arm. Follow-up was too short to detect a survival benefit.

“Hypofractionated radiotherapy achieved a higher relapse-free survival rate compared with conventional fractionated radiotherapy, but the difference between the two arms was not statistically significantly different. The acute and late toxicities are comparable between the two schedules. At this point, we can say that hypofractionated radiotherapy is safe and of interest to be introduced in the clinic,” said lead author Luca Incrocci, MD, PhD, Professor of Genito-Urinary Radiotherapy at Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

Luca Incrocci, MD, PhD

The HYPRO trial enrolled 820 patients with intermediate- or high-risk prostate cancer (stage T1b to T4) at 7 centers in the Netherlands between March 2007 and December 2010. Patients were randomized 1:1 to receive hypofractionated radiotherapy (19 fractions of 3.4 Gy in 6.5 weeks at 3 fractions per week) or conventional fractionated radiotherapy (39 fractions of 2 Gy in 8 weeks at 5 fractions per week). Baseline characteristics were

similar between both arms of the study.

This study was designed as a noninferiority trial in intermediate- and highrisk patients. The median age of patients was 71 years, and about 66% were taking concomitant hormone therapy.

Acute gastrointestinal toxicity (grade 2 or higher) at 120 days was about 10% higher in the hypofractionated arm: 31.2% vs 42%, respectively.

Acute genitourinary toxicity was 57.8% for the conventional arm vs 60.5% for hypofractionation, an absolute difference of 2.7%. The latter difference was not statistically significant.

Dr. Incrocci said that the late toxicity results will be published in the future, but he observed no significant differences in late genitourinary, gastrointestinal, and sexual function between the two arms. continued on page 22

EXPERT POINT OF VIEW

I

n an interview with The ASCO Post, incoming ASTRO President David Beyer, MD, provided his perspective on the use of hypofractionation in prostate cancer. Dr. Beyer is Medical Director of the Cancer Centers of Northern Arizona in Sedona.

is still coming in for treatment for a number of days.”

Several investigators are looking at ways to cut down the associated costs and timing of radiation therapy, including techniques such as brachytherapy or stereotactic body radiation therapy.

These three studies help support radiation oncologists who have already adopted hypofractionation in selected cases. The standard of care will change slowly.

—David Beyer, MD

“Fractionation has been an important topic over the past few years. It’s had been on our radar in breast, lung, and head and neck cancers, and the question is whether we can deliver radiation therapy more quickly without compromising efficacy or safety.

The three studies asked the same question with different modifications and different endpoints to answer the question of how many weeks of a man’s life does he need to give up to get radiation,” Dr. Beyer explained.

“Even with hypofractionation, he

More on the Three Studies The study by Incrocci et al. was mounted to show that hypofractionation is better than conventional radiation therapy and that larger fractions given on fewer days will lead to better outcomes. “There are theoretical reasons why that might be the case.

The unique biology of prostate cancer might be more amenable to bigger doses. However, the outcomes in this trial were equivalent,” Dr. Beyer noted.

The next study by Lee, Sandler, and colleagues proved noninferiority

of hypofractionation vs conventional fractionation. Outcomes were similar with the two techniques.

“Two studies that ask the same questions using different statistical approaches end up in the same place: Is cancer control the same? They indicate that it is,” he continued.

The third study by Shaikh et al. asked a different but important question related to the patient’s perspective on outcomes, Dr. Beyer continued. “There are subtle differences in the regimens. The data from Shaikh et al. are fairly mature. There is no difference in patient-reported outcomes for hypofractionation vs conventional fractionation with intensity-modulated radiation therapy,” Dr. Beyer stated.

Moving Forward Cautiously “These three studies explored the issue of whether we can start to give our treatments more quickly. I think the answer is probably yes. But when do we get to the point where that becomes standard of care? It is unclear how many studies need to be done to cross that threshold,” revealed Dr. Beyer. “These three studies all show equivalence, but other studies have shown greater toxicity, and some radiation oncologists are leery about

adopting this as a new standard too quickly.”

Dr. Beyer continued: “In most practices, radiation oncologists are starting to consider hypofractionation in selected patients. It depends on the practice environment; I won’t make a wholesale shift in my patients. But for patients who have travel issues, I can look them in the eye and say, ‘You don’t have to give me 2 months of your life.’”

“People who support hypofractionation based on economics are probably pushing the envelope further. There are still more studies to consider, and an even shorter regimen of 5 fractions or brachytherapy may be an alternative,” he added.

Dr. Beyer concluded: “These three studies help support radiation oncologists who have already adopted hypofractionation in selected cases. The standard of care will change slowly.

The main advantages of hypofractionation are fewer clinic visits and more time to enjoy your life. In areas where there are physician and technology shortages, hypofractionation could be safely adopted. The impetus is to find ways to be less wasteful.” n Disclosure: Dr. Beyer reported no potential conflicts of interest.

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PAGE 22

ASTRO Annual Meeting Hypofractionated Radiotherapy continued from page 20

Early-Stage Patients RTOG 0415 was a randomized phase III noninferiority study that compared two fractionation schedules for intensity-modulated radiation therapy in low-risk early-stage prostate cancer2—a different patient population than in the HYPRO trial.

“Standard radiotherapy for prostate cancer takes 8–9 weeks, which can be a long-time commitment and somewhat daunting. Shorter treatments may

In more than 300 men per arm followed for more than 5 years, 82% of the hypofractionated arm and 76% of the conventional arm were alive with no evidence of disease. This finding demonstrates noninferiority of the two schedules, Dr. Sandler stated.

Physician-reported toxicity showed no significant difference between the two arms in acute or late adverse events.

A small absolute difference of 2.6% in gastrointestinal toxicity favored the conventional arm.

“These results suggest that this shorter regimen is a treatment regi-

I will change my practice based on these studies and offer hypofractionation to early-stage patients who progress on active surveillance as well as to selected patients in intermediate- and high-risk groups.

—Howard Sandler, MD

be a better way to treat prostate cancer.

Although shorter schedules have been assessed in single-institution studies, to date there have been limited definitive clinical trials,” said senior author Howard Sandler, MD, Professor and Chair of Radiation Oncology at CedarsSinai Medical Center in Los Angeles. W. Robert Lee, MD, MS, of Duke University, Chapel Hill, North Carolina, was the lead author of the RTOG 0415 study.

men that physicians can be comfortable discussing and prescribing for their patients,” Dr. Sandler said.

He added that the data will have an impact on his clinical practice. “Standard treatment is standard fractionation, but for myself, I will change my practice based on these studies and offer hypofractionation to early-stage patients who progress on active surveillance as well as to selected patients in intermediate- and high-risk groups,” Dr. Sandler told listeners at a press conference at the 2015 ASTRO Annual Meeting.

Patient-Reported Outcomes

Robert Lee, MD

Men with early-stage, low-risk prostate cancer—defined as not palpable, prostate-specific antigen < 10 ng/mL, or Gleason score of 6 or lower—were randomized to receive standard radiation treatment over 8.2 weeks or hypofractionated treatment over 5.6 weeks.

Long-term patient-reported outcomes showed no significant differences in short- and long-term quality of life in patients treated with hypofractionated radiation therapy vs conventional radiation therapy.3 These results were from a 5-year follow-up of a randomized phase III trial that found no difference in biochemical outcomes when hypofractionated radiation therapy was compared with conventional radiation therapy as primary treatment for 303 men with low- to high-risk prostate cancer.4

Talha Shaikh, MD

The radiation schedules compared in the trial follow: hypofractionated: 70 Gy in 26 fractions at 2.7 Gy per fraction; conventional radiation therapy: 76 Gy in 38 fractions at 2 Gy per fraction.

“Hypofractionated radiation therapy delivers higher doses per day with a shorter treatment time and reduced cost,” explained lead author Talha Shaikh, MD, Resident at Fox Chase Cancer Center, Philadelphia.

In the absence of long-term quality-of-life data to compare these two intensity-modulated radiation therapy techniques, patients were asked to complete three quality-of-life questionnaires: Expanded Prostate Cancer Index Composite (EPIC; 5 domains), International Prostate Symptom Score (IPSS; measure of urinary function), and the EuroQol (EQ-5D); they measure mobility, pain, and general health. There were no differences between the two arms of the trial on any of these measures at baseline.

No significant differences in long-term quality of life based on mean score change for EPIC bowel, sexual, hormonal, or urinary domains were reported. Patients in the hypofractionated arm exhibited a larger decrease in the EPIC urinary incontinence domain at 3 years vs the conformal radiotherapy arm, although this improved with further follow-up and was no longer

significantly different after 5 years. On the IPSS, there was a trend for worse urinary function at 3 and 4 years in the hypofractionated arm, but this was improved with further follow-up.

Baseline function was the strongest predictor of outcomes, and Dr. Shaikh suggested that men with poor baseline urinary function should be counseled about the potential impact of hypofractionated radiation therapy on quality of life. n

Disclosure: Drs. Incrocci and Shaikh reported no potential conflicts of interest. Dr. Sandler has spoken at a Varian User Group meeting and is on the medical advisory board of Eviti, part of NantHealth.

References 1. Incrocci L, Wortel RC, Aluwini A, et al: Hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year oncologic outcomes of the Dutch randomized phase 3 HYPRO trial. 2015 ASTRO Annual Meeting. Abstract LBA2. Presented October 18, 2015.

2. Lee WR, Dignam JJ, Amin M, et al: NRG Oncology RTOG 0415: A randomized phase III non-inferiority study comparing two fractionation schedules in patients with low-risk prostate cancer. 2015 ASTRO Annual Meeting. Abstract LBA 6. Presented October 19. 2015.

3. Shaikh T, Li T, Johnson ME, et al: Long-term patient reported outcomes from a phase 3 randomized prospective trial of conventional versus hypofractionated IMRT radiation therapy for localized prostate cancer. 2015 ASTRO Annual Meeting. Abstract 77. Presented October 19. 2015.

4. Pollack A, Walker G, Horwitz EM, et al: Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol 31:3860-3868, 2013.

Clinical Update on Hypofractionated Radiation Therapy ■■ Hypofractionated radiation therapy allows delivery of higher doses of radiotherapy over shorter periods compared with conventional radiation therapy. Hypofractionated radiation therapy is being used in breast, lung, and other cancers.

■■ Two phase III studies and an analysis of a separate phase III study suggest that the two radiation techniques are similarly effective, with not much difference in long- and short-term side effects in men with prostate cancer.

■■ Taken together, these data should motivate more radiation oncologists to adopt hypofractionation schedules in their clinical practice, especially when travel time is taken into consideration.

More From the 2015 ASTRO Annual Meeting To view interviews with experts recorded live during the 2015 ASTRO Annual Meeting, visit The ASCO Post Newsreels at http://video.ascopost.com/

ASCOPost.com | NOVEMBER 25, 2015

PAGE 23

ASTRO Annual Meeting Neuro-oncology

Study Lowers the Age Bar for Radiation in Children With Ependymoma

By Alice Goodman

T

he good news is that children as young as 1 year old with the aggressive brain tumor ependymoma can be treated safely and effectively with immediate postoperative radiation therapy, according to the results of a trial presented at the 2015 ASTRO Annual Meeting.1 “Ependymoma is the third most common brain tumor, and affects hundreds of children each year in the United States,” explained Thomas E. Merchant, DO, PhD, Chairman of the Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis. “Many children who develop ependymoma are under the age of 3 years.”

“This is the first study to include children under the age of 3. Outcomes were favorable whether children were under or over the age of 3,” Dr. Merchant said.

“This trial was a success and will be a benchmark for others to consider in designing future trials.”

one-third of patients were younger than age 2; more than 200 patients were younger than age 6. The median age was 5.3 years old. Children were enrolled within 56 days of surgery.

The Children’s Oncology Group ACNS0121 trial was designed to observe patients with WHO grade II, supratentorial ependymoma after microscopically complete resection (stratum 1); administer chemotherapy with optional second surgery prior to conformal radiation therapy for patients with subtotal resection at the time of protocol enrollment (stratum 2); provide immediate postoperative conformal radiation therapy for patients after near-total resection (defined as < 5 mm residual thickness) or macroscopic grosstotal resection (stratum 3); and provide immediate postoperative conformal radiation therapy for patients with WHO grade III, supratentorial, or any grade, infratentorial, ependymoma after microscopically complete resection (stratum 4).

This is the first study to include immediate postoperative radiation therapy in children under the age of 3 years. This trial is a success and will be a benchmark for others to consider in designing future trials.

—Thomas E. Merchant, DO, PhD

“The previous standard was surgery and chemotherapy, but results were poor,” he added. “Children over age 3 were also treated with radiation therapy in the past, but there was room for improvement. The advent of conformal and intensity-modulated radiation therapy allowed more focused radiation to the tumor bed. St. Jude Children’s Research Hospital showed early positive outcomes including cognitive preservation. The Children’s Oncology Group designed a new study that included conformal radiation therapy and included children aged 12 months to 21 years.”

Study Details and Results The study included 378 patients with newly diagnosed intracranial ependymoma from 115 institutions. About

At a median follow-up of 7 years, 5-year event-free survival was 61% for stratum 1. “Now we would not recommend observation alone for this group outside of a clinical trial,” Dr. Merchant stated.

For those in stratum 2, 5-year event-

EXPERT POINT OF VIEW

“T

his study pushes the envelope of how to use our therapies to give the most benefit to patients we otherwise wouldn’t be treating: in this case, children under the age of 3. This age group has historically been a ‘no man’s land.’ Now we see we can treat children as young as 1 year,” said Anita Mahajan, MD, a radiation oncologist at The University of Texas MD Anderson Cancer Center in Houston, who moderated the press Anita Mahajan, MD conference at the 2015 ASTRO Annual Meeting where these findings were discussed.

“We used to give chemotherapy to these children and wait until they were older to give radiation, but by then, they were harder to salvage,” she added.

“We know early radiation is important for tumor control. With modern techniques and multidisciplinary care, it is possible to improve outcomes in these young children,” concluded Dr. Mahajan. n Disclosure: Dr. Mahajan reported no potential conflicts of interest.

free survival was 39%. However, 39% of this group underwent a second surgery (59% of those were able to achieve gross-total resection), and 5-year eventfree survival was 50% in those who had a second surgery and 27% in those who did not. “We were able to [nearly] double the event-free survival for the group that had second surgery,” he added.

Strata 3 and 4 had 5-year event-free survival rates of 67% and 70%, respectively. “This represents an excellent outcome for this very aggressive tumor,” Dr. Merchant remarked.

When analyzed according to age, outcomes were not statistically different. In children under the age of 3, 5-year event-free survival was 63%, and 5-year overall survival was 87%.

In all children aged 3 or older, 5-year event-free survival was 71%,

Postoperative Radiotherapy in Young Children With Ependymoma ■■ In children as young as 1 year old with ependymoma, postoperative radiation therapy improves outcomes, depending on the tumor grade and surgery.

■■ Observation alone is not sufficient for children with low-risk supratentorial tumors after surgery.

■■ Postoperative radiation should now be considered for all children with ependymoma, and age under 3 years should no longer be a barrier to treatment.

and 5-year overall survival was 86%.

Tumor grade influenced outcome, with patients who had differentiated tumors having a more favorable outcome than those with anaplastic tumors. Five-year event-free survival was 74.6% for those with grade 2 tumors and 60.7% for those with grade 3 tumors (P = .0047).

“All children with ependymoma should receive expert care, and treatment teams should follow protocol guidelines similar to those used in this study, with consideration given to the importance of gross total tumor resection and advances in radiation therapy methods. Other treatments, in addition to surgery and radiation therapy, should be investigated to further increase the rate of tumor control,” Dr. Merchant stated. n Disclosure: Dr. Merchant reported no potential conflicts of interest.

Reference 1. Merchant TE, Bendel AE, Sabin N, et al: A phase II trial of conformal radiation therapy for pediatric patients with local ependymoma, chemotherapy prior to second surgery for incompletely resected ependymoma and observation for completely resected, differentiated, supratentorial ependymoma. 2015 ASTRO Annual Meeting.

Abstract 1. Presented October 18, 2015.

More on Radiation Oncology See page 68 for a discussion on accelerated partial-breast vs whole-breast irradiation after surgery for early breast cancer, as reported in The Lancet by Vratislav Strnad, MD, and colleagues. Jay R. Harris, MD, comments on the study, beginning on page 1.

The ASCO Post | NOVEMBER 25, 2015

PAGE 24

Announcements

Kara Kelly, MD, Will Head Joint Pediatric Hematology/Oncology Program at Roswell Park and Three Other Buffalo Institutions

K

ara Kelly, MD, has been appointed as the new leader of the joint program in pediatric hematology/oncology, a partnership of Women & Children’s Hospital of Buffalo (WCHOB), Roswell Park Cancer Institute (RPCI), UBMD Pediatrics, and the University at Buffalo (UB). WCHOB, RPCI, and UB have provided pediatric hematology and cancer care through a comprehensive and collaborative program for more than 40 years.

Kara Kelly, MD

Dr. Kelly is currently Professor of Pediatrics at the Columbia University College of Physicians and Surgeons.

Her appointments as Chair of Pediatric Oncology, Professor of Oncology, and the Waldemar J. Kaminski Endowed Chair of Pediatrics at RPCI and Medical Director of the Pediatric Hematology/Oncology Service Line at WCHOB will take effect on February 15, 2016.

Dr. Kelly will also assume the responsibilities of Division Chief of Hematology and Oncology at both UBMD Pediatrics and the Department of Pediatrics in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, where she will be appointed Research Professor.

Clinical Trial Expertise Dr. Kelly is recognized internationally as an expert in the treatment of pediatric lymphoma and leukemia, and serves as the Chairperson of the Hodgkin Lymphoma Committee of the Children’s Oncology Group. Dr. Kelly brings a wealth of knowledge in clinical trials and integrative medicine.

Dr. Kelly has taken a leading role in efforts to increase clinical trial access for adult and pediatric minority patients. She is the lead investigator for the Columbia University Minority/Underserved Site National Cancer Institute Community Oncology Research Program, which links adult and pediatric minority patients with opportunities to participate in clinical trials.

The Pediatric Hematology/Oncology Program is an integrated academic and clinical program based at both WCHOB and RPCI. Inpatients will be cared for within the new John R. Oishei

Children’s Hospital, currently under construction on the Buffalo Niagara Medical Campus, and outpatient care will be delivered at RPCI. Relocation of WCHOB and the Ja-

cobs School of Medicine and Biomedical Sciences to the medical campus will allow for enhanced services, drawing on the strengths of each of the institutions involved. n

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 25, 2015

PAGE 25

Announcements

Howard Hochster, MD, Named President-Elect of ISGIO

T

he International Society of Gastrointestinal Oncology (ISGIO) has named Howard Hochster, MD, as President-Elect. Dr. Hochster, Professor of Medical Oncology; Associate Director for Clinical Sciences at Yale Cancer Center; and Director of the Gastroin-

testinal Cancers Program at Smilow Cancer Hospital at Yale-New Haven, will serve a 2-year term as PresidentElect, followed by 2 years as President.

ISGIO is a unique society dedicated to a high level of research and education in gastrointestinal cancers.

Dr. Hochster is an expert in cancer clinical trials and early drug development, particularly in gastrointestinal cancer. He joined the Yale faculty in 2010 as Yale Cancer Center Associate Director and Director of Gastrointestinal Oncology. n

Howard Hochster, MD

The ASCO Post | NOVEMBER 25, 2015

PAGE 26

ASTRO Annual Meeting Head and Neck Cancer

Evidence Mounts for Less-Intense Chemoradiation Therapy for Low-Risk Oropharyngeal Cancer

By Alice Goodman

A

new study shows that deintensification of chemoradiation therapy translates to excellent pathologic complete response rates in low-risk human

papillomavirus (HPV)-associated oropharyngeal cancer.1 Patient-reported outcomes showed that side effects declined after 8 weeks. The hope is that

these excellent response rates will translate to long-term disease control and reduced side effects.

“About 50% of patients with HPV-

associated oropharyngeal cancer would qualify for deintensification of therapy,” said Bhishamjit Chera, MD, lead author of the phase II study presented at the 2015 ASTRO Annual Meeting. “There are other ongoing and recently completed phase II clinical trials suggesting that reduced-intensity treatment may be efficacious. Our study is unique in that we reduced both radiation and chemotherapy and patients received neither induction chemotherapy nor definitive surgery.”

Dr. Chera continued, “Patients are savvy, and it is not likely that we can randomize them to two very different treatments, so we may be left with very good phase II studies. Deintensification of chemoradiotherapy is not yet ready for prime time,” he noted.

Low-Risk Disease The incidence of HPV-associated oropharyngeal squamous cell carcinoma is on the rise. Concurrent chemoradiation is standard of care, followed by surgery if a 12-week post-treatment PET/ CT scan is positive. Although many lowrisk patients are cured with chemoradiotherapy, the side effects are particularly bothersome and have a negative impact on quality of life, including difficulty swallowing and sticky saliva.

“It is likely that we are overtreating low-risk patients. Thus, deintensification is an attractive option,” Dr. Chera told listeners at a press conference.

Catherine Park, MD

“We stand to make a lot of headway by reducing the intensity of chemoradiation for low-risk HPV-associated oropharyngeal cancer,” said Catherine Park, MD, of the University of California, San Francisco, who moderated the press conference where these data were discussed. “Here is an example of where understanding the biology of HPV-related oral cancers can lead to innovations in treatment, decreased side effects, and better outcomes.”

“These data are highly encouraging and await prospective longer-term validation,” she added. n

ASCOPost.com | NOVEMBER 25, 2015

PAGE 27

ASTRO Annual Meeting Study Details and Results Patients with HPV-positive and/or p16-positive oropharyngeal squamous cell carcinoma were enrolled in the trial (n = 43); 82% were never-smokers. They were treated with 16% less radiotherapy and 40% less cisplatin chemotherapy compared with standard therapy. Study patients receive intensity-modulated radiation therapy at 60 Gy at 2 Gy/d for

6 weeks and cisplatin 30 mg/m2 in six weekly doses. All patients had a biopsy of their primary tumor site and supraselective removal of pretreatment positive nodes approximately 9 weeks after deintensified chemoradiotherapy.

Dr. Chera explained that when designing this phase II study he wanted to choose a more robust primary endpoint other than clinical response. Also, he

EXPERT POINT OF VIEW

“H

PV-associated oropharyngeal cancer is becoming more and more prevalent. This is a ‘different beast’—distinct from the squamous cell carcinomas of the tonsil and tongue that arise from standard risk factors of tobacco and alcohol. Patients without a smoking history have an 85% to 90% cure rate, which seems to be independent of tumor T stage. With cure rates this high, we think we may be overtreating some patients; this is important because the side effects are related to the intensity of treatment,” said Paul M. Busse, MD, PhD, Clinical Director of Radiation Oncology at Massachusetts General Hospital,

Many of these patients are in their 40s and 50s and will live a long time. If we can give them less-intensive chemoradiation and maintain the high cure rates, it will be a win-win situation.

—Paul M. Busse, MD, PhD

Boston, who was not involved in this study.

“Many of these patients are in their 40s and 50s, otherwise healthy, and will live a long time. If we can treat them with less-intensive chemoradiation while maintaining high cure rates, it will be a win-win situation,” Dr. Busse continued.

Devil Is in the Details But the devil is in the details. “There are several possible ways to de­intensify treatment; however, no one knows the best way to achieve this. Less toxicity is in the eye of the beholder. Experts have advocated for a reduction in the dose of radiation, eliminating or reducing chemotherapy or doing surgery with or without adjuvant therapy. We don’t want to lose our ability to cure people by deintensifying therapy,” he said.

According to Dr. Busse, the best regimen will be identified by careful examination of well-designed phase II studies that have sufficient follow-up to characterize side effects.

“The study by Chera and colleagues is well done, systematic, and a step in the right direction. They were able to show a good result. Longer follow-up will be informative,” Dr. Busse commented. n Disclosure: Dr. Busse reported no potential conflicts of interest.

It is likely that we are overtreating low-risk patients [with oropharyngeal carcinoma]. Thus, deintensification is an attractive option.

—Bhishamjit Chera, MD

was concerned with the possible lack of efficacy with this deintensified regimen.

Thus, pathologic complete response was chosen as the primary ­endpoint.

Forty-three patients were evaluable for the primary endpoint, and 37 patients (86%) achieved a pathologic complete response. Pathologic complete response was achieved in the primary tumor in 40 of 41 patients (98%) and in 33 of 39 patients (84%) with nodal metastases. At a median follow-up of 21 months, all patients were alive, with no evidence of cancer recurrence. At least 1 year of follow-up is available for nearly 85% of p­ atients.

Tolerability Regarding tolerability, by all measures, adverse events peaked at 6 to 8 weeks and declined thereafter. Forty percent of patients required a feeding tube for a median duration of 15 weeks; no patient required a permanent feeding tube.

Dr. Chera pointed out that historically with standard chemoradiation, feeding tubes are required in up to 80% of patients, with around 10% requiring permanent feeding tubes.

Patients rated the following acute toxicities as severe/very severe: mucositis (45%), pain (48%), nausea (52%), vomiting (34%), dysphagia (55%), and xerostomia (75%).

On the EORTC QLQ-H&N35 (European Organisation for Research and Treatment of Cancer Quality of Life module for head and neck cancer), dry mouth, sticky saliva, and difficulty swallowing were the most common adverse events. On a scale from 0–100, dry mouth and sticky saliva declined from peak by 20 points each at 12 months, and swallowing declined by 10 points (signaling “mild to moderate” difficulty, said Dr. Chera). A similar pattern was revealed in patient-reported outcomes.

“We still need more patients, and we need a minimum follow-up of 2 years.

We are conducting another phase II trial with 60 patients that asks more nuanced questions. Other groups, including NRG Oncology, are mounting other phase II trials with our regimen. These data will add up,” concluded Dr. Chera. n

Disclosure: Dr. Chera reported no potential conflicts of interest. Dr. Park has a financial interest in OncoSynergy, a startup biotech company.

Reference 1. Chera BS, Amdur RJ, Tepper JE, et al: A prospective phase II trial of deintensified chemoradiation therapy for low risk HPV associated oropharyngeal squamous cell carcinoma. 2015 ASTRO Annual Meeting. Abstract 3. Presented October 18, 2015.

Deintensified Chemoradiation in Low-Risk Oropharyngeal Cancer ■■ Although many patients with low-risk HPV-associated oropharyngeal cancer may be cured with chemoradiation therapy, the side effects can be debilitating.

■■ Deintensified chemoradiation therapy appears to be able to achieve pathologic complete response while reducing the severity of side effects.

■■ More study is needed to establish this approach as standard. Biomarkers are need for patients who can be safely and effectively treated with this type of regimen.

More From the 2015 ASTRO Annual Meeting For more reports from the 2015 ASTRO Annual Meeting, held recently in San Antonio, see pages 15 through 27 in this issue of The ASCO Post. Plus, visit http://video.ascopost.com/ to view videos of interviews with experts filmed live during the annual congress.

IN APPROACHING HR+ ADVANCED BREAST CANCER

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

Š 2015 Novartis

HAVE YOU LEFT YOUR PATIENTS VULNERABLE TO PI3K-mTOR SIGNALING? When overlooked, hyperactivation of the PI3K-mTOR pathway drives resistance to endocrine monotherapy and HR+ disease progression1,2 • PI3K-mTOR is the most common aberrantly activated pathway in breast cancer, with genetic defects occurring in >70% of cases2,3 • The PI3K-mTOR pathway is a major source of resistance and progression in HR+ advanced breast cancer1,2 • Novartis is committed to realizing the full therapeutic potential of targeting the PI3K-mTOR pathway for patients with HR+ advanced breast cancer

HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin.

References: 1. Miller T. Endocrine resistance: what do we know? Am Soc Clin Oncol Educ Book.

2013:e37-e42. 2. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224-235. 3. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med. 2014;7:203-215.

The PI3K-mTOR pathway is an important component to consider in approaching HR+ advanced breast cancer. Find out more at TargetingPI3K-mTOR.com.

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European Cancer Congress Quick Takes From ECC 2015 Include New Data in Melanoma, Prostate and Breast Cancers, and Renal Cell Carcinoma

By Caroline Helwick and Alice Goodman

T

he 2015 European Cancer Congress (ECC), held recently in Vienna, represented the combined efforts of the European Cancer Organisation (ECCO), the European Society for Medical Oncology (ESMO), and other partner organisations, constituting the largest European platform for oncology education. At this year’s Congress, a global audience heard the first presentations of groundbreaking data, including dozens of “best” and “late-breaking” abstracts, and gained practical insights from some of the world’s foremost clinicians.

The ASCO Post has provided indepth coverage of the meeting, both in print and online with The ASCO Post Evening News and The ASCO Post Newsreels. With the following brief summaries, we offer more noteworthy research coming out of the meeting.

STAMPEDE Update: No Benefit for Zoledronic Acid An updated analysis of the STAMPEDE trial, which evaluated the early use of docetaxel and zoledronic acid in advanced prostate cancer, found no benefit of zoledronic acid in reducing deaths or skeletal-related events while confirming the significant overall survival benefit conveyed by docetaxel.1 “We saw a statistically significant and highly clinically significant improvement in overall survival with the addition of docetaxel for men starting hormone therapy for the first time. Docetaxel also significantly prolonged the time to first reported symptomatic skeletal-related event. But we also saw no evidence supporting the upfront use of zoledronic acid,” said Nicholas David James, MD, PhD, Director of the Cancer Research Unit at the University of Warwick and Queen Elizabeth Hospital Birmingham, in the United Kingdom.

For the comparison reported at ECC 2015, STAMPEDE accrued 2,962 advanced hormone therapy– naive prostate cancer patients, either newly diagnosed or relapsed. The current analysis focused on the comparisons between standard treatment with androgen-deprivation therapy with or without radiotherapy (n = 1,184), vs standard treatment plus zoledronic acid (n = 593), docetaxel (n = 592) or the combination (n = 593).

Dr. James presented updated data

for survival and skeletal-related events, after a median follow-up of 43 months.

Compared to standard of care only, the addition of docetaxel, zoledronic acid, or the combination yielded the following hazard ratios for survival: standard treatment plus docetaxel (hazard ratio [HR] = 0.78, P = .006), standard treatment plus zoledronic acid (HR = 0.94,

with the relevant gene-expression profile, according to Javier Cortes, MD, PhD, Head of the Breast Cancer Program at Vall d’Hebron University Hospital, Barcelona.2 Triple-negative breast cancer comprises multiple subtypes and oncogenic drivers, including a subtype that may be driven by androgen receptor signal-

We saw a statistically significant and highly clinically significant improvement in overall survival with the addition of docetaxel for men starting hormone therapy for the first time.… But we also saw no evidence supporting the upfront use of zoledronic acid.

—Nicholas David James, MD, PhD

P = .450), standard treatment plus the combination of docetaxel and zoledronic acid (HR = 0.82, P = .022).

Hazard ratios were similar for patients with newly diagnosed and previously treated disease. Patients with metastatic disease at presentation derived the most benefit from docetaxel. Only 20 deaths were observed in the nonmetastatic group receiving docetaxel.

In preventing skeletal-related events, Dr. James said, “Given what might have been expected, we saw a remarkably weak effect” for zoledronic acid—ie, a nonsignificant trend toward delaying events (HR = 0.89, P = .221). Among patients with bone metastases, the trend toward benefit was unexpectedly weak (HR = 0.94, P = .564).

In contrast, docetaxel was associated with a large treatment effect. The number of skeletal-related events was 328 with standard treatment vs 112 with the addition of docetaxel (HR = 0.60, P = .00000127), with similar protection seen among newly diagnosed men with bone metastases. The addition of zoledronic acid to this regimen did not enhance the benefit.

Enzalutamide in Triple-Negative Breast Cancer In patients with advanced triplenegative breast cancer, treatment with a drug that inhibits the androgen receptor improved overall survival in patients

ing. Enzalutamide (Xtandi), a potent androgen receptor–signaling inhibitor, significantly improves overall survival in metastatic castration-resistant prostate cancer and is currently being developed for patients with breast cancer

Javier Cortes, MD, PhD

who have an androgen-driven gene signature, Dr. Cortes explained.

MDV3100–11 is an open-label study evaluating enzalutamide in 118 patients with advanced triple-negative breast cancer patients, both untreated and previously treated. All patients expressed the androgen receptor, according to immunohistochemistry (> 0%). Previous studies have shown that more than three-fourths of triple-negative tumors express this receptor to some degree.

The study also evaluated patients according to the presence of an androgendriven gene signature, as determined by the PREDICT AR assay. The assay was developed by prior gene-profiling analysis and validated in two independent data sets. Of 118 patients enrolled, 56 (47%) were PREDICT AR–positive.

More Data From ECC 2015

U

pdated analysis of the STAMPEDE trial found no benefit for zoledronic acid in reducing deaths or skeletal-related events and confirmed the overall survival benefit of docetaxel in men with advanced hormone-sensitive prostate cancer.

MDV3100, in advanced triple-negative breast cancer, found a therapeutic benefit with enzalutamide in patients expressing the androgen receptor. Median overall survival was 12 months, extended to 18 months for patients with a favorable genetic profile, according to the PREDICT AR assay.

In patients with early melanoma, restricting the time interval between primary surgical excision and sentinel node biopsy to less than 6 weeks does not appear to be necessary. Patients had similar survival outcomes at any cutoff interval from 1 to 8 weeks.

In patients with advanced melanoma, the sequence of checkpoint inhibitors may matter. Nivolumab (Opdivo) followed by ipilimumab (Yervoy) may be more efficacious, but it is also more toxic than the opposite sequence.

Investigators evaluating PD-L2 as a potential biomarker for response to pembrolizumab (Keytruda) found that approximately two-thirds of all tumors scored PD-L2–positive, and response rates were twice as high if tumors were positive for both PD-L1 and PD-L2 expression.

The IMA901 multipeptide vaccine failed to improve overall survival when combined with sunitinib vs sunitinib alone in patients with metastatic renal cell carcinoma in an open-label phase III trial.

In an analysis of survival after a diagnosis of gastrointestinal cancer (not just colorectal cancer), 5-year survival was higher in patients who used aspirin postdiagnosis—75% vs 42% among nonusers. n

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PAGE 31

European Cancer Congress “We found evidence of clinical activity in patients treated with enzalutamide in this phase II study,” Dr. Cortes reported. “We also found that a novel gene-expression profiling assay may identify triple-negative patients who appear to derive more benefit from enzalutamide.”

Median overall survival was 10.5 months longer in the PREDICT AR– positive vs PREDICT AR–negative patients (18.0 vs 7.5 months). Median overall survival for the whole population was 12.0 months. All other outcomes were also more improved in patients with a positive PREDICT AR status.

Median progression-free survival was 16.0 weeks in the PREDICT AR– positive group vs 8.0 weeks in the negative group. In the positive subset with no more than one prior treatment regimen (or none), median progression-

Our results show that there is no scientific rationale for advocating a strict time limit between primary excision and sentinel node biopsy [in melanoma patients].

—Charlotte Oude Ophuis, MD

free survival exceeded 32 weeks.

The clinical benefit rate at 16 weeks, which was the primary endpoint, was 39% in the PREDICT AR–positive group and 11% in the negative group.

There were few responses, however: 9% and 3%, respectively. Median treatment duration for the positive group was 15 weeks.

In a multicovariate analysis of survival, both PREDICT AR status and line of therapy were significantly and independently associated with progression-free survival.

“Enzalutamide, a hormonal therapy that inhibits androgen-receptor signaling, may represent a novel therapeutic option in PREDICT AR–positive patients who would otherwise receive cytotoxic chemotherapy,” Dr. Cortes suggested.

Timing of Sentinel Node Biopsy in Melanoma Restricting the time interval between primary surgical excision and sentinel node biopsy to less than 6 weeks does not appear to be necessary for patients with melanoma. Patients had similar survival outcomes at any cutoff interval from 1 to 8 weeks, according to a retro-

spective, multicenter cohort study presented during the Presidential Session.3 In both sentinel node–negative and –positive patients, melanoma-specific survival was not significantly different for any excision-to–sentinel node biopsy time interval cutoff from 1 to 8 weeks.

“Our results show that there is no scientific rationale for advocating a

strict time limit between primary excision and sentinel node biopsy,” said Charlotte Oude Ophuis, MD, a PhD candidate at Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

“Subanalyses in matched cohorts from the four centers with data on both sentinel node–positive and sentinel node–negacontinued on page 32

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The ASCO Post | NOVEMBER 25, 2015

PAGE 32

European Cancer Congress Quick Takes From ECC 2015 continued from page 31

tive patients (n = 2,848) confirmed our finding that the time interval until sentinel node biopsy had no significant impact on melanoma-specific survival and diseasefree survival,” she added.

Most international guidelines recommend reexcision plus sentinel node biopsy as soon as possible after primary excision, she explained, but before this study there were no data to support this recommendation.

The study analyzed data from 998 sentinel node biopsy–positive melanoma patients from nine different EORTC Melanoma Group Centers and 2,886 biopsy-negative melanoma patients from four different EORTC Melanoma Group Centers diagnosed between 1993 and 2012 with known primary excision dates. Compared with sentinel node–negative patients, those who were positive had tumors that were thicker (median Breslow thickness = 3.0 mm vs 1.7 mm) and more likely to be ulcerated (44% vs 25%).

The median time interval between primary excision and biopsy was similar in the two groups: 42 days in sentinel node–negative patients and 46 days in sentinel node–positive patients.

Among sentinel node–negative patients, older age and thinner tumors were associated with a shorter time interval until sentinel node biopsy. No significant associations were found between tumor or baseline characteristics and time interval in sentinel node–positive patients.

Advanced Melanoma: Sequencing of Checkpoint Inhibitors In the treatment of advanced melanoma with checkpoint inhibitors, an unanswered question has been which agent to initiate first. The results of CheckMate 064, presented at ECC 2015 by F. Stephen Hodi, MD, Director of the Melanoma Center and Director of the Center for Immuno-Oncology at Dana-Farber Cancer Institute, Boston, suggested that starting off with nivolumab (Opdivo) is more efficacious but also more toxic.4 CheckMate 064 was a randomized, open-label phase II study evaluating the safety and efficacy of two immune checkpoint inhibitors given sequentially with a planned switch, in 138 patients who were treatment-naive or had received no more than one prior regimen that did not include antibodies against programmed cell death protein 1 (PD-1) or its ligand (PDL1) or ipilimumab (Yervoy).

F. Stephen Hodi, MD

Patients received nivolumab at 3 mg/kg every 2 weeks for six cycles, followed by ipilimumab at 3 mg/kg every 3 weeks for four cycles (with a 2-week treatment-free interval in between) or the same regimens in the opposite order (with a 3-week treatment-free interval). All continued on nivolumab at 3 mg/kg every 2 weeks.

More patients had disease progression on the ipilimumab-followed-bynivolumab schedule (56%) than with nivolumab followed by ipilimumab (27%). However, ipilimumab followed by nivolumab was associated fewer treatment discontinuations due to toxicity (14%) than nivolumab followed by ipilimumab (31%).

“Consistent improvement in efficacy outcomes was demonstrated with [nivolumab followed by ipilimumab] vs [ipilimumab followed by nivolumab],” said Dr. Hodi.

Confirmed responses were observed in 41.2% vs 20.0%; when unconfirmed responses were included, the response rates were 47.7% and 22.6%, respectively. Median changes in tumor burden from baseline at week 13 was −27% with nivolumab folowed by ipilimumab and +10% with ipilimumab followed by nivolumab and at week 25 were −50% and −17%, respectively.

During the induction periods, grade 3–4 adverse events were observed in 50% of patients receiving nivolumab followed by ipilimumab and in 43% of those given ipilimumab followed by nivolumab. There were no treatmentrelated events.

“The nature of the adverse events was similar to those previously observed with either agent, alone and in combination, and the frequency of ad-

verse events was consistent with previous reports for the combination,” Dr. Hodi said.

In correspondence with The ASCO Post, he emphasized, “The trial was designed as a biomarker trial and had a forced switch from one agent to another. Patients did not switch at the time of progression, but switched whether they were responding or not. Efficacy data need more time to mature.”

PD-L2 Expression: Biomarker?

Efforts to identify a biomarker for response to anti–PD-1 therapy have focused on tumor expression of the PD-1 ligand, PD-L1. New insights suggest

Jennifer Yearley, DVM, PhD

Ignacio Melero, MD, PhD

that PD-L2 expression may be a potential biomarker for clinical response to pembrolizumab (Keytruda), an anti– PD-1 antibody.5 “PD-L2 is one of two known binding partners of PD-1, and it has been shown to be involved with disease severity in murine models,” said Jennifer Yearley, DVM, PhD, the Anatomic Pathology Group Lead at Merck.

Using a proprietary immunohistochemistry assay to detect PD-L2 expression, the investigators sought to determine the potential relevance of PD-L2 expression in multiple cancers being treated with pembrolizumab in

We saw no improvement in overall survival when adding IMA901 to firstline sunitinib…. Immune responses need to be significantly improved before further development of IMA901.

—Brian Rini, MD

the clinic, including renal cell carcinoma, bladder cancer, non–small cell lung cancer, head and neck squamous cell carcinoma, triple-negative breast cancer, gastric cancer, and melanoma.

In these cohorts, PD-L2 was expressed in varying degrees.

Each cohort was evaluated for overall expression of PD-L2 in stromal cells, tumor cells, and endothelial cells. Particularly high levels of PD-L2 expression were observed in gastric carcinoma and triple-negative breast cancer.

Both concordance and discordance were observed between PD-L1 and PDL2 expression, but in general, the patterns of one closely mirrored the other.

PD-L2 expression can occur in the absence of PD-L1 expression, Dr. Yearley said. In a pilot analysis of data from the KEYNOTE-12 study in patients with head and neck cancer, about two-thirds of all tumors scored PD-L2–positive, and response rates were twice as high for tumors positive for both PD-L1 and PD-L2 expression as for tumors positive only for PD-L1, she added.

In the KEYNOTE-12 cohort, PD-L2 expression was associated with higher response rates and longer progressionfree survival in pembrolizumab-treated patients, she said.

“This is a tale of two ligands. The study is hypothesis-generating based on archived material. It needs to be validated with pembrolizumab and nivolumab. This will be very important to guide development of PD-1 blockers further,” said formal discussant Ignacio Melero, MD, PhD, Senior Investigator at the University of Navarra in Pamplona, Spain.

Vaccine Fails in Renal Cell Carcinoma The IMA901 multipeptide vaccine failed to improve overall survival when combined with sunitinib vs sunitinib alone in patients with metastatic renal cell carcinoma in an open-label phase III trial.6 “We saw no improvement in overall survival when adding IMA901 to firstline sunitinib. Survival was comparable between the two arms of the study in favorable patients, and sunitinib alone achieved longer overall survival in intermediate-risk patients. Immune responses need to be significantly improved before further development of IMA901,” said lead author Brian Rini, MD, a hematologist/oncologist at the Cleveland Clinic, Ohio. The disappointing phase III results failed to replicate positive findings in a phase II trial, he noted. continued on page 37

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FL=follicular B-cell non-Hodgkin lymphoma; PI3Kδ=phosphatidylinositol 3-kinase delta.

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

FL

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

IMPORTANT SAFETY INFORMATION (cont'd) Contraindications • History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN) Warnings and Precautions • Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients.

In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3× upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5× ULN, withhold ZYDELIG and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs • Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea • Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5% • Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting • Severe cutaneous reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development

of severe cutaneous reactions and discontinue ZYDELIG if a reaction occurs • Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue ZYDELIG permanently and institute appropriate supportive measures if a reaction occurs • Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31% of ZYDELIG-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months.

In patients with neutrophil counts <1.0 Gi/L, monitor weekly • Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ZYDELIG and to use effective contraception during and at least 1 month after treatment with ZYDELIG Adverse Reactions • Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash • Most frequent serious adverse reactions (SAR) were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients and 53% of patients discontinued or interrupted therapy due to adverse reactions • Most common lab abnormalities (incidence ≥30%; all grades) were neutrophils decreased and ALT/AST elevations

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• Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash; 53% of patients discontinued or interrupted therapy due to adverse reactions Drug Interactions • CYP3A inducers: Avoid coadministration with strong CYP3A inducers • CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for ZYDELIG toxicity • CYP3A substrates: Avoid coadministration with CYP3A substrates Dosage and Administration • Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food.

Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown • Dose modification: Consult the ZYDELIG full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations,

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

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WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions].

• Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions].

• Fatal and serious pneumonitis can occur in ZYDELIG-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions].

• Fatal and serious intestinal perforation can occur in ZYDELIGtreated patients. Discontinue ZYDELIG for intestinal perforation [See Warnings and Precautions].

INDICATIONS AND USAGE: • ZYDELIG is indicated in combination with rituximab for the treatment of adults with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other comorbidities.

• ZYDELIG is indicated for the treatment of adults with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received ≥2 prior systemic therapies.

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• Accelerated approval was granted for FL and SLL based on overall response rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

See Warnings and Precautions, Adverse Reactions, and Use in Specific Populations for additional information.

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

Severe diarrhea or colitis (≥Grade 3) occurred in 14% of ZYDELIG-treated patients across clinical trials. ZYDELIG-induced diarrhea can occur at any time and responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month following ZYDELIG interruption with or without enteric or systemic corticosteroids. Avoid concurrent use of ZYDELIG with drugs that cause diarrhea. [See Dosage and Administration].

Fatal and serious pneumonitis occurred in ZYDELIG-treated patients.

Patients taking ZYDELIG who present with pulmonary symptoms (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, >5% decrease in oxygen saturation) should be evaluated for pneumonitis. If pneumonitis is suspected, withhold ZYDELIG until etiology of pulmonary symptoms has been determined. Patients thought to have ZYDELIG-induced pneumonitis were treated with ZYDELIG discontinuation and corticosteroids.

Fatal and serious intestinal perforation occurred in ZYDELIG-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Permanently discontinue ZYDELIG in patients who experience intestinal perforation.

Severe Cutaneous Reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions (dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, skin disorder) have been reported. Monitor patients for severe cutaneous reactions and discontinue ZYDELIG. Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported in ZYDELIG-treated patients. Permanently discontinue ZYDELIG and institute appropriate supportive measures in patients who develop serious allergic reactions.

Neutropenia: Treatment-emergent neutropenia (Grade 3 or 4) occurred in 31% of ZYDELIG-treated patients across clinical trials. Monitor blood counts every 2 weeks for the first 3 months, and weekly when neutrophils are <1 Gi/L [See Dosage and Administration].

Embryo-fetal Toxicity: Idelalisib is teratogenic in rats and may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after treatment [See Use in Specific Populations].

ADVERSE REACTIONS: See BOXED WARNING and Warnings and Precautions for additional serious adverse reactions.

Dose Modifications:

Subjects with Relapsed CLL:

• Pneumonitis: discontinue ZYDELIG for any symptomatic pneumonitis

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

• Hepatotoxicity: – ALT/AST >3 to 5x ULN or bilirubin >1.5 to 3x ULN: maintain ZYDELIG dose; monitor weekly until ≤1x ULN – ALT/AST >5 to 20x ULN or bilirubin >3 to 10x ULN: withhold ZYDELIG; monitor weekly until ≤1x ULN then resume ZYDELIG 100 mg BID – ALT/AST >20x ULN or bilirubin >10x ULN: permanently discontinue ZYDELIG • Diarrhea: – Moderate (increase of 4-6 stools/day over baseline): maintain ZYDELIG dose; monitor weekly until resolved – Severe (increase of ≥7 stools/day over baseline) or hospitalization: withhold ZYDELIG; monitor weekly until resolved then resume ZYDELIG 100 mg BID – Life-threatening: permanently discontinue ZYDELIG • Neutropenia: – ANC 1 to <1.5 Gi/L: maintain ZYDELIG dose – ANC 0.5 to <1 Gi/L: maintain ZYDELIG dose; monitor weekly – ANC <0.5 Gi/L: withhold ZYDELIG; monitor weekly until ≥0.5 Gi/L then resume ZYDELIG 100 mg BID • Thrombocytopenia: – Platelets 50 to <75 Gi/L: maintain ZYDELIG dose – Platelets 25 to <50 Gi/L: maintain ZYDELIG dose; monitor weekly – Platelets <25 Gi/L: withhold ZYDELIG; monitor weekly until ≥25 Gi/L then resume ZYDELIG 100 mg BID • For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce dose to 100 mg BID if resuming treatment.

Permanently discontinue ZYDELIG if severe or life-threatening toxicities recur upon rechallenge.

CONTRAINDICATIONS: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis (TEN).

WARNINGS AND PRECAUTIONS: Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. ALT or AST >5x ULN have occurred, usually within the first 12 weeks of treatment and were reversible with dose interruption. Upon resuming

• Adverse Reactions: Most common (≥2%) serious adverse reactions reported in 49% of subjects were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%). Most common adverse reactions (incidence ≥5% and occurring at ≥2% higher incidence in ZYDELIG-treated subjects; all Grades) were pyrexia (35%), nausea (25%), pneumonia (23%), diarrhea (21%), chills (21%), rash (18%), vomiting (13%), headache (10%), sepsis (8%), sinusitis (8%), pain (7%), arthralgia (7%), GERD (6%), stomatitis (6%), bronchitis (6%), nasal congestion (5%), and urinary tract infection (5%). Most common adverse reactions leading to dose reductions in 15% of subjects were elevated transaminases, diarrhea or colitis, and rash. Most common adverse reactions leading to discontinuation in 10% of subjects were hepatotoxicity and diarrhea/colitis.

• Laboratory Abnormalities: Treatment emergent laboratory abnormalities (incidence ≥10% and occurring at ≥5% higher incidence in ZYDELIG-treated subjects; all Grades) were decreased neutrophils (60%), hypertriglyceridemia (56%), hyperglycemia (54%), increased ALT (35%), increased GGT (26%), increased lymphocytes (25%), increased AST (25%), decreased lymphocytes (20%), hyponatremia (20%), and hypoglycemia (11%).

• Laboratory Abnormalities: Treatment emergent laboratory abnormalities (all Grades) were decreased neutrophils (53%), increased ALT (50%), increased AST (41%), decreased hemoglobin (28%), and decrease platelets (26%).

DRUG INTERACTIONS: • CYP3A Inducers: Strong CYP3A inducers decreased idelalisib AUC by 75%. Avoid coadministration with strong CYP3A inducers (e.g., rifampin, phenytoin, St. John’s wort, carbamazepine).

• CYP3A Inhibitors: Strong CYP3A inhibitors increased idelalisib AUC 1.8-fold. Monitor for signs of ZYDELIG toxicity during coadministration and follow dose modifications for adverse reactions [See Dosage and Administration].

• CYP3A Substrates: ZYDELIG is a strong CYP3A inhibitor. Avoid coadministration with CYP3A substrates as AUC of sensitive CYP3A substrates increased 5.4-fold when coadministered.

USE IN SPECIFIC POPULATIONS: Pregnancy: ZYDELIG is Pregnancy Category D and may cause fetal harm.

In pregnant rats, embryo-fetal toxicities were observed, including decreased fetal weights, external malformations (short tail), skeletal variations (delayed ossification and/or unossification of the skull, vertebrae and sternebrae), urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, microphthalmia/anophthalmia). Women who are or become pregnant during ZYDELIG treatment should be apprised of the potential hazard to the fetus [See Warnings and Precautions].

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

Pediatric Use: Safety and effectiveness of ZYDELIG in children <18 years of age have not been established.

Geriatric Use: In clinical trials of ZYDELIG in patients with FL, SLL, and CLL, 63% of patients were ≥65 years old; no major differences in effectiveness were observed.

• In patients with iNHL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (28% vs. 20%), serious adverse reactions (64% vs. 37%), and death (11% vs. 5%).

• In patients with CLL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (11% vs. 5%), serious adverse reactions (51% vs. 43%), and death (3% vs. 0%).

Contraception in Females of Reproductive Potential: ZYDELIG may cause fetal harm. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after taking the last dose of ZYDELIG. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking ZYDELIG [See Warnings and Precautions].

Renal Impairment: No dose adjustment of ZYDELIG is necessary for patients with creatinine clearance ≥15 mL/min.

Hepatic Impairment: Idelalisib AUC increased up to 1.7-fold in subjects with ALT, AST, or bilirubin >ULN compared to healthy subjects with normal ALT, AST, or bilirubin. Safety and efficacy data are not available in patients with baseline ALT or AST >2.5x ULN or bilirubin >1.5x ULN as these patients were excluded from Studies 1 and 2. Monitor patients with baseline hepatic impairment for signs of ZYDELIG toxicity and follow dose modifications for adverse reactions [See Warnings and Precautions, Dosage and Administration].

205858-GS-000-PI July 2014

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

Subjects with Indolent Non-Hodgkin Lymphoma (iNHL): The safety assessment of ZYDELIG 150 mg BID is based on data from 146 adult subjects with iNHL. The median duration of exposure to ZYDELIG was 6.1 months (range: 0.3 to 26.4 months).

• Adverse Reactions: Most common serious adverse reactions reported in 50% of subjects were pneumonia (15%), diarrhea (11%), and pyrexia (9%). Most common adverse reactions (incidence ≥10%; all Grades) were diarrhea (47%), fatigue (30%), cough (29%), nausea (29%), pyrexia (28%), abdominal pain (26%), pneumonia (25%), rash (21%), dyspnea (17%), decreased appetite (16%), vomiting (15%), upper respiratory tract infection (12%), asthenia (12%), night sweats (12%), insomnia (12%), headache (11%), and peripheral edema (10%). Most common adverse reactions leading to dose interruption or discontinuation in 53% of subjects were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

© 2015 Gilead Sciences, Inc. All rights reserved.

ZYDP0192 08/2015 ZYDELIG, ZYDELIG logo, GILEAD and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its related companies.

All other marks are the property of their respective owners.

S:13”

DOSAGE AND ADMINISTRATION:

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

ASCOPost.com | NOVEMBER 25, 2015

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European Cancer Congress Quick Takes From ECC 2015 continued from page 32

T:13.75”

The study enrolled 339 patients with favorable- or intermediate-risk metastatic renal cell carcinoma who were HLA-A–positive. Patients were randomly assigned 2:1 to receive first-line sunitinib plus IMA901 (n = 204) vs sunitinib alone (n = 135). Sunitinib was chosen as the comparator arm because it is standard first-line therapy.

Median overall survival was 33.1 months for the experimental arm vs not yet reached for sunitinib alone (P = .08). When survival was analyzed according to risk level, the curves overlapped for favorable-risk patients and favored the control arm in the intermediate-risk group. Progression-free survival was similar in both arms, about 15 months by central review.

Adverse events were similar across both arms. Dr. Rini hypothesized that the effect of sunitinib on monocytes may have had a negative effect on the vaccine response.

Although IMA901-specific CD8 Tcell responses were observed with the vaccine, there was no clear association between survival and observed immune response.

“This is another example of a huge difference between our goals with tumor vaccines and what actually happens.

Many trials in tumor vaccines fail,” said Dr. Melero, who was formal discussant for the trial. “Many steps are needed to develop therapeutic vaccines.”

He added, “The data from phase II were not replicated. Those patients who mounted an immune response did not do better.”

Aspirin as Secondary Prevention Aspirin improves survival in patients diagnosed with gastrointestinal tumors, according to results of a large study.7 This is the first study that analyzed survival from patients with tumors located at different sites in the gastrointestinal tract at

the same time, rather than one type.

The study was based on 13,715 patients from the southern region of the Netherlands who had been diagnosed with a gastrointestinal cancer between 1998 and 2011. These cases were linked to drug-dispensing information from PHARMO, a database that contains prescription data from these patients.

About 30% of patients used aspirin before diagnosis, 8.3% used aspirin only

lyze individual tumor specimens in patients with a beneficial response to aspirin to try to identify characteristics associated with benefit, said study coordinator Martine Frouws, MSc, a PhD candidate at Leiden University Medical Center in the Netherlands.

The authors hypothesized that the beneficial effect of aspirin is related to its antiplatelet effects. Aspirin’s inhibition of platelet function may allow the

Given that aspirin is an inexpensive, off-patent drug with relatively few side effects, [findings that aspirin improves survival in patients diagnosed with gastrointestinal tumors] will have a great impact on health-care systems as well as patients.

—Martine Frouws, MSc

after a diagnosis, and 61.1% took no aspirin either before or after diagnosis.

Distribution of the most common tumor types was: colon (42.8%), rectum (25.4%), and esophagus (10.2%). Median follow-up was 48.6 months.

Survival was twice as high in patients who used aspirin post diagnosis. Overall survival at 5 years was 75% among aspirin users, compared to 42% among nonusers. An approximately 50% reduction in death was observed for all patients with a gastrointestinal malignancy. The effect persisted in all individual tumor types (esophageal cancer, colon cancer, rectal cancer, hepatobiliary cancer, stomach cancer). However, the effect was not present in pancreatic cancer.

The survival benefit of postdiagnosis aspirin was observed in an analysis that adjusted for confounding factors such as age, sex, stage of cancer, surgery, radiotherapy, chemotherapy, and comorbidities.

The researchers would like to ana-

immune system to attack these circulating tumor cells.

An ongoing multicenter randomized, placebo-controlled trial in the Netherlands is evaluating daily aspirin (80 mg) in patients with colon cancer. The primary endpoint is overall survival.

“Given that aspirin is an inexpensive, off-patent drug with relatively few side effects, this will have a great impact on health-care systems as well as patients,” said Ms. Frouws. n Disclosure: Dr. James has served on the Advisory Board of and has received research funding and honoraria from Sanofi-Aventis. Dr. Cortes has been a consultant for Celgene and Roche and has received honoraria from Celgene, Roche, Novartis, and Eisai. Dr. Hodi has served as a consultant or advisor for Bristol-Myers Squibb, Novartis, and Merck and has received research funding from Bristol-Myers Squibb, Genentech, Novartis, and Merck. Dr. Yearley is an employee of Merck. Dr. Rini disclosed a relationship with Immatics and Pfizer. Dr. Oude Ophuis and Ms. Frouws reported no potential conflicts of interest.

References 1. James ND, Sydes MR, Mason MD, et al: Docetaxel +/- zoledronic acid for hormone-naive prostate cancer: First overall survival results from STAMPEDE and treatment effects within subgroups.

2015 European Cancer Congress. Abstract LBA19. Presented September 27, 2015.

2. Cortes J, Crown J, Awada A, et al: Overall survival (OS) from the phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) signaling inhibitor, in AR+ advanced triple-negative breast cancer. 2015 European Cancer Congress.

Abstract 1802. Presented September 26, 2015.

3. Oude Ophuis CO, Verhoef C, Rutkowski P, et al: The interval between primary melanoma excision and sentinel node biopsy does not affect survival, regardless of SNB status: An EORTC Melanoma Group study. 2015 European Cancer Congress. Abstract 2BA. Presented September 28, 2015.

4. Hodi FS, Gibney G, Sullivan R, et al: An open-label, randomized, phase 2 study of nivolumab given sequentially with ipilimumab in patients with advanced melanoma (CheckMate 064). 2015 European Cancer Congress. Abstract 23LBA. Presented September 27, 2015.

5. Yearley J, Gibson C, Yu N, et al: PDL2 expression in human tumors: Relevance to anti-PD-1 therapy in cancer. 2015 European Cancer Congress. Abstract 18LBA. Presented September 27, 2015.

6. Rini B, Stenzl A, Zdrojowy R, et al: Results from an open-label, randomized, controlled phase 3 study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/metastatic RCC. 2015 European Cancer Congress. Abstract 17LBA. Presented September 27, 2015.

7. Frouws M, Bastiaannet E, Van HerkSukel M, et al: Aspirin and gastrointestinal malignancies improved survival not only in colorectal cancer. 2015 European Cancer Congress. Abstract 2306. Presented September 28, 2015.

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 ASCO Post | NOVEMBER 25, 2015

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European Cancer Congress Head and Neck Cancer

Lenvatinib in Refractory Thyroid Cancer: Survival Benefit or Not?

By Alice Goodman

I

n the original phase III SELECT trial, no overall survival benefit was observed for lenvatinib (Lenvima) vs placebo in progressive radioactive iodine– refractory differentiated thyroid cancer.

Overall survival was a secondary endpoint in that trial. However, in an updated analysis of SELECT, which was presented at the 2015 European Cancer Congress, investigators revisited the trial data using a sophisticated modeling computation that unearthed a survival benefit.1 It is not clear whether this finding will translate to a real clinical benefit for patients.

“We did an updated analysis of overall survival to account for the high per-

centage of crossover [from placebo to lenvatinib] in SELECT. In this updated overall survival analysis, lenvatinib improved overall survival in iodinerefractory thyroid cancer,” said lead investigator Lori Wirth, MD, of the Department of Medicine, Massachusetts General Hospital, Boston.

Lenvatinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of radioactive iodine–refractory differentiated thyroid cancer. This type of cancer is a rare, aggressive, difficult-to-treat thyroid cancer with limited treatment options and a poor prognosis.

EXPERT POINT OF VIEW

“I

am actually not comfortable discussing this analysis,” said formal discussant Vincent Grégoire, MD, PhD, of the Department of Radiation Oncology, St-Luc University Hospital, Brussels, Belgium. “Instead of me you need a biostatistician. Nevertheless, I will try to address the study.”

“The study raises the question about what it means to use models to try to analyze data. On the positive side, the rank-preserving structural failure time

Not to decrease the interest in these findings, for me, I need to know more about the power and adequacy of the model used to estimate a survival benefit.

—Vincent Grégoire, MD, PhD

analysis was prespecified. But the issue is the power of the analysis. We need to have confidence about the model used. There are other models that could have been used,” Dr. Grégoire continued.

Radioactive iodine–refractory differentiated thyroid cancer is a complex disease with strange behavior, and treatment may not be needed upfront, he noted.

“Not to decrease the interest in these findings, for me, I need to know more about the power and adequacy of the model used to estimate a survival benefit,” he concluded. n Disclosure: Dr. Grégoire reported no potential conflicts of interest.

In this updated overall survival analysis, lenvatinib improved overall survival in iodine-refractory thyroid cancer.

—Lori Wirth, MD

Original Analysis SELECT is a multicenter, doubleblind, placebo-controlled, phase III trial of 392 patients with radioactive iodine– refractory differentiated thyroid cancer who progressed on up to one prior VEGF (vascular endothelial growth factor) therapy within the past 13 months. They were randomized 2:1 to receive lenvatinib vs placebo and treated until disease progression. Placebo patients could cross over to lenvatinib at disease progression.

In the original analysis of SELECT, a significant progression-free survival benefit was observed for lenvatinib vs placebo: 18.3 months vs 3.3 months with placebo, representing a 79% improvement favoring lenvatinib (P < .001).

Overall survival, a secondary endpoint in the trial, was analyzed in 2013.

Median overall survival was not reached in either arm at that time, and the survival data were immature.

At the time of the original analysis, 83% of the placebo arm crossed over to lenvatinib. In the adjusted analysis, 88% had crossed over. To account for the confounding effect of crossover, the investigators used a prespecified rank–preserving structural failure time adjustment, which is a model that calculated the effect of lenvatinib on survival without crossover. Overall survival curves were estimated using the Kaplan-Meier method, and the hazard ratio was estimated by a Cox proportional

hazard model fitted to rank-preserving structural failure time–adjusted overall survival data, Dr. Wirth explained.

Updated Findings The updated analysis found a significant survival effect for lenvatinib: 36% died in the lenvatinib arm vs 42% in the placebo arm. Median overall survival has not yet been reached in the lenvatinib arm vs 19.1 months for placebo (nominal P value = .005, hazard ratio, 0.53 [95% confidence interval: 0.34–0.82]).

“These patients had all progressed within the past 13 months. Lenvatinib does not cure patients, and like other drugs, it has toxicity. Other data show slightly better outcomes on the lenvatinib arm from the beginning compared with those who crossed over.

This study suggests that we don’t want to wait too long to start treating patients. This study supports that. The prespecified analysis was approved by the FDA,” Dr. Wirth told listeners. n

Disclosure: This study was funded by Eisai.

Dr. Wirth disclosed financial relationships with Eisai and Novartis.

Reference 1. Guo M, Sherman S, Wirth L, et al: Overall survival gain with lenvatinib vs. placebo in radioactive iodine refractory differentiated thyroid cancer: An updated analysis. 2015 European Cancer Congress. Abstract 2805. Presented September 26, 2015.

More From the European Cancer Congress For more reports from the European Cancer Congress, held recently in Vienna, see pages 30 through 40 in this issue of The ASCO Post. Plus, visit http://video.ascopost.com/ to view videos of interviews with experts filmed live during the annual congress.

ASCOPost.com | NOVEMBER 25, 2015

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European Cancer Congress Neuro-oncology

Actionable Targets Identified in Brain Metastases

By Alice Goodman

N

ew research shows that paired primary tumor and brain metastases share a common ancestor, but as the metastases develop in the brain, they exhibit novel genetic alterations that can activate a number of signaling pathways. More than half of the mutations represent potential therapeutic targets. Despite these exciting

Priscilla Brastianos, MD, a neurooncologist and Director of the Brain Metastasis Program at Massachusetts General Hospital, Boston, who presented these study results at the 2015 European Cancer Congress.1 The study report was published simultaneously in Cancer Discovery.2 “Brain metastases are not routine-

Genomic analysis of primary tumors and other extracranial metastatic sites may miss a substantial number of opportunities for targeted therapies in brain metastases.

—Priscilla Brastianos, MD

findings, much remains to be done before they can be incorporated into clinical practice, according to experts not involved in the research.

“Brain metastases represent an unmet need in current cancer care. More than half of the patients diagnosed with brain metastases will die within a few months,” said lead researcher

ly biopsied. When brain metastasis tissue is available as part of clinical care, we suggest sequencing and analyzing that sample. It may offer more therapeutic opportunities for the patient,” she added. “Genomic analysis of primary tumors and other extracranial metastatic sites may miss a substantial number of opportuni-

ties for targeted therapies in brain ­metastases.”

Study Details and Results The study was based on genomic analysis of primary tumors and brain metastases collected from 104 patients. Of those patients, 86 were of adequate quality for analysis. Novel computational techniques allowed the investigators to estimate the clonal architecture of matched primary tumors and metastases and to reconstruct the phylogenetic tree, relating subclones from each patient. Biopsy samples were obtained from the primary tumor, brain metastases, and normal tissues for each study participant. In addition, extracranial metastases were analyzed. This is the largest comprehensive sequencing study of matched brain metastases and primary tumors to date.

“Across all our samples and phylogenetic trees, we found the data were consistent with branched evolution, meaning we detected a common ancestor shared by the brain metastasis and the primary tumor, but there was continued divergent evolution between the

primary tumor and the brain metastasis,” Dr. Brastianos pointed out.

For example, a sample of a primary renal cell carcinoma showed the mutations VHL pL188P, PBRM1 p.T43fs, and mTOR p.K1452N, all of which were shared by the brain metastasis and the primary tumor in that patient.

However, additional mutations— PIK3CA p.E542K and CDKN2A/B del—were found in the brain metastasis sample and not detected in the primary tumor sample, despite adequate power.

Further analysis showed that 53% of cases of brain metastasis had “clinically actionable” genetic mutations that were not present in the primary tumor tissue sample. Fiftytwo percent of cases had mutations associated with sensitivity to cyclindependent kinase inhibitors, and in 43% of cases, the alterations were sensitive to inhibitors of the PI3K/ AKT/mTOR cell cycle regulation pathway.

Extracranial metastases had mutations that were dissimilar to those in continued on page 40

EXPERT POINT OF VIEW

P

eter Naredi, MD, European CanCer Organization (ECCO) Scientific Co-Chair of the Congress, stated in a press release: “In my view, Dr. Brastianos and colleagues very elegantly show what we mean with precision medicine, how genetic pro-

Some mutations will be targetable, and some won’t be.

In some cases, we may be able to interrupt the pathway, but in others we can’t.

—Michael Brada, MD, DSc

Peter Naredi, MD

filing can support our understanding of the metastatic process, and how it opens up different pathways for treatment. It is not enough to rely on the characteristics of the primary tumor, because brain metastases have other specific gene alterations, and in many patients, this gives us better treatment alternatives.” Dr. Naredi is Professor

of Surgery at Sahlgrenska University Hospital, Gothenburg, Sweden.

Formal discussant of this study Michael Brada, MD, DSc, Professor of Radiation Oncology at the University of Liverpool, United Kingdom, who was not involved in this study, called the study “excellent.” He added: “This gives us a better understanding of the metastatic process.”

According to Dr. Brada, an important consideration from a clinical perspective is whether a metastasis is an early or late event in the lifetime of the primary tumor, because that may

impact the success of therapy. It is possible that the current study could shed light on whether a metastasis is early or late, because the number of mutations observed is a function of time and can provide clues on the timeline of an individual metastasis. The data presented do not show whether these metastatic events were early or late.

Targetable vs Nontargetable Mutations Due to the heterogeneity of cancer, “some mutations will be targe-

table, and some won’t be. In some cases, we may be able to interrupt the pathway, but in others we can’t,” Dr. Brada suggested. He said that it wasn’t possible from the data presented to tell whether metastases are heterogeneous or arise from a single dormant cell that lodges in the brain.

“The answer may be a mixture of both,” he noted.

Even though targetable mutations were identified within the brain metastases, there are many challenges to overcome in attempting to use targeted therapy. “Those challenges include the existence of multiple targets within each cell, the enormous heterogeneity of the cells within the brain, and the heterogeneity of systemic diseases seen in the patients,” Dr. Brada continued.

“Certainly, this is an avenue to explore. Just because there is heterogeneity, doesn’t mean we shouldn’t be trying,” he added.n Disclosure: Drs. Naredi and Brada reported no potential conflicts of interest.

The ASCO Post | NOVEMBER 25, 2015

PAGE 40

European Cancer Congress Brain Metastases continued from page 39

the brain. “By contrast, regionally and anatomically separated brain metastasis sites were genetically homogeneous and shared nearly all alterations detected,” she said.

Genomic Characterization of Brain Metastases

identified in brain metastases would improve overall survival. She was surprised by the “tremendous” genetic divergence when comparing brain metastases to primary tumors.

“The clinical relevance of our findings needs to be studied in prospective clinical trials. We still need to determine whether targeting the genetic mutations

in the brain will lead to improved clinical outcomes,” she told the audience. n Disclosure: Dr. Brastianos has served as a consultant for Merck.

References S:6.75” S, Santagata S, et 1. Brastianos P, Carter al: Genomic characterization of brain metastases and paired primary tumors reveals

branched evolution and potential therapeutic targets. 2015 European Cancer Congress. Abstract 2905. Presented September 27, 2015.

2. Brastianos P, Carter S, Santagata S, et al: Genomic characterization of brain metastases and paired primary tumors reveals branched evolution and potential therapeutic targets. Cancer Discov 5:1164-1177, 2015.

■■ Genomic analysis using novel computational techniques found that paired primary tumor samples and brain metastases from those sites share a common ancestor.

■■ However, the metastases in the brain have novel genetic alterations that differ from those in the primary tumor, more than 50% of which are “actionable.”

■■ Genetic changes in brain metastases are not observed in extracranial metastases and thus are independent of both the primary tumor and extracranial lesions.

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

■■ More study needs to be done to confirm whether therapy targeted to specific mutations in brain metastases can improve survival.

Attack from multiple angles

The clinical implication of this is that exclusive sampling of the primary tumor and/or regional lymph nodes would fail to identify potentially actionable mutations in the brain metastases, Dr. Brastianos explained.

Clinical Relevance During the question-and-answer session following her presentation, Dr. Brastianos acknowledged that it is not clear whether targeting the mutations

Contact

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

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

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.

Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%).

Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

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Announcements

ASH Announces Stephen S. Chung, MD, as Inaugural Jake Wetchler Foundation ASH Scholar for Pediatric Innovation Recipient

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he American Society of Hematology (ASH) recently announced that Stephen S. Chung, MD, will receive the inaugural Jake Wetchler Foundation ASH Scholar Award for Pediat-

ric Innovation for his research on the mechanisms of bone marrow failure syndromes. ThisS:6.75” work could ultimately lead to an improved understanding of a severe form of pediatric leukemia that

develops in the setting of bone marrow failure. The award is the result of a new partnership between ASH and The Jake Wetchler Foundation for Innovative Pediatric Cancer Research ( JWF)

to cooperatively fund novel pediatric cancer research that challenges existing paradigms.

Through this partnership, JWF continued on page 42

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)

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

PFS

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Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.

Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330).

Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).

Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).

In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.

Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

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Announcements Stephen S. Chung, MD continued from page 41

will fund 50% of select ASH awards granted to investigators whose research has a line of sight to effective and safe treatments for pediatric acute myeloid leukemia (AML). Dr. Chung’s award will total $100,000 over a period of 2 years.

Dr. Chung is an instructor and medical oncologist at Memorial Sloan Kettering Cancer Center. His current research focuses on the role of CD99, a cell surface protein expressed at increased levels on malignant stem cells.

Dr. Chung aims to determine whether CD99-targeted treatments can eradicate the stem cells that are often respon-

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.

S:6.75”

Stephen S. Chung, MD

sible for disease relapse, as well as develop new diagnostic tests for AML and myelodysplastic syndromes.

Dr. Chung received his medical degree from Washington University School of Medicine in St. Louis and completed fellowships at Massachusetts General Hospital and Memorial Sloan Kettering Cancer Center. n

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days.

The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

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

Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5 Palmar-plantar erythrodysesthesia syndrome.

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Centers for Medicare & Medicaid Services Releases 2016 Medicare Physician Fee Schedule: Impact on Radiation Oncology

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The final rule comes after a comprehensive advocacy campaign led by ­ASTRO. In September, 207 members of Congress representing both chambers and both major parties signed letters to CMS articulating serious concerns with the proposed cuts to radiation oncology and urging CMS to avoid imposing barriers to patient care. The effort, led by Senators Richard Burr (RNorth Carolina) and Debbie Stabenow (D-Michigan) and Representatives Devin Nunes (R-California) and Paul Tonko (D-New York), called particular attention to the burden that community-based clinics would face by losing the payment stability, which is essential to ensure accessible, affordable care for their patients.

“We appreciate the work of our Congressional partners in protecting patient access to radiation oncology care and helping avert more drastic cuts,” said Bruce D. Minsky, MD, FASTRO, Chair of ASTRO’s Board of Directors.

“ASTRO will continue urging CMS to heed the call from Congress to end the uncertainty and instability facing radiation therapy practices and their patients.”

A July 2015 survey conducted by ­ASTRO of the nearly 1,400 communitybased radiation therapy centers in the United States found that cuts of 5% to 10% could cause nearly 30% of these practices to close. More than 40% of respondents said such cuts would force them to discontinue accepting patients covered by Medicare, and more than 60% reported they would have to consolidate practice locations.

In scaling back the proposed cuts, CMS said it will delay the implementation of new conventional radiation oncology, intensity-modulated radiation therapy, and image-guided radiation therapy codes and retain the G-codes created as placeholders for deleted predecessor codes in the 2015 final rule for another year.

Changes in allowed charges and payment rates will take effect on January 1, 2016. n S:9.75”

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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

underserved areas, will vary based on their patient and modality mix. Although reductions specific to these practices were less than those proposed in July, uncertainty remains as to the viability of freestanding clinics given the potential for more substantial cuts to accompany the future implementation of new codes. The 2016 reductions compound preexisting reimbursement cuts of more than 20% to freestanding clinics in the past 6 years.

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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.

general. CMS scaled back reductions initially proposed in July 2015.

The impact of the final rule on community-based radiation therapy centers, including those in rural and medically

QC

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

vere than anticipated, according to a news release issued by the American Society for Radiation Oncology S:6.75” (ASTRO). The final rule reduced physician payment rates by 2% for the radiation oncology specialty in

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Collaborative Group on Inherited Colorectal Cancer Gastrointestinal Oncology

Oncologists Encouraged to Learn More About Lesser-Known Heritable Gastrointestinal Cancers

By Caroline Helwick

T

he genetic basis for inherited colorectal cancer is proving to be a much bigger and more complicated “pie” than was appreciated just a few years ago, according to Michael Hall, MD, Director of Gastrointestinal Risk Assessment at Fox Chase Cancer Center, Philadelphia.

“With next-generation sequencing, we can now test panels of tens to hundreds of genes at one time, and we are

Oncologists can benefit from involvement in the CGA, he said. “We know that oncologists are aware of Lynch syndrome and have at least some experience with [familial adenomatous polyposis], but they may not be aware of the many other inherited gastrointestinal conditions,” Dr. Hall noted.

About one in six colorectal cancer patients under the age of 50 has an inherited oncogenic mutation, many of

We need to be more aggressive in identifying hypermutable cancers, because these patients might be great candidates for PD-1 inhibitor therapy.

—Michael Hall, MD

identifying more pieces of this pie,” Dr. Hall said in an interview following the 19th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA) in Baltimore.

The ASCO Post asked Dr. Hall, a gastrointestinal medical oncologist and member of the organization, to describe the CGA, its mission, and some of the most provocative presentations from its recent conference.

What Is the CGA? The CGA was established in 1995 to improve understanding of the basic science of inherited colorectal cancer and the clinical management of affected families. The group’s focus is on the growing group of inherited conditions that extend beyond the more recognized entities such as Lynch syndrome and familial adenomatous polyposis. The mission is to educate clinicians regarding genetics and management, improve access to trials, develop resources and support for registries, maintain a forum for the exchange of ideas, and serve as the authoritative voice of hereditary colorectal cancer health care in the Americas.

“CGA basically started out as a working group, and now 20 years later, we have grown into an organization that holds a yearly conference attended by a mix of gastroenterologists, oncologists, surgeons, pathologists, genetic counselors, and other researchers from around the world,” said Dr. Hall.

them in genes that would not typically be suspected, he pointed out. “We think it’s important for oncologists to understand that when they see a patient under 50 with [colorectal cancer], this could be an inherited condition,” he added.

While the primary focus of the CGA is colorectal cancer research, its reach also includes health services and behavioral research and heritable forms of other gastrointestinal malignancies.

The group’s 20th Annual Meeting will be held October 2–3, 2016, in Seattle.

The following summaries describe abstracts of interest from this year’s CGA meeting.

Genetic Testing: Look Beyond Lynch Syndrome Rachel Pearlman, MS, LGC, and colleagues from The Ohio State University Comprehensive Cancer Center, Columbus, evaluated the germline mutation spectrum in 250 colorectal cancer patients diagnosed under the age of 50 in the Ohio Colorectal Cancer Prevention Initiative.1 Genetic testing was performed on cohorts with mismatch repair–deficient tumors and mismatch repair–proficient tumors.

Of the 250 patients, 40 (16.8%) were found to have at least one pathogenic germline mutation (9.6% Lynch syndrome, 7.2% other hereditary cancer syndromes). Testing with a comprehensive panel of genes detected mutations that would have otherwise been missed.

Rachel Pearlman, MS, LGC

“Had targeted testing for polyposis or a panel with only highly penetrant [colorectal cancer] genes been ordered, 9 of the detected germline mutations (22%) would have been missed,” the authors indicated. These pathogenic mutations in clinically actionable hereditary cancer genes provide valuable information for [colorectal cancer] patients and their families, they suggested.

“Ms. Pearlman’s group used the full force of the genetic testing that is available to screen tumors from high-risk individuals. This was a huge effort to recruit every colorectal cancer case in Ohio and get these patients in for genetic testing,” Dr. Hall observed.

“They found a high frequency of mutations in this under-50 group, and while quite a few were associated with Lynch syndrome genes, there were others that we would not necessarily expect but yet are clinically actionable, such as BRCA1 or BRCA2, PALB2, and P16 mutations,” he noted. “This argues that these under-50 colorectal cancer patients need a broader type of genetic investigation to make sure we are not missing other genes contributing to hereditary cancer risk and health risk.”

Modulating Genes and Reducing Polyp Burden Deboarah Neklason, PhD, and colleagues from the Huntsman Cancer Institute, Salt Lake City, found that targeted inhibition of the cyclooxygenase-2 (COX2) and epidermal growth factor receptor (EGFR), in patients with familial adenomatous polyposis, downregulates oncogenes and results in regression of duodenal neoplasia.2 They conducted a phase II doubleblind randomized trial evaluating the effect of inhibiting COX2 with sulindac and EGFR with erlotinib. They evaluated the drugs’ effect on polyp burden and on gene expression by comparing normal and polyp duodenal tissue before and after the 6-month treatment.

This comparison revealed more than 600 differentially expressed genes among the placebo group, compared to only 58 differentially expressed genes from patients on treatment, who also had fewer polyps.

“This suggests that pathways activated in polyp formation are blocked by this drug combination,” the authors wrote.

The study identified molecular drivers of familial andenomatous polyposis, resulting in information that may someday have practical implications, according to Dr. Hall. While colectomy in young adulthood can help prevent colorectal cancer in these patients, upper gastrointestinal polyposis remains problematic as a precursor to malignancy and ultimately could benefit from a pharmacologic intervention.

Deboarah Neklason, PhD

“At baseline and in the placebo group, we saw an overexpression of many genes we would not expect. In the treatment group, however, the number of differentially expressed genes fell tremendously, showing that the combination of these agents was suppressing many important driver pathways in polyps—ERK, ERBB2, SMAD4, betacatenin and others,” Dr. Hall said.

“This provides proof of principle that there are molecular pathways that might be modulated therapeutically,” he continued. “Patients with dense poly­posis, which can be very difficult to manage endoscopically, are a subset of patients with familial adenomatous polyposis who are at risk for upper gastrointestinal cancers. This drug combination could be a great option for them.”

Biallelic Mismatch Repair Syndrome Described Biallelic mismatch repair deficiency syndrome is an aggressive inherited cancer predisposition syndrome. Individuals harboring biallelic germline continued on page 46

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Collaborative Group on Inherited Colorectal Cancer Heritable Gastrointestinal Cancers continued from page 44

mutations in the mismatch repair genes develop brain tumors, hematologic malignancies, and gastrointestinal cancers.

In stark contrast to patients with Lynch syndrome, where the mean age of gastrointestinal cancer diagnosis is 47 years, almost all patients with biallelic mismatch repair deficiency syndrome develop gas-

Luis A. Diaz, MD

trointestinal malignancies before age 18.

There is evidence that these tumors may be amenable to treatment with immune checkpoint inhibitors.

An international team of investigators used a multiassay approach to detect biallelic mismatch repair deficiency syndrome in suspected patients and to assess mismatch repair capabilities in known patients.3 Exome and genome sequencing determined mutation frequency in all biallelic mismatch repair

deficiency syndrome cancers. They found that 74% of all tumors and 37% of gastrointestinal tumors were microsatellite-stable. In contrast, there was a complete lack of staining of protein in the affected gene in 95% of cases.

Exome sequencing of 29 biallelic mismatch repair deficiency syndrome cancers revealed extremely high mutation frequencies, very distinct from other childhood cancers.

Again, in contrast to tumors arising from Lynch syndrome, microsatelliteinstability analysis was not informative in detecting biallelic mismatch repair deficiency syndrome, but both immunohistochemistry and the in vitro G/T mismatch repair assay were highly specific and sensitive for detection of the syndrome.

The findings point to a “hypermutant” phenotype that is unique to biallelic mismatch repair deficiency syndrome and diagnostic in these pediatric cancers. The extremely high mutation rate in gastrointestinal cancers predicts excellent response to immunotherapy, the authors maintained.

“This genetic syndrome is probably more common than we think—because Lynch syndrome itself is common— but it’s not on people’s radar,” Dr. Hall said. “What is very impressive about this work is that the researchers col-

Lynn Sage Breast Cancer Symposium

Judy Garber, MD, MPH

C. Richard Boland, MD

lected enough subjects to conduct these studies.”

Data presented in the past year suggested that programmed cell death protein 1 (PD-1) inhibitors may be effective in mismatch repair–deficient tumors such as these, he added.

Indeed, the researchers of this study reported that these brain tumors had striking responses to PD-1 inhibitors.

“This suggests that we need to be more aggressive in identifying hypermutable cancers, because these patients might be great candidates for PD-1 inhibitor therapy,” he commented.

Other Meeting Highlights

Nancy Davidson, MD, second from right, Director of the University of Pittsburgh Cancer Institute and UPMC Cancer Center, is recognized for serving as distinguished lecturer at the 17th Annual Lynn Sage Breast Cancer Symposium, conducted by the Robert H. Lurie Comprehensive Cancer Center, Chicago.

Expressing their appreciation to Dr. Davidson are, from left: Nora Hansen, MD, symposium co-chair and Chief of the Division of Breast Surgery and Director of the Lynn Sage Comprehensive Breast Center at Lurie Comprehensive Cancer Center, William Gradishar, MD, symposium chair, and Director of the Maggie Daley Center for Women’s Cancer Care at Lurie Comprehensive Cancer Center, and symposium co-chairs Monica Morrow, MD, Chief of the Breast Service at Memorial Sloan-Kettering Cancer Center, New York, and V. Craig Jordan, OBE, PhD, DSc, Professor of Breast Medical Oncology and Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center. See upcoming issues of The ASCO Post for coverage of the Lynn Sage Breast Cancer Symposium.

Luis A. Diaz, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, reviewed data on the impact of the PD-1 inhibitor pembrolizumab (Keytruda) in mismatch repair–deficient colorectal cancer. Dr. Diaz was senior author of the phase II study recently published in The New England Journal of Medicine involving 41 patients with metastatic carcinoma, with or without mismatch repair deficiency.4 Patients with mismatch repair– deficient colorectal cancers in that study had a 40% response rate and 78% progression-free survival rate; median progression-free and overall survival was not reached. In contrast, those with mismatch repair–proficient colorectal cancers had poor outcomes.

Pembrolizumab reduced the risk of progression by 90% (P < .001) and mortality risk by 78% (P = .05) in the mismatch repair–deficient group.

Dr. Diaz also indicated that tumors

caused by mutations in the relatively newly described DNA polymerase genes, POLE and POLD1, can also be modulated by immunotherapy, suggesting that individuals with mutations in these genes might also derive benefit from checkpoint inhibitors.

A lecture by Judy Garber, MD, MPH, of Dana-Farber Cancer Institute, Boston, focused on the clinical challenge of genetic testing for large numbers of genes, especially the problem of variants of unknown significance. “Management of [variants of unknown significance] is a contentious issue,” Dr. Hall noted. “Dr. G ­ arber gave a nice overview that explained why these incidental findings are here to stay, why they are a difficult aspect of the genetic testing arena, and how she thinks they should be managed.”

The CGA also bestowed a Lifetime Achievement Award on C. Richard Boland, MD, of Baylor Scott & White Health, Dallas. Dr. Boland’s seminal research helped explain microsatellite instability and its implications for cancer therapy. n

Disclosure: Dr. Hall, and Dr. Neklason reported no potential conflicts of interest. Ms. Pearlman reported that The Ohio Colorectal Cancer Prevention Initiative is receiving free genetic testing from Myriad and discounted genetic testing from the University of Washington.

References 1. Pearlman R, Hampel H, Allen B, et al: Ohio Colorectal Cancer Prevention Initiative: Germline mutation spectrum in 250 colorectal cancer patients diagnosed under age 50. Collaborative Group of the Americas for Hereditary Colorectal Cancer Annual Meeting. Abstract 14. Presented October 11, 2015.

2. Neklason DW, Delker DA, Samadder NJ, et al: Molecular pathways impacted in FAP patients treated with COX and EGFR combined inhibition. Collaborative Group of the Americas for Hereditary Colorectal Cancer Annual Meeting. Abstract 6. Presented October 11, 2015.

3. Campbell B, Aronson M, Shlien A, et al: Functional characterization of biallelic mismatch repair deficiency and its implications for novel therapies. Collaborative Group of the Americas for Hereditary Colorectal Cancer Annual Meeting. Abstract 2. Presented October 11, 2015.

4. Le DT, Uram JN, Wang H, et al: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509-2520, 2015.

Approving Biosimilars in the United States: The Food and Drug Administration (FDA) Perspective The Biologics Price Competition and Innovation (BPCI) Act was signed into law as part of the Affordable Care Act in 2010, amending the Public Health Service (PHS) Act and facilitating the creation of an abbreviated, or tailored, licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product.1 This abbreviated pathway, which is made possible by utilizing knowledge from the reference products and the European Medicines Agency experience, which approved its first biosimilar in 2006, is intended to eliminate unnecessary (and, therefore, unethical) testing of biosimilars in animals and humans.2

TOTALITY OF EVIDENCE: WHAT DOES IT MEAN? FDA guidance represents a paradigm shift in the way biosimilars are evaluated. The biosimilar approval pathway that the FDA has outlined builds on the knowledge gained from the reference biologic, and is based on a “Totality of Evidence” Approach.3 The “Totality of Evidence” Approach4

When a manufacturer decides to submit a product for review as a biosimilar, a 351(k) biologics license application is submitted, which must include information demonstrating biosimilarity, such as1: • Analytical studies that demonstrate that the biological product is “highly similar” to the reference product (only minor differences in clinically inactive components are permitted) • Animal studies (including assessment of toxicity) • Clinical studies, including the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD), that sufficiently demonstrate safety, purity and potency in one or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product

ity r a il is m o Bi

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2012

Clinical Knowledge Human PK and PD

Structural and Functional Characterization

The goal of this stepwise approach is to establish the totality of the evidence that supports the demonstration of biosimilarity.3 This pathway also takes into account the lack of scientific benefit in repeating the entire development program of the reference product.2 Establishing a high degree of similarity at the molecular level with a robust foundation of analytical characterization reduces the need for extensive animal and clinical testing, compared with that required for a new originator biologic.3

First Biosimilar Approved11:

1. Scientific Considerations5 2. Quality Considerations6 3. Questions and Answers7

Draft Guidance Clinical Pharmacology Data on Biosimilarity9

The first approved biosimilar is filgrastim, currently referred to as filgrastim-sndz until the FDA clarifies how to “name” biosimilars.

Draft Guidance on Biosimilars:

FEBRUARY

MAY

MARCH

MAY

Draft Guidance on Biosimilars:

2011

Animal Studies

Clinical Immunogenicity

The FDA Has Developed Guidance for the Regulatory Approval of Biosimilars

2010

Clinical Studies

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Additonal Questions and Answers14

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BPCI Act Passed as Part of the Affordable Care Act

Draft Guidance on Formal Meetings With FDA and Sponsors (procedural) 8

FDA Announces “Purple Book”10:

Final Guidance on Biosimilars:

Lists biological products, including FDA licensed biosimilar and interchangeable biological products. It enables users to see whether a licensed biologic is biosimilar to, or interchangeable with, a reference biologic.

1. Scientific Considerations 3 2. Quality Considerations12 3. Questions and Answers13

ROBUST ANALYTICAL TESTING: DEMONSTRATING BIOSIMILARITY Using a Multifactorial Approach Analytical testing is a major focus of biosimilar development.

Physicochemical studies are used to sufficiently establish relevant product attributes such as those that define a product’s identity, quantity, purity, potency and consistency.

Bioactivity assays are used to evaluate how similar the biosimilar acts like the reference product. Differences in attributes between the proposed biosimilar and the reference product may be compared via a fingerprint-like analysis algorithm.12 New techniques and advancements in analytics are available.

More than one test method may be used to test a single quality attribute. Analytical comparisons for biosimilars are likely to be more extensive and comprehensive than those made for reference biologics after a manufacturing change.

Analytical testing will greatly reduce the number of residual uncertainties requiring clarification with subsequent animal and human studies.3

design with non-inferiority or equivalence margins. If the sponsor believes comparative testing is not required, they may provide scientific justification in support.3

Immunogenicity: A Focus at Every Stage in the Process The goal of immunogenicity assessment is to ascertain potential differences between the biosimilar and the reference product in the incidence and severity of human immune responses.3 At least one clinical study comparing the immunogenicity of the biosimilar and reference product is the norm, but because immunogenicity is of concern for any biologic product, it is evaluated at all stages of biosimilar development.

Demonstrating Biosimilarity Multifactorial Approach

Human PK/PD Studies

Comparative Clinical Immunogenicity Evaluations Assessment

Human PK/PD Studies The use of comparative human PK/PD studies is fundamental in demonstrating a high degree of similarity and is generally expected, unless scientific evidence can be provided to show that such studies are unnecessary. Some endpoints, including some PD measures, may be more sensitive from those used in the reference product’s clinical trials, and such alternative endpoints may allow more precise comparisons of therapeutic effects.3 One example is the use of the international normalized ratio as a more sensitive endpoint than the incidence of cerebral bleeding or stroke.

Comparative Clinical Evaluations Comparative clinical evaluations are done on a case-bycase basis when they are deemed necessary, usually when there are residual uncertainties about whether any clinically meaningful differences exist between the biosimilar and the reference product. If a comparative study is required, some of the considerations that will go into the study design include selecting a patient population and condition of use adequately sensitive to detect any clinically meaningful differences with the reference product, endpoints that enable precise and meaningful comparison to the reference product and a study

Biosimilarity When it comes to getting new biosimilar products on the market, FDA has taken an innovative approach to supporting their development at every step of the process. These... documents are designed to help industry develop biosimilar versions of currently approved biological products, which can enhance competition and may lead to better patient access and lower cost to consumers. 15 —FDA Center for Drug Evaluation and Research

References: 1. U.S. Food and Drug Administration (FDA). Biosimilars. March 6, 2015. FDA [website]. Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241720.htm. Accessed May 11, 2015. 2. Kozlowski S, Woodcock J, Midthun K, et al. Developing the nation’s biosimilars program. N Engl J Med. 2011;365(5):385-388. 3. U.S. Food and Drug Administration (FDA). Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference product. April 2015. 4. Sherman RE. Biosimilar biological products. Biosimilar guidance webinar. February 15, 2012. 5. U.S. Food and Drug Administration (FDA). Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference product. February 2012. 6. U.S. Food and Drug Administration (FDA).

Guidance for industry: Quality considerations in demonstrating biosimilarity to a reference protein product. February 2012. 7. U.S. Food and Drug Administration (FDA). Guidance for industry: Biosimilars: Questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. February 2012. 8. U.S. Food and Drug Administration (FDA). Guidance for Industry: Formal meetings between the FDA and biosimilar biological product sponsors or applicants. March 2013. 9. U.S. Food and Drug Administration (FDA). Guidance for industry: Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. May 2014. 10. U.S. Food and Drug Administration (FDA). Purple Book: Lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. April 30, 2015. FDA [website]. Available at http://www.fda.gov/Drugs/ Development ApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418. htm. Accessed May 8, 2015. 11. U.S. Food and Drug Administration (FDA). FDA approves first biosimilar product Zarxio [press release]. March 6, 2015.

FDA [website]. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm. Accessed April 29, 2015.12. U.S. Food and Drug Adminstration (FDA). Guidance for industry: Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. April 2015. 13. U.S. Food and Drug Administration (FDA). Guidance for industry: Biosimilars: Questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. April 2015. 14. U.S. Food and Drug Administration (FDA). Guidance for industry: Biosimilars: Additional questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. May 2015. 15. U.S. Food and Drug Administration (FDA). Press Announcements: FDA issues draft guidance on biosimilar product development. February 9, 2012. FDA [website]. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm291232.htm. Accessed May 11, 2015.

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

P15-0727-4-Jul., 15.

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Physiatry in Discussion Roundtable Oncology Hematology

The State of Progress in Hematologic Malignancies

A Conversation With David A. Williams, MD, Michael E. Williams, MD, ScM, and S. Vincent Rajkumar, MD

By Jo Cavallo

T

he number of targeted therapies approved by the U.S. Food and Drug Administration (FDA) in the treatment of a variety of cancers, especially hematologic malignancies, continues to rise. In 2014 alone, 4 of the 10 new agents directed at discrete molecular targets approved by the FDA were for blood cancers: blinatumomab (Blincyto) for acute lymphoblastic leukemia, belinostat (Beleodaq) for peripheral T-cell lymphoma, and two therapies in the treatment of chronic lymphocytic leukemia (CLL)—idelalisib (Zydelig) and ibrutinib (Imbuvica). (Ibrutinib was initially approved in 2013 in the treatment of mantle cell lymphoma.) The FDA also approved two immunotherapies for newly diagnosed CLL—obinutuzumab (Gazyva) and ofatumumab (Arzerra)—prompting ASCO to name the transformation of treatment for CLL its cancer Advance of the Year.

So far in 2015, the FDA has approved new indications for four drugs in the treatment of hematologic malignancies, including brentuximab vedotin (Adcetris) for Hodgkin lymphoma, carfilzomib (Kyprolis) in combination with lenalidomide (Revlimid) and dexamethasone for relapsed multiple myeloma, panobinostat (Farydak) in combination with bortezomib (Velcade) and dexamethasone for relapsed myeloma, and ibrutinib for Waldenström’s macroglobulinemia.

In the near future, advances in genomic profiling for hematologic cancers, new drug combinations, and chimeric antigen receptor (CAR) T-cell gene therapy all promise to improve clinical outcomes for the more than 162,000 people diagnosed with leukemia, lymphoma, or multiple myeloma each year.1 Just before the 57th American Society of Hematology (ASH) Annual Meeting, to be held December 5–8, in Orlando, Florida, The ASCO Post conducted a roundtable discussion with three leaders in the treatment of leukemia, lymphoma, and multiple myeloma to learn about the current state of progress being made in these blood cancers and what is on the 10-year horizon.

Our participants included David A. Williams, MD, Leland Fikes Professor of Pediatrics at Harvard Medical School

About the Faculty

David A. Williams, MD

Michael E. Williams, MD, ScM

S. Vincent Rajkumar, MD

Leland Fikes Professor of Pediatrics at Harvard Medical School and President of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston, and current President of the American Society of Hematology

Byrd S. Leavell Professor of Medicine and Chief of the Hematology/Oncology Division at the University of Virginia Health System in Charlottesville

Edward W. and Betty Knight Scripps Professor of Medicine, Division of Hematology at the Mayo Clinic in Rochester, Minnesota

and President of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston, and current President of ASH; Michael E. Williams, MD, ScM, Byrd S. Leavell Professor of Medicine and Chief of the Hematology/ Oncology Division at the University of Virginia Health System in Charlottes-

and clinical research meeting. I anticipate seeing presentations that reflect a continued maturation of the field of targeted therapies in the treatment of lymphoma, leukemia, and myeloma. By that I mean we will see an increase in the use of combination-targeted therapies with conventional therapies and

these advantages will have the combined effect of improving outcomes and reducing treatment toxicities and long-term side effects.

We are defining the genetic landscape of diseases, and ultimately, that will allow us to better select patients most likely to respond to targeted therapy as well as patients who are not going to respond so we can prescribe alternative therapies.

—David A. Williams, MD

ville; and S. Vincent Rajkumar, MD, Edward W. and Betty Knight Scripps Professor of Medicine, Division of Hematology at the Mayo Clinic in Rochester, Minnesota.

ASH 2015 First, Dr. David Williams, please talk about the areas of clinical advancements you expect to see presented at this year’s ASH meeting.

Dr. D. Williams: This is going to be a huge meeting, with about 25,000 hematologists from around the world in attendance. We have over 6,000 abstracts submitted, so this will be an outstanding basic research meeting as well as an outstanding translational

also the combination of targeted therapies with new immune therapies.

Of course, we are still learning about the genomic signatures of diseases like leukemia, and I think there will be more science around the importance of mutations in the development and evolution of blood cancers—particularly the evolution of resistance to therapy—and that will allow us to treat patients more precisely in the future.

We are defining the genetic landscape of diseases, and ultimately, that will allow us to better select patients most likely to respond to targeted therapy as well as patients who are not going to respond so we can prescribe alternative therapies. I think

New Insights From each of your perspectives, what are you learning about the prevention, detection, diagnosis, and treatment of blood cancers?

Dr. D. Williams: We are learning that certain mutations appear to predispose patients to the evolution of leukemia as well as the complexity of relapse and resistance to therapy.

Dr. M. Williams: Improved diagnostics are providing a deeper understanding of the heterogeneity of blood cancers at both the molecular and cellular levels.

This has led to a greater understanding of cancer biomarkers for individual patients that in turn are predictive of their clinical course. A corollary of these advances is the ability to risk-adapt treatment for many blood cancers, including lymphoma, myeloma, or CLL, and to optimally apply either current chemoimmunotherapy approaches or to employ newer agents to achieve better outcomes for our patients.

Dr. Rajkumar: In multiple myeloma, there is a move toward early diagnosis and the initiation of treatment before organ and bone damage occurs.

We have been treating myeloma only when we see end-organ damage. That continued on page 50

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Physiatry in Discussion Roundtable Oncology Hematologic Malignancies continued from page 49

was okay when we had limited options for therapy, but now that our treatments are very effective and prevent complications, it doesn’t make sense to wait for complications before we initiate therapy, particularly when the complications are so devastating, such as serious bone fractures or kidney failure. So the main area that has changed and will be changing substantially over the next few years is in the use of biomarkers to diagnose myeloma and start therapy early.

We are also going to see clinical trials for patients with smoldering myeloma to investigate how to delay or prevent disease progression.

Genomic Sequencing What are you learning about these cancers from genomic sequencing, including new mutations, subtypes, and treatment strategies?

Dr. D. Williams: We are finding many new mutations in leukemia, and we are just beginning to understand how to use genes to predict treatment response and disease outcome as well as how to define risk factors for the development of side effects and bad outcomes. Details of these types of findings will be presented at the ASH Annual Meeting.

In terms of new therapy for leukemia, this is a pretty exciting time because there are several aspects of gene therapy that are evolving in the treatment of the disease. One is the growth of the gene therapy platform using hematopoietic stem cells to expand indications. We now have a half-dozen diseases where stem cell gene therapy has been clearly shown to effect what appears to be cure of the disease. As a next step, that modality will likely be applied to treat diseases that we would not have thought about treating in this way—for example, the use of progeny of gene-modified hematopoietic stem cells with blood as a delivery system for cross-correction of diseases that we do not consider to be stem cell diseases.

Another evolving area is the identification of new targets that can generate CAR-modified T-cells to recognize a specific protein on tumor cells. The big success so far is in CAR T-cells targeting CD19 in B-cell leukemias. But many other antigens will be identified and then exploited for immune therapy, and that is what a lot of basic research is currently exploring.

So immunomodulation as an approach to therapy, immune therapy in the form of CAR T cells, and continued

study results show that adding lenalidomide to R-CHOP abrogates the adverse impact of the non–germinal center Bcell diffuse large B-cell lymphoma.2 That combination may become a standard of care in the treatment of this diffuse large B-cell lymphoma subtype if ongoing studies confirm benefit.

Dr. Rajkumar: Cytogenetically, there are at least six distinct types of myeloma. Many of them have a unique presentation, clinical course, response to therapy, and prognosis. Myeloma is

As we go forward, we are going to see more selective use of stem cell transplantation for the non-ALL lymphoid malignancies as regimens improve to provide deep remissions, as assessed by minimal residual disease markers or circulating tumor DNA, and as consolidation or maintenance strategies are developed via immunotherapeutics and targeted agents.

—Michael E. Williams, MD, ScM

unraveling of the molecular landscape of tumors will all allow precision medicine to move forward.

Dr. M. Williams: In lymphoma, we now recognize molecular subtypes that are clinically relevant. A good example is diffuse large B-cell lymphoma. There are at least two major subtypes based on cell of origin: germinal center B-cell, and non–germinal center B-cell, which includes the activated B-cell subtype. Patients appear to have different outcomes whether they are treated with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) or dose-adjusted EPOCH-R (etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab).

The non–germinal center B-cell subtype, which has a poorer prognosis than germinal center B-cell, can be very responsive to lenalidomide (Revlimid) or ibrutinib (Imbruvica), so there is a rationale for incorporating these drugs into initial treatment to improve patient outcomes in poor-risk settings. Early

a rare disease, and it has been difficult to do trials in each of the disease subtypes. But we have learned that certain types of myeloma respond better to specific treatment approaches.

For example, high-risk patients with t(4;14) myeloma respond well to bortezomib and require bone marrow transplantation followed by ­bortezomib maintenance; the overall survival of patients with deletion 17p can be improved with bortezomibbased maintenance therapy; and patients with chromosomal trisomies are exquisitely sensitive to lenalidomide. So we can now tailor treatments depending on the baseline cytogenetic type of myeloma without resorting to genomic sequencing and instead incorporate standard fluorescence in situ hybridization (FISH) studies to inform treatment strategies. We have been using FISH mainly for prognosis, but increasingly, FISH and newer genomic approaches are being used to predict response and select treatments for myeloma.

Through sequencing studies, we are just beginning to understand the extent of genomic abnormalities in myeloma.

We have learned that there are many recurrent mutations, but each one is only seen in a small number of patients.

Some mutations are not targetable, but some are—for example, the BRAF V600E mutation, which is seen in about 5% of patients with myeloma. There are already patients with the BRAF mutation who have been treated with vemurafenib (Zelboraf) and have had sustained responses. We are trying to get myeloma patients included in the NCIMolecular Analysis for Therapy Choice (MATCH) clinical trial so we can identify new targeted therapeutic options.

In terms of new therapies, there are many in development, and some are close to being FDA-approved. At least three new proteasome inhibitors have shown activity in myeloma: ixazomib (MLN9708), oprozomib (ONX0912), and marizomib (NPI-0052).

We are also going to have improved immunomodulatory agents. Although we welcome new proteasome inhibitors and immunomodulatory agents, merely having more drugs in the same class is not going to be a major advance.

It is more important to identify new drugs that have a different mechanism of action than the ones we already know work in myeloma.

In that regard, we are poised for at least two monoclonal antibodies to be approved by the FDA within the next few months. One is elotuzumab, which, in combination with lenalidomide and dexamethasone, has produced significant improvement in response rate and progression-free survival in relapsed/refractory myeloma in a phase III trial.3 The other is daratumumab, which binds to CD38 and has shown single-agent activity against relapsed/refractory disease in about one-third of myeloma patients studied. (Editor’s Note: Daratumumab was approved shortly before this issue of The ASCO Post went to press.)

Close on the heels of these two agents is another monoclonal antibody continued on page 55

57th ASH Annual Meeting and Exposition Watch upcoming issues of The ASCO Post for coverage of the 57th Annual Meeting of the American Society of Hematology, December 5–8, 2015, in Orlando.

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

NSCLC=non-small cell lung cancer.

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

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

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events.

In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel.

Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs)

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

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

Hypertension

• An increased incidence of severe hypertension occurred in patients

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

CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs. Gastrointestinal Perforations

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

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

Impaired Wound Healing

• Impaired wound healing can occur with antibodies inhibiting the VEGF

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

Clinical Deterioration in Child-Pugh B or C Cirrhosis

• Clinical deterioration, manifested by new onset or worsening

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

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

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

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

Proteinuria Including Nephrotic Syndrome

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

for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

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

1.0

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

10.5

15% INCREASE IN MEDIAN OS

MONTHS

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

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

3

6

12

15

18

21

24

27

30

33

36

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

9

527

415

329

231

156

103

70

45

23

11

2

0

501

386

306

197

129

86

56

36

23

9

0

0

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

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

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

Thyroid Dysfunction

• Monitor thyroid function during treatment with CYRAMZA.

Embryofetal Toxicity

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

when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions

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

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

• The most common serious adverse events with CYRAMZA plus docetaxel

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

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

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

• Treatment discontinuation due to adverse reactions occurred more

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

• For patients with nonsquamous histology, the overall incidence of

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

the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.

• Clinically relevant adverse reactions reported in ≥1% and <5% of

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

Drug Interactions

• No pharmacokinetic interactions were observed between ramucirumab

and docetaxel.

Use in Specific Populations

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

fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks.

No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

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

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

• Females of Reproductive Potential: Advise females of reproductive potential

that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page.

RB-L HCP ISI 24APR2015 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.

Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/fda-docetaxel/print. Accessed August 26, 2014.

4. National Cancer Institute. Cancer drug information. FDA approval for ramucirumab. http://www.cancer.gov/ cancertopics/treatment/drugs/fda-ramucirumab#nsclc. Accessed May 4, 2015. 5. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 6. Garon EB, Ciuleanu T-E, Arrieta O, et al.

Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

RB96549 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved.

CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.

In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

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

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

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women.

Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease.

Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intratumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology.

Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation.

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

For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%).

The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 CYRAMZA plus docetaxel Placebo plus docetaxel (N=627) (N=618) Adverse Reactions (MedDRA) System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10 Neutropenia 55 49 46 40 Thrombocytopenia 13 3 5 <1 Gastrointestinal Disorders Stomatitis/Mucosal inflammation 37 7 19 2 Eye Disorders Lacrimation increased 13 <1 5 0 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1 Vascular Disorders Hypertension 11 6 5 2 Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36).

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information.

PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event.

• Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment.

• Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. Additional information can be found at www.CYRAMZAhcp.com.

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2015, Eli Lilly and Company. All rights reserved.

RB-L HCP BS 04MAY2015 CYRAMZA® (ramucirumab) injection

RB-L HCP BS 04MAY2015

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Roundtable Discussion Hematologic Malignancies continued from page 50

against CD38—SAR650984—which is also highly active in myeloma, and we will see how it fits in as a therapeutic option for patients. Then there is dinaciclib, a novel cyclin-dependent kinase inhibitor, which has shown singleagent activity in relapsed disease; venetoclax, a Bcl-2 selective inhibitor, which has shown responses as a single agent in some types of myeloma; LGH447, a Pan-Pim kinase inhibitor that has also shown single-agent activity in myeloma; and finally, there is filanensib, which is a kinesin spindle protein inhibitor that has shown single-agent activity in myeloma as well.

Many drugs in myeloma have shown synergistic activity when used in combination with known active drugs. But the drugs that I have mentioned are of particular interest because, with the exception of elotuzumab, they all have single-agent activity in relapsed/refractory disease. Thus, they are likely to become very powerful tools for us in the near future.

There is also a great deal of interest in immunotherapy with either CAR T cells or checkpoint inhibitors. CAR T cells directed against B-cell maturation antigen are going to be tested in many centers. There are also trials investigating checkpoint inhibitors in this setting. Time will tell how immunotherapy fits in as a viable treatment for myeloma.

Stem Cell Transplant With so many effective therapies available for hematologic cancers, what is the role of stem cell transplantation in these diseases?

Dr. M. Williams: Autologous stem cell transplantation remains a very important aspect of management for patients with relapsed diffuse large B-cell lymphoma and Hodgkin lymphoma, as well as some cases of relapsed follicular lymphoma. Autologous stem cell transplantation is also important in treating younger and medically fit patients with mantle cell lymphoma as consolidation after first-line therapy.

I think as we go forward we are going to see more selective use of stem cell transplantation for the non-ALL lymphoid malignancies as regimens improve to provide deep remissions, as assessed by minimal residual disease markers or circulating tumor DNA, and as consolidation or maintenance strategies are developed via immunotherapeutics and targeted agents.

Dr. Rajkumar: I agree; stem cell

transplant will continue to play a role in blood cancers. As long as myeloma remains incurable, stem cell transplant, particularly autologous transplants, will play a huge role in the treatment of this disease.

Mantle Cell Lymphoma Although there has been a lot of progress in the treatment of non-Hodgkin lymphoma, mantle cell lymphoma remains clinically challenging. What are you learning about the biology of this disease, and what progress has been made in its treatment?

Dr. M. Williams: Survival rates are improving well beyond 5 years for many patients with mantle cell lymphoma given the many effective agents and regimens for the disease, including bortezomib, lenalidomide, and ibrutinib. The clinical spectrum of the disease is also being better appreciated in recent years. About 20% of patients with mantle cell have a very indolent clinical course.

These patients often present with a CLLlike pattern, including lymphocytosis and splenomegaly but little adenopathy, and many can be observed for months or years in some cases before treatment.

At the other end of that spectrum are patients with blastoid variants or very advanced disease who require active treatment right up front. The molecular underpinnings of this spectrum of clinical behavior are now better understood, and identify pathways that can be therapeutically targeted.

Indolent Disease What is the current strategy for treating indolent forms of lymphoma and CLL? Dr. M. Williams: These diseases are very important testing grounds for newer immunotherapeutics and targeted drugs, such as tyrosine kinase inhibitors and proapoptotic agents. We have the opportunity to start moving away from traditional chemotherapy-based treatment to regimens that use very minimal or lower intensity cytotoxics complemented by newer monoclonal antibody and cell signaling or apoptosis targeted agents either alone or incorporated into a backbone anti-CD20/chemotherapybased regimen.

Obstacles to Improved Care What is the biggest obstacle to advancing care for hematologic cancers over the next 5 years?

Dr. D. Williams: I’m a pediatrician, and almost all of the diseases I take care of are considered rare. In pediatrics, we recognized a long time ago that we have to do things collaboratively across many continued on page 56

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Roundtable Discussion Hematologic Malignancies continued from page 55

to therapy. Along with the continued development of work to harness the immune system in the treatment of these malignancies, these are major advances I anticipate in both pediatric and adult oncology.

It is a great time to be a hematologist/

as the goal of therapy, allowing at least some patients to stop therapy once that goal is achieved. We will see the incorporation of immunotherapy in the myeloma treatment paradigm to maintain responses long term.

Finally, if we are lucky, we will cure this disease. n Disclosure: Dr. David Williams has done sponsored research from Bluebird Bio (for non– cancer-related studies and received licensing fees from Bluebird Bio (for non–cancerrelated gene therapy technology). Dr. Michael Williams has been a consultant or advisor for Celgene and Takeda and has received research support from Celgene, Jansen, Pharmacyclics, and Takeda. Dr Rajkumar reported no potential conflicts of interest.

We cannot continue to treat every patient with a onesize-fits-all approach. We will be using a surrogate marker like minimal residual disease as the goal of therapy, allowing at least some patients to stop therapy once that goal is achieved.

—S. Vincent Rajkumar, MD

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What progress do you predict in the treatment of hematologic cancers over the next decade?

Dr. D. Williams: We will increase our understanding of the aberrant pathways that drive both the transformation of normal cells and the initiation of the cancer as well as resistance

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Future Progress

oncologist, and I am very excited to see the fruits of the research done over the References 1. American Cancer Society: Cancer past 20 years come to the clinic. We have many more therapies to offer our pa- Facts & Figures 2015. Available at cancer.org/ S&Hresearch/cancerfactsstatistics/cancerfactsfigtients than we did just 5 years ago.

Dr. M. Williams: I agree, this is ures2015. Accessed November 3, 2015.

2. Nowakowski GS, LaPlant B, Macon a remarkable time to be working on these diseases. Over the next 10 years WR, et al: Lenalidomide combined with I anticipate patients living longer, hav- R-CHOP overcomes negative prognostic ing higher cure rates, and enjoying im- impact of non-germinal center B-cell pheproved quality of life both during and notype in newly diagnosed diffuse large after treatment. We will see a move- b-cell lymphoma: A phase II study. J Clin ment away from reliance on traditional Oncol 33:251-257, 2015.

3. Lonial S, Dimopoulos MA, Palumchemotherapy and radiation therapy to bo A, et al: ELOQUENT-2: A phase III, more effective, less toxic regimens.

Dr. Rajkumar: We are going to randomized, open-label study of lenalidosee more risk-adapted therapy for my- mide (Len)/dexamethasone (dex) with/ eloma. We cannot continue to treat without elotuzumab (Elo) in patients with every patient with a one-size-fits-all relapsed/refractory myeloma (RRMM). approach. We will be using a surrogate 2015 ASCO Annual Meeting. Abstract marker like minimal residual disease 8508. Presented June 2, 2015.

GNH_HER_52783K_JA_D01.indd

couple of antibodies, treatment is going to be prohibitively expensive, especially for patients on continuous therapy.

Another obstacle is in the treatment of high-risk myeloma. Almost all of the progress in this disease is happening in low-risk patients. Patients with highrisk translocations, high-risk gene-expression profiling, or early relapse after first-line therapy still do not do well. We need to design specialty trials for them.

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JOB#: 52783K CLIENT: Genentech DESC: Journal Ad 3-pg FILE NAME: GNH_HER_52783K_JA_D01.indd PG: WangJames/DilenaM AD: R Vetrano-Pyke x4077 PM: B Fu x4416 AE: K McGinty x3950 TRIM: 15.5” x 10.5” BLEED: 17.5” x 11.5” SAFETY: 14.75” x 9.875” PROD: M Haight x4245 FONTS: Myriad Pro (Bold, Regular, Bold Condensed, Light), Helvetica Neue LT Std (45 Light) IMAGES: 52783K_JA_1_fn.tif (CMYK; 300 ppi; 100%), 52783K_glow_fn.psd (CMYK; 300 ppi; 100%), Perjeta_US_MBC_NEO_4C.eps (69.5%) INKS: Cyan, Magenta, Yellow, Black DOC PATH: Macintosh HD:Users:wangjames:D...:52783K:GNH_HER_52783K_JA_D01.indd NOTES: None

centers to have enough patients to conduct informative clinical trials. That is a paradigm that will have to be used in adult diseases as we get more personalized in our approaches to treatment.

Dr. M. Williams: I would answer that in two ways. The biggest obstacle from a scientific and clinical standpoint of so many promising new agents is finding the resources and patient base to test new regimens, and creating well-designed clinical trials to clearly establish where they fit into current treatment algorithms. For example, if you are going to combine two targeted drugs, how do you rationally select the agents? How do you dose, schedule, and sequence them?

The other obstacle is establishing the value, not just the cost, of care. The cumulative cost for individual patients and for society is not sustainable at the current levels, thus creating an oncologic, economic, and societal mandate to justify approaches to the management of hematologic malignancies and, indeed, all cancers.

Dr. Rajkumar: For me, the biggest obstacle is the lack of large randomized trials that test treatment strategies—not just one regimen vs another, but overall strategies. For example, trials might test combination vs sequential approaches, ie, cure vs control.

Such trials are very difficult to design because the sample sizes have to be huge, and we need to improve patient

accrual in order to achieve those goals.

I agree with Dr. [Michael] Williams that cost of care is another huge obstacle. The cost of a triplet combination of VRD (bortezomib, lenalidomide, and dexamethasone) is already nearly $200,000 a year, and if you add in a

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Alfred Goldberg, PhD, and Paul Richardson, MD, to Present 2015 ASH Ernest Beutler Lecture

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he American Society of Hematology (ASH) will honor Alfred Goldberg, PhD, of Harvard Medical School, and Paul Richardson, MD, of Dana-Farber Cancer Institute, with the 2015 Ernest Beutler Lecture and Prize for their significant research advances in the area of proteasome inhibitors and their development as novel therapies for multiple myeloma.

development of proteasome inhibition for the therapy of relapsed and refractory multiple myeloma and its rapid integration into initial treatment as well as maintenance therapy and consolidation.

Alfred Goldberg, PhD Dr. Goldberg is Professor of Cell Biology at Harvard Medical School. He B:8.75” earned his doctorate inT:7.75” physiology from Harvard University. S:6.875”

Dr. Goldberg’s major discoveries are related to the mechanisms and physiological regulation of protein breakdown in cells and the importance of this procontinued on page 58

Alfred Goldberg, PhD

Paul Richardson, MD

The Ernest Beutler Lecture, named for the late Ernest Beutler, MD, Past President of ASH, is a two-part lectureship that recognizes major translational advances related to a single topic. The award honors two individuals, one who has enabled advances in basic science and another for achievements in clinical science or translational research.

Drs. Goldberg and Richardson will present their lecture, “Understanding the Proteasome: From Protein Degradation to Disease Therapy,” on Monday, December 7, at the 57th ASH Annual Meeting and Exposition in Orlando, Florida. The lecture will be moderated

by Kenneth C. Anderson, MD, Director of the Lebow Institute of Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute and a recognized leader in the area of multiple myeloma.

During their lecture, Dr. Goldberg will address the proteasome’s unusual mechanisms, critical functions, and the preclinical development of the proteasome inhibitors, which are now widely used in the clinic and as research tools in cell biology and immunology. Dr. ­Richardson will focus on the clinical

STRENGTHEN HER DEFENSE

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

Indication

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

Boxed WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity • PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function.

• Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death.

Advise patients of these risks and the need for effective contraception.

Please see additional select Important Safety Information throughout, and the Brief Summary of full Prescribing Information including Boxed WARNINGS on the following pages.

Announcements ASH Ernest Beutler Lecture continued from page 57

cess in human disease. His laboratory first discovered the ATP-dependent system for protein breakdown, now termed the ubiquitin-proteasome pathway. After identifying and characterizing the proteasome, Dr. Goldberg’s lab was the first to demonstrate that its function in

cells can be inhibited with small molecules, initiating the research effort that led to the development of bortezomib (Velcade), a proteasome inhibitor now commonly used to treat multiple myeloma. Dr. Goldberg’s current work is focused on the regulation of proteasome function and its roles in eliminating misfolded proteins that cause neurodenera-

tive disease and the excessive protein in immune recognition.

Dr. Goldberg is among the top 1% of the most highly cited researchers in the life sciences. He is an elected member of the National Academy of Sciences and the American Academy of Arts and Sciences, S:6.875” and is a fellow of the American Association for the Advancement of Science.

Paul Richardson, MD Dr. Richardson is Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and the R.J. Corman Professor of Medicine at Harvard Medical School. He earned his medical degree at the Medical College of St. Bartholomew’s Hospital,

PERJETA + Herceptin (trastuzumab) + docetaxel

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

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

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Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction (LVEF) assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

Important Safety Information

Additional Important Safety Information

• PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects.

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

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Boxed WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity

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

HR=hazard ratio; CI=confidence interval.

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

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PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

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

Infusion-Associated Reactions

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

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University of London, and completed Internal Medicine residencies at Beth Israel Deaconess Medical Center and the St. Bartholomew’s, Newcastle General, Freeman, and the Royal Marsden Hospitals. He completed fellowships in hematology and oncology at Baystate Medical Center, Tufts University School of Medicine, and Dana-Farber before

joining the Dana-Farber Department of Medical Oncology.

Dr. Richardson is renowned for his translational research on small molecules as novel treatments for multiple myeloma and has been integral in the development of new drugs in the field, most S:6.875” lenalidomide (Revnotably bortezomib, limid), pomalidomide (Pomalyst), and

panobinostat (Farydak), as well as the next-generation proteasome inhibitors ixazomib and marizomib. His work has established lenalidomide, bortezomib, and dexamethasone as a new treatment standard for both newly diagnosed patients and those with relapsed or refractory myeloma. Most recently, his areas of clinical innovation have included the

development of breakthrough monoclonal antibodies including elotuzumab and daratumumab for the treatment of myeloma. His research has also focused on regimen-related toxicity, including treatment-emergent neuropathy in myeloma and the development of defibrotide to treat hepatic veno-occlusive disease complicating stem cell transplantation. n

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

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

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

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

HER2 Testing

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

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Printed in USA.

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Most Common Adverse Reactions • In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at 1-888-835-2555.

For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp.

Please see additional select Important Safety Information throughout, and the Brief Summary of full Prescribing Information including Boxed WARNINGS on the following pages.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.2.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed April 23, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline.

J Clin Oncol. 2014;32(19):2078-2099. 3. PERJETA Prescribing Information. Genentech, Inc. 2015.

4. Data on file. Genentech, Inc. 5. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

B:11.5”

Hypersensitivity Reactions/Anaphylaxis

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

T:10.5”

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

S:9.875”

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

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Announcements

ASH Honors Nancy Speck, PhD, and Karl Welte, MD, With 2015 Henry M. Stratton Medal

T

he American Society of Hematology (ASH) will recognize Nancy Speck, PhD, of the University of Pennsylvania Perelman School of Medicine, and Karl Welte, MD, of Hannover

Medical School, with the 2015 Henry M. Stratton Medal for their seminal contributions in the areas of basic and clinical/translational hematology research, respectively.

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012

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

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in eventfree survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)].

Limitations of Use: • The safety of PERJETA as part of a doxorubicincontaining regimen has not been established.

• The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established.

4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

5 WARNINGS AND PRECAUTIONS 5.1 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)].

Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxeltreated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel.

Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with

The Henry M. Stratton Medal is named after the late Henry Maurice Stratton, cofounder of Grune and Stratton, the medical publishing house that first published ASH’s journal Blood. trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients.

In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed

by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient.

PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m 2 of doxorubicin or its equivalent.

Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)].

5.2 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug or within 7 months following the last dose of PERJETA in combination with trastuzumab, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known.

5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion.

The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency

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The prize honors two senior investigators whose contributions to both basic and clinical/translational hematology research are well recognized and have taken place over a period of several of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.

During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.

In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2.

Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)].

5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1.

In Study 2, two patients in the PERJETA- and docetaxeltreated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grade 3 – 4.

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)].

Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)].

5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive

by FISH, but did not demonstrate protein overexpression

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

Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Left Ventricular Dysfunction [see Warnings and Precautions (5.1)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)]

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years. Drs. Speck and Welte will accept their awards on Tuesday, December 8, during the 57th ASH Annual Meeting and Exposition in Orlando, Florida.

Nancy Speck, PhD Dr. Speck is Professor of Cell and Developmental Biology at the University of Pennsylvania and Associate

Nancy Speck, PhD

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional 2.75 years of follow-up (median total follow-up of 50 months) in Study 1.

The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 Placebo PERJETA + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades Grades, % 3–4, %

All Grades, %

Grades 3–4, %

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

Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA‑treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebotreated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebotreated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment.

All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).

Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1.

The most common adverse reactions (>30%) were alopecia, neutropenia, diarrhea, and nausea.

The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

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

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

27.1 0.0 26.2 0.9 12.0 17.8 0.0 20.6 1.9 2.8

0.0 25.5 1.1 0.0 16.0 2.1

10.3 0.0

2.8

0.0

0.9

0.0

5.3

0.0

21.5 0.0 26.2 1.9 10.3 0.0 16.8 0.0

2.8 8.3

0.0 25.5 0.0 0.0 8.5 0.0

66.4 0.0 65.4 0.0 2.8 21.5 1.9 26.2 0.9 11.1

0.0 67.0 0.0 0.0 28.7 1.1

Skin and subcutaneous tissue disorders Alopecia Rash

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Director of Penn’s Institute for Regenerative Medicine. She co-leads the Hematologic Malignancies Program at Penn’s Abramson Cancer Center and is an investigator at the Abramson Family Cancer Research Institute. Over the course of her 30-year career, Dr. Speck has made key contributions to the understanding of developmental hemaGastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 Peripheral Sensory Neuropathy 12.1 0.9 8.4 0.9 1.9 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 Metabolism and nutrition disorders Decreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0

54.3 36.2 16.0 9.6

4.3 1.1 2.1 0.0

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

0.0

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

Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (>30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (>2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity.

The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3.

topoiesis, as well as the translation of these findings into leukemogenesis.

Her contributions to the field include the identification of proteins Runx1 and CBFβ, mutations of which are frequently found in leukemia. Dr. Speck’s careful biochemical and molecular characterization of these factors—both continued on page 62

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before and after linking them to leukemia—has enabled rapid progress in the understanding of their role in normal and malignant hematopoiesis.

Dr. Speck earned her PhD in biochemistry from Northwestern University and completed postdoctoral Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab

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

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

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

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

research fellowships in retroviral pathogenesis and eukaryotic gene regulation at the Whitehead Institute for Biomedical Research and at MIT. She joined the University of Pennsylvania in 2008.

Dr. Speck is a member of ASH and has chaired study sections at the National Institutes of Health and the Leukemia and Lymphoma Society.

Karl Welte, MD Dr. Welte is Senior Professor and Head of the Department of Molecular Hematopoiesis at Hannover Medical School. He has devoted his career to the study of neutrophil development and treatment. Dr. Welte is best known for his groundbreaking work to purify and assess the biochemical characteristics of

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

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

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

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

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, the patient should be apprised of the potential hazard to the fetus.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg.

These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryofetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.

8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

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Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175).

8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 7 months following the last dose of PERJETA in combination with trastuzumab.

granulocyte colony-stimulating factor (G-CSF) and his work to clone and produce recombinant human G-CSF (filgrastim [Neupogen]). He was involved in the design and performance of the phase I–III studies with G-CSF in chemotherapy-induced neutropenias and initiated the first clinical use of G-CSF in congenital neutropenias in Europe.

He has also made major contributions to the identification of germline mutations causing congenital neutropenias such as ELANE, HAX1, and G6PC3, as well as aberrant G-CSF signaling in patients with congenital neutropenia. Dr. Welte’s studies of the natural history of leukemia in severe congenital neutropenia have extended to the molecular pathways of leukemogenesis, helping to pave the way for new treatments for the disease.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)].

8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab.

10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

17 PATIENT COUNSELING INFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.1)] • Advise pregnant women and females of reproductive potential that PERJETA exposure can result in fetal harm, including embryo-fetal death or birth defects [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)] • Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 7 months following the last dose of PERJETA in combination with trastuzumab [see Warnings and Precautions (5.2) and Use in Special Populations (8.6)] • Advise nursing mothers treated with PERJETA to discontinue nursing or discontinue PERJETA, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.3)] • If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who are exposed to PERJETA during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.6)]

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

PERJETA is a registered trademark of Genentech, Inc. 06/15 PER/041015/0031(2) © 2015 Genentech, Inc. 10139000

Karl Welte, MD

After earning his medical degree from the Free University of Berlin, Dr. Welte completed an internship at City Hospitals Berlin, a residency in pediatrics at the Free University of Berlin, and fellowships in both pediatrics and molecular biology at the University of Frankfurt. Dr. Welte joined Hannover Medical School in 1987 and became Head of the Department of Pediatric Hematology and Oncology in 1996. In 2008, he became the first Lower Saxony Professor in Hannover, Germany.

Dr. Welte is a member of ASH, the European Hematology Association, and the German Society of Pediatric Hematology and Oncology, and an elected member of the German Academy of Sciences. n

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PAGE 63

In the Clinic Dermatologic Oncology

Ipilimumab in Adjuvant Treatment of Cutaneous Melanoma With Nodal Involvement

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 28, 2015, ipilimumab (Yervoy) was approved for adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes > 1 mm who have undergone complete resection, including total lymphadenectomy.1,2

Supporting Efficacy Data Approval was based on improvement in recurrence-free survival in a double-blind trial in which 945 patients with resected stage IIIA (lymph node > 1 mm), IIIB, and IIIC (with no intransit metastases) cutaneous melanoma were randomly assigned to receive ipilimumab at 10 mg/kg (n = 471) or placebo (n = 474) via intravenous infusion for four doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at week 24 up to a maximum of 3 years.2,3

OF NOTE Ipilimumab blocks the interaction of CTLA-4 with its ligands, thereby increasing activation and proliferation of tumor-infiltrating T-effector cells and possibly increasing antitumor immune response.

Overall, patients had a median age of 51 years (range = 18–84 years), 62% were male, 99% were white, and 94% had Eastern Cooperative Oncology Group performance status of 0. Disease stage was IIIA in 20%, IIIB in 44%, and IIIC in 36%. Ipilimumab-treated patients received a median of four doses (range = 1–16), and 36% received ipilimumab for > 6 months.

Median recurrence-free survival, the primary endpoint, was 26 months (95% confidence interval [CI] = 26–39 months) in the ipilimumab group vs 17 months (95% CI = 13–22 months) in the placebo group (hazard ratio = 0.75, P < .002).

How It Works Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands (CD80/CD86). CTLA-4 is a negative regulator of T-cell activity. Blockade of CTLA-4 increases T-cell activation and proliferation, including activation and proliferation of tumor-infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including antitumor immune response.

How It Is Used The recommended dose of ipilimumab in the new indication is 10 mg/ kg given intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years. For toxicity, doses are omitted, not delayed.

Ipilimumab should be permanently discontinued and systemic high-dose corticosteroid therapy should be started for severe immune-mediated adverse reactions. Recommended treatment modifications for immune-mediated adverse reactions include withholding of treatment for symptomatic endocrinopathy and resuming treatment after complete or partial resolution to grade 0 or 1 in patients receiving < 7.5 mg/d of prednisone or its equivalent.

Treatment should be permanently discontinued for symptomatic reactions lasting ≥ 6 weeks and if the prednisone (or equivalent) dose cannot be reduced to ≤ 7.5 mg/d. Ipilimumab should be permanently discontinued for ophthalmologic grade 2 to 4 reactions that require systemic treatment or that do not improve to grade 1 within 2 weeks during topical therapy.

For other immune-mediated adverse reactions, treatment should be withheld for grade 2 adverse events and can be resumed after complete or partial resolution to grade 0 or 1 in patients receiving < 7.5 mg/d of prednisone/equivalent.

It should be permanently discontinued for grade 2 reactions lasting ≥ 6 weeks, if prednisone/equivalent dose cannot be reduced to ≤ 7.5 mg/d, and for grade 3 or 4 adverse events.

Safety Profile The most common adverse events of any grade in the ipilimumab group

Expanded Indication for Ipilimumab ■■ Ipilimumab (Yervoy) was approved for adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes > 1 mm who have undergone complete resection.

■■ The recommended dose of ipilimumab in the new indication is 10 mg/kg given intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years.

in the phase III trial were rash (50% vs 20% in placebo group), diarrhea (49% vs 30%), fatigue (46% vs 38%), pruritus (45% vs 15%), headache (33% vs 18%), and weight loss (32% vs 9%). The most common grade ≥ 3 adverse events were diarrhea (10% vs 2.1%) and colitis (8% vs 0.4%). The most common grade 3 or 4 laboratory abnormalities were increased alanine transaminase (10% vs 0%), increased aspartate transaminase (9% vs 0.2%), and increased lipase (9% vs 4.5%). Ipilimumab was discontinued due to adverse events in 52% of patients.

terocolitis, dermatitis, neuropathy, and endocrinopathy and should undergo evaluation with clinical chemistries, including liver function tests, adrenocorticotropic hormone level, and thyroid function tests, before starting treatment and before each dose.

Ipilimumab also carries warnings/ precautions for immune-mediated adverse reactions, immune-mediated hepatitis, immune-mediated endocrinopathies, and embryofetal toxicity. Women should discontinue breast-feeding during treatment. n

OF NOTE

References 1. U.S. Food and Drug Administration: Ipilimumab (Yervoy). Available at www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm470061.htm. Accessed November 4, 2015.

2. Yervoy (ipilimumab) injection for intravenous use prescribing information, Bristol-Myers Squibb, October 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/125377s073lbl.pdf.

Accessed November 4, 2015.

3. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Adjuvant ipilimumab versus placebo after complete resection of highrisk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial.

Lancet Oncol 16:522-530, 2015.

Ipilimumab carries a boxed warning for immune-mediated adverse reactions, including fatal cases.

Grade 3 to 5 immune-mediated adverse events occurred in 41% of ipilimumab recipients, including enterocolitis in 16%, hepatitis in 11%, endocrinopathy in 8%, dermatitis in 4%, and neuropathy in 1.7%. The five treatment-related deaths in ipilimumab-treated patients were due to immune-mediated adverse reactions of enterocolitis in three patients, Guillain-Barré syndrome in one patient, and myocarditis in one patient.

Ipilimumab carries a boxed warning for immune-mediated adverse reactions, including fatal cases. These reactions may involve any organ system; however, the most common severe reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of reactions have onset during treatment; however, a minority occurred weeks to months after discontinuation of ipilimumab.

Patients should be routinely assessed for signs and symptoms of en-

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).

Treating patients with polycythemia vera (PV)

When monitoring hematocrit (Hct), keeping levels below 45% made a difference in the rate of thrombotic complications > In a study published in The New England Journal of Medicine in 2013, 365 adult patients with PV were randomized into 2 groups1: More-intensive treatment, n = 182, target Hct <45% (low Hct)

Less-intensive treatment, n = 183, target Hct 45% to 50% (high Hct)

The rate of cardiovascular death and major thrombosis was ≈4-fold higher with Hct level of 45% to 50% compared with Hct level of <45% Rate of Cardiovascular Death and Major Thrombosis: Study Published in The New England Journal of Medicine, 2013 Probability of Remaining Event-free

Primary End Point: Death From Cardiovascular Causes or Thrombotic Events 1.0

Low Hct (<45%)

P = 0.004 by log-rank test

0.9

High Hct (45% to 50%)

0.8

Hazard ratio Low Hct High Hct

0.7 0.0

0

Number at risk Low Hct 182 (0) High Hct 183 (6)

6

5/182 (2.7%) 18/183 (9.8%) 12

18

1.00 3.91 (95% CI, 1.45%-10.53%) 24

30

36

42

48

95 (0) 92 (2)

62 (0) 54 (1)

18 (0) 12 (0)

0 1

Months 177 (1) 168 (0)

168 (2) 160 (3)

154 (1) 143 (4)

129 (1) 110 (2)

Adapted with permission from Massachusetts Medical Society.

> In this randomized clinical trial: • • • • • •

Baseline characteristics were balanced between both groups ≈50% had received an initial diagnosis of PV within 2 years before randomization 67.1% were at high risk because of advanced age or previous thrombosis Therapy options for maintaining Hct levels were phlebotomy, cytoreductive drugs, or both The composite primary end point was the time until death from cardiovascular causes or major thrombotic events Platelet levels did not differ in the 2 arms, whereas white blood cell counts persisted at significantly higher levels in the high-Hct group compared with the low-Hct group (P < 0.001)

Reference: 1. Marchioli R et al. N Engl J Med. 2013;368(1):22-33.

45%

more or less?

Hct

Š 2015, Incyte Corporation. All rights reserved. EDU-1351b 10/15

The ASCO Post | NOVEMBER 25, 2015

PAGE 66

In the Clinic Dermatologic Oncology

Talimogene Laherparepvec for Treatment of Unresectable Cutaneous, Subcutaneous, and Nodal Melanoma Lesions

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 27, 2015, talimogene laherparepvec (Imlygic) was approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. It is the first U.S. Food and Drug Administration–approved oncolytic virus therapy.

Supporting Efficacy Data Approval was based on the finding of an improved durable response rate in an open-label phase III trial in which 436 patients with stage IIIB, IIIC, or IV melanoma considered to be unresectable were randomly assigned to receive talimogene laherparepvec (n = 295) or granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]).1,2 Talimogene laherparepvec was given via intralesional injection at an initial concentration of 106 plaque-forming units (PFU)/mL on day 1 followed by a concentration of 108 PFU/mL on day 21 and every 2 weeks thereafter at a dose of up to 4 mL per visit. The agent was injected into only cutaneous, subcutaneous, or nodal melanoma lesions. GMCSF was given subcutaneously in 28-day cycles consisting of 125 μg/m2 daily for 14 days followed by 14 days with no treatment. Patients were to be treated for at least 6 months or until there were no injectable lesions.

Overall, patients had a mean age of 63 years, 57% were men, 98% were white, 70% had Eastern Cooperative Oncology Group performance status of 0, 70% had stage IV (27% M1a, 21% M1b, and 22% M1c), and 30% had stage III disease, 53% had received prior therapy for melanoma (other than surgery, adjuvant

OF NOTE Talimogene laherparepvec is a genetically modified live oncolytic herpes virus therapy that causes lysis of tumors, followed by release of tumor-derived antigens.

therapy, or radiation), and 58% were seropositive for wild-type herpes simplex virus 1 (HSV-1).

The durable response rate, defined as the proportion of patients with complete or partial response maintained continuously for ≥ 6 months, was 16.3% in the talimogene laherparepvec group vs 2.1% in the GM-CSF group (unadjusted relative risk = 7.6, P < .0001). Median time to response was 4.1 months (range = 1.2–16.7 months) in the talimogene laherparepvec group. Median overall survival was 22.9 vs 19.0 months (P = .116).

How It Works Talimogene laherparepvec is a genetically modified live oncolytic herpes virus therapy designed to replicate within tumors and to produce the immune stimulatory protein GM-CSF. It causes lysis of tumors, followed by release of tumorderived antigens; this, together with vi-

OF NOTE Talimogene laherparepvec carries warnings and precautions for accidental exposure to the agent, herpetic infections, injection-site complications, immune-mediated events, and plasmacytoma at the injection site.

mL for > 0.5 cm to 1.5 cm, and up to 0.1 mL for ≤ 0.5 cm.

Treatment should continue for ≥ 6 months unless other treatment is required or until there are no injectable lesions to treat. Treatment should be reinitiated if new unresectable cutaneous, subcutaneous, or nodal lesions appear after a complete response.

Safety Profile In the phase III trial, the most common adverse events of any grade in

Talimogene Laherparepvec for Melanoma ■■ The oncolytic virus therapy talimogene laherparepvec (Imlygic) was approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.

■■ The recommended starting dose is up to a maximum of 4 mL at a concentration of 106 PFU/mL. For the second dose (3 weeks later) and all subsequent treatments (2 weeks after prior administration), the recommended dose is up to 4 mL at 108 PFU/ mL.

rally derived GM-CSF, may promote an antitumor immune response. The exact mechanism of action is unknown.

How It Is Used Talimogene laherparepvec is injected into cutaneous, subcutaneous, or nodal lesions that are visible, palpable, or detectable by ultrasound guidance. The total injection volume for each treatment visit should not exceed 4 mL for all injected lesions combined.

The recommended starting dose is up to a maximum of 4 mL at a concentration of 106 PFU/mL. The second dose should be given 3 weeks after the first, and all subsequent treatments, including reinitiation, should be given at 2 weeks after the prior dose. For the second dose and all subsequent treatments, the recommended dose is up to 4 mL at 108 PFU/ mL. Recommended injection volume by lesion size is up to 4 mL for > 5 cm, up to 2 mL for > 2.5 cm to 5 cm, up to 1 mL for > 1.5 cm to 2.5 cm, up to 0.5

talimogene laherparepvec recipients occurring at an incidence ≥ 5% higher vs GM-CSF recipients were fatigue (50% vs 36%), chills (49% vs 9%), pyrexia (43% vs 9%), nausea (36% vs 20%), and influenza-like illness (30% vs 15%). Grade ≥ 3 adverse events were of low incidence; the most common was cellulitis. Pyrexia, chills, and influenza-like illness were more frequent during the first 3 months of treatment but also occurred thereafter.

Other adverse events in talimogene laherparepvec patients included glomerulonephritis, vitiligo, and oral herpes.

Talimogene laherparepvec carries warnings and precautions for accidental exposure to the agent, herpetic infections, injection-site complications, immune-mediated events, and plasmacytoma at the injection site.

Accidental exposure may lead to transmission of the agent and herpetic infection. Health-care providers and close patient contacts should avoid direct contact with injected lesions, dress-

ings, or body fluids of treated patients.

Health-care providers who are immunocompromised or pregnant should not prepare or administer the agent. If accidental exposure occurs, exposed individuals should clean the affected area.

Patients who develop herpetic infections should be advised to follow standard hygienic practices to prevent viral transmission. The risks and benefits of continuing treatment should be considered if persistent infection or delayed healing develops at the injection site.

Risks and benefits of treatment should be considered before starting treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events. Risks and benefits of treatment should be considered in patients with multiple myeloma or in whom plasmacytoma develops during treatment.

The agent is contraindicated in immunocompromised patients and in pregnant patients. Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with talimogene laherparepvec. Breastfeeding women should discontinue treatment or nursing. n References 1. Imlygic (talimogene laherparepvec) suspension for intralesional injection prescribing information, Amgen, Inc, October 2015. Available at http://www.imlygic. com/. Accessed November 6, 2015.

2. Andtbacka RH, Kaufman HL, Collichio F, et al: Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33:2780-2788, 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).

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The ASCO Post | NOVEMBER 25, 2015

PAGE 68

Journal Spotlight Breast Cancer

Accelerated Partial-Breast vs Whole-Breast Irradiation After Surgery for Early Breast Cancer

By Matthew Stenger

A

s reported in The Lancet by Vratislav Strnad, MD, of University Hospital Erlangen, Germany, and colleagues, 5-year results of a phase III noninferiority trial showed no difference in local relapse, disease-free survival, or overall survival with adjuvant accelerated partial breast irradiation using multicatheter brachytherapy vs whole-breast irradiation in women with stage 0, I, or IIA breast cancer undergoing breast-conserving treatment.1

dose of 50 Gy, with pulses of 0.60 to 0.80 Gy/hour at 1 pulse/24 hours a day.

After randomization, 98 patients assigned to whole-breast irradiation and 42 assigned to accelerated partial-breast irradiation either withdrew consent or were excluded due to administrative error; in addition, some patients refused assigned treatment and asked for the alternative treatment after learning the result of randomization. In total, 633 patients in the accelerated partial-breast irradiation group

Accelerated partial breast irradiation using multicatheter brachytherapy can be regarded as a valid alternative treatment option after breast-conserving surgery and can be offered for all low-risk breast cancer patients in clinical routine.

—Vratislav Strnad, MD, and colleagues

This trial was conducted by the Groupe Européen de Curiethérapie of the European Society for Radiotherapy and Oncology (GEC-ESTRO).

Study Details In the open-label trial, 1,328 patients with low-risk invasive disease or ductal carcinoma in situ with clear resection margins after lumpectomy at 16 sites in Austria, the Czech Republic, Germany, Hungary, Poland, Spain, and Switzerland were randomized between April 2004 and July 2009 to receive adjuvant accelerated partial-breast irradiation using sole interstitial multicatheter brachytherapy (n = 673) or whole-breast irradiation with 50 Gy and a tumor-bed boost of 10 Gy (n = 655). High-dose–rate brachytherapy consisted of a total dose of 32.0 Gy in 8 fractions or 30.3 Gy in 7 fractions, with fractionation twice a day; pulsed-dose– rate brachytherapy consisted of a total

and 551 in the whole-breast irradiation group were included in as-treated analysis.

The primary endpoint was local recurrence on as-treated analysis.

Patient and tumor characteristics were similar in the two groups. Patients had a median age of 62 years, 83% were postmenopausal, 95% had invasive carcinoma, and 86% had a primary tumor ≤ 2 cm. Adjuvant treatment included hormone therapy in 87% of patients and chemotherapy in 11%.

Local Recurrence At a median follow-up of 6.6 years, local recurrence had been observed in 1.44% (95% confidence interval [CI] = 0.51%–2.38%) of the accelerated partialbreast irradiation group vs 0.92% (95% CI = 0.12%–1.73%) of the whole-breast irradiation group (difference = 0.52%, 95% CI = –0.72% to 1.75%, P = .42, within the noninferiority relevance margin of 3%). In a sensitivity analysis, per-

Radiation Therapies After Breast-Conserving Surgery ■■ Accelerated partial-breast irradiation using multicatheter brachytherapy was noninferior to whole-breast irradiation in the risk for local recurrence after breast-conserving surgery in women with early-stage breast cancer.

■■ No significant difference in disease-free or overall survival was observed.

protocol analysis among 586 patients who had accelerated partial-breast irradiation and 525 patients who had wholebreast irradiation showed similar results, with 5-year local recurrence of 1.38% vs 0.97% (difference = 0.41%, 95% CI = –0.86% to 1.69%, P = .53).

Additional Efficacy Outcomes At 5 years, cumulative incidence rates were 0.48% vs 0.18% (difference = 0.30%, P = .39) for regional recurrence, 0.80% vs 0.93% (difference = –0.13%, P = .81) for distant metastases, 0.81% vs 0.96% (difference = –0.15%, P = .81) for second primary contralateral tumors, 4.36% vs 2.47% (difference = 1.89%, P = .778) for second primary tumors at nonbreast sites, and 0.49% vs 0.75% (difference = –0.27%, P = .56) for second primary ipsilateral breast cancers.

Five-year disease-free survival was 95.03% (95% CI = 93.34%–96.75%) with accelerated partial-breast irradiation vs 94.45% (95% CI = 92.54%–96.4%) with whole-breast irradiation (difference = 0.58%, 95% CI = –2.00% to 3.16%, P = .79). Five-year overall survival was 97.27% (95% CI = 96.00%–98.56%) vs 95.55% (95% CI = 93.82%–97.31%; difference = 1.72%, 95% CI = –0.44% to 3.88%, P = .11). There was no difference in breast cancer–related mortality (four deaths in each group, P = .84).

Late Toxicity The 5-year risk of grade 2 or 3 late skin toxicity was 3.2% with accelerated partial-breast irradiation vs 5.7% with whole-breast irradiation (P = .08). The

risk of grade 2 to 3 late subcutaneous tissue side effects was 7.6% vs 6.3% (P = .53). The 5-year risk of grade 3 fibrosis was 0% vs 0.2% (P = .46). No late grade 4 toxicity was observed.

The investigators concluded: “The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant accelerated partial breast irradiation using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival.”

They continued: “Our trial is the first phase 3 study proving non-inferiority of accelerated partial breast irradiation compared with whole-breast irradiation for selected patients with early-stage breast cancer. Based on our results, accelerated partial breast irradiation using multicatheter brachytherapy can be regarded as a valid alternative treatment option after breast-conserving surgery and can be offered for all low-risk breast cancer patients in clinical routine.” n

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

Reference 1. Strnad V, Ott OJ, Hildebrandt G, et al: 5-Year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: A randomised, phase 3, non-inferiority trial. Lancet. October 19, 2015 (early release online).

5-Year Results of GEC-ESTRO Is There Any Impact?

Beginning on page 1, Jay Harris, MD, shares his perspective of the study by Strnad et al conducted by the Groupe Europeen de Curietherapie of the European Society for Radiotherapy and Oncology (GEC-ESTRO).

ASCOPost.com | NOVEMBER 25, 2015

PAGE 69

Perspective GEC-ESTRO Trial continued from page 1

ing, showing no differences in local recurrence, disease-free survival, toxicity, or overall survival with adjuvant accelerated partial-breast irradiation using multicatheter brachytherapy vs whole-breast irradiation in 1,184 women with stage 0, I, or IIA breast cancer undergoing breastconserving treatment. Results of similar trials are also available from Hungary (258 patients, 10-year results) and Italy (520 patients, 5-year results).2,3 The mature results of the large NSABP/RTOG Dr. Harris is Professor of Radiation Oncology, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, and Chair, Harvard Radiation Oncology Program Executive Committee.

(National Surgical Adjuvant Breast and Bowel Project/Radiation Therapy Oncology Group) B-32 trial are awaited with keen anticipation but are still pending.

A Word of Caution I don’t believe that the available data establish accelerated partial-breast irradiation as equivalent to whole-breast irradiation. Mature 10-year results from trials are needed. There is experience in which 5-year results looked promising, but 10-year results manifested problems in both tumor control and toxicity.4 The American Society for Radiation Oncology (ASTRO) published guidelines in 2009 for the use of accelerated partial-breast irradiation, classifying patients as ‘suitable,’ ‘cautionary,’ or ‘unsuitable’ for treat-

ment with accelerated partial-breast irradiation.5 These guidelines are currently being updated, with only minor changes. n Disclosure: Dr. Harris reported no potential conflicts of interest.

References 1. Strnad V, Ott OJ, Hildebrandt G, et al: 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: A randomised, phase 3, non-inferiority trial. Lancet. October 19, 2015 (early release online).

2. Polgár C, Fodor J, Major T, et al: Breast-conserving therapy with partial or whole breast irradiation: Ten-year results

of the Budapest randomized trial. Radiother Oncol 108:197-202, 2013.

3. Livi L, Meattini I, Marrazzo L, et al: Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer 51:451-463, 2015.

4. Hattangadi JA, Powell SN, MacDonald SM, et al: Accelerated partial breast irradiation with low-dose-rate interstitial implant brachytherapy after wide local excision: 12-year outcomes from a prospective trial. Int J Radiat Oncol Biol Phys 83:791-800, 2012.

5. Smith BD, Arthur DW, Buchholz TA, et al: Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). J Am Coll Surg 209:269-277, 2009.

Announcements

City of Hope Announces New Appointments

C

ity of Hope in Duarte, California, recently announced the following new appointments.

Susanne G. Warner, MD Dr. Warner has been appointed Assistant Clinical Professor in the Department of Surgery. She received her medical degree from Texas A&M Health Science Center College of Medicine, where she was selected as a member of the Gold Humanism Honor Society. She pursued her training as a general surgery resident at the Mayo Clinic in Phoenix, Arizona, where she was appointed to the hospital Ethics Committee.

In 2010, Dr. Warner completed a research fellowship in Yuman Fong, MD’s laboratory at Memorial Sloan Kettering Cancer Center. Following her residency, Dr. Warner completed a clinical fellowship in hepatopancreatobiliary and advanced gastrointestinal surgery at the University of Michigan Medical Center, where she was also a clinical lecturer.

Dr. Warner’s research interests include clinical applications of oncolytic viral therapies and humanities research centered on the spiritual, emotional, and physical optimization of the perioperative patient experience.

Ling Li, PhD Dr. Li has been appointed Assistant Professor in the Gehr Family Center for Leukemia Research and Division of

Hematopoietic Stem Cell and Leukemia Research. His research focuses on studying the aberrantly regulated epigenetics that initiate or maintain the leukemia specifically acute myeloid leukemia (AML).

Edwin R. Manuel, PhD Irina Chilian, MD Ling Li, PhD Susanne G. Warner, MD He was the first to report that aberrant Dr. Manuel has developed a bac- versity in Armenia. While in Armenia, activity of SIRT1 leads to deacetylation and, therefore, suppression of p53-sig- terial-based approach that effectively she continued her education with an naling contributing to survival of leuke- targets a variety of immunosuppres- internship in internal medicine and milsive proteins to rescue antitumor itary field surgery training, before servmia stem cells.

Dr. Li’s laboratory is currently de- responses in preclinical models of ing as a staff internist at Razdan County termining the epigenetic-related resis- melanoma and pancreatic cancer. Us- Hospital.

Dr. Chilian then pursued her posttance mechanisms of leukemia stem ing this platform, he is also explorcells to the treatment of tyrosine ki- ing additional cancer-specific targets, graduate training beginning in 1996 nase inhibitors. The primary goal of such as oncogenes required for tu- with a clerkship in psychiatry at the this effort is to develop novel thera- mor survival, as another approach Metropolitan State Hospital in Norpeutics to specifically target leukemia to induce growth arrest in primary walk, California. She completed an exstem cells and advance these strategies tumor cells and cancer stem cells in ternship in pediatrics at Cedars-Sinai pancreatic cancer.

Medical Center, where she also volunfor clinical trials in AML. teered as an attending scientist in kidEdwin R. Manuel, PhD Irina Chilian, MD ney transplant immunology.

Dr. Manuel has been appointed AsDr. Chilian has been appointed AsShe continued her professional sistant Professor in the Department of sociate Professor in the Department development with an internship at Experimental Therapeutics. His current of Medical Specialists, specializing Chestnut Hill Hospital in Philadelresearch focuses on approaches to over- in neurology. She joins City of Hope phia, followed by a neurology residencome mechanisms of tumor escape, after being in private practice for 13 cy at VA/UCLA. In 2002, Dr. Chilian which is an important hallmark of can- years and serving as a consultant to completed a clinical neurophysiology cer that can significantly compromise City of Hope since 2012. fellowship at the University of Souththe efficacy of current immunotheraDr. Chilian earned her medical de- ern California’s Keck School of Medipeutic strategies. gree from Yerevan State Medical Uni- cine/VA Medical Center. n

DISCOVERING HOW FAR THERAPY CAN GO IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients.

Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood.

IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA®. Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification.

Second Primary Malignancies - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden).

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman.

Advise women to avoid becoming pregnant while taking IMBRUVICA®. 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.

IMBRUVICA® (ibrutinib) is the first and only FDA-approved therapy for use in patients with Waldenström’s macroglobulinemia (WM) IMBRUVICA® is approved for use in 4 indications IMBRUVICA® is indicated for the treatment of patients with Mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

Chronic lymphocytic leukemia with 17p deletion.

Waldenström’s macroglobulinemia (WM).

ADVERSE REACTIONS The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%†, NA‡), bruising (30%, 12%†, 16%†), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%†, 22%†). *Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased). † Includes multiple ADR terms. ‡ Not applicable; no associated ADRs. The most common Grade 3 or 4 non-hematological adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse events.

Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse © Pharmacyclics LLC 2015 © Janssen Biotech, Inc. 2015 06/15 PRC-01166

events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose.

Please review the Brief Summary of full Prescribing Information on the following pages.

To learn more, visit

www.IMBRUVICA.com

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in Full Prescribing Information].

Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in Full Prescribing Information].

Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in Full Prescribing Information].

Waldenström’s Macroglobulinemia: IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.3) in Full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in Full Prescribing Information].

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. [See Adverse Reactions]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation.

Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in Full Prescribing Information].

Second Primary Malignancies: Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %).

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden).

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience: Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia

All Grades (%) 51 31 25 24 23 17 11 34 14 14 14 13 41 35 18 14

Grade 3 or 4 (%) 5 0 0 5 0 1 0 0 3 7 5 1 5 3 1 3

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) (continued) System Organ Class

Preferred Term

Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

All Grades (%)

Grade 3 or 4 (%)

30 25 11 37 14 11 27 19 11 21 12 14 13

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

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).

Adverse reactions leading to dose reduction occurred in 14% of patients.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.

Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia.

Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea.

Adverse events leading to dose reduction occurred in approximately 6% of patients.

Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 All Grades (%)

Grade 3 or 4 (%)

Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

63 23 21 21 19 15 13 48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

4 2 2 0 2 0 0 2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

Second malignancies*

10*

0

Laceration

10

2

Anxiety Insomnia Hypertension

10 10 17

0 0 8

System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders Metabolism and nutrition disorders Neoplasms benign, malignant, unspecified Injury, poisoning and procedural complications Psychiatric disorders Vascular disorders

Preferred Term

*One patient death due to histiocytic sarcoma.

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström’s Macroglobulinemia (N=63) (continued)

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2.

Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%)

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

11

0

3

0

10

0

3

0

Subjects with multiple events for a given ADR term are counted once only for each ADR term.

The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria Waldenström’s Macroglobulinemia The data described below reflect exposure to IMBRUVICA in an open label clinical trial that included 63 patients with previously treated WM. The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.

Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients.

Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial.

Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström’s Macroglobulinemia (N=63) System Organ Class Gastrointestinal disorders Skin and subcutaneous tissue disorders

Preferred Term Diarrhea Nausea Stomatitis* Gastroesophageal reflux disease Rash* Bruising* Pruritus

All Grades (%) 37 21 16 13 22 16 11

Grade 3 or 4 (%) 0 0 0 0 0 0 0

System Organ Class

Preferred Term Fatigue

All Grades (%) 21

Grade 3 or 4 (%) 0

General disorders and administrative site conditions Musculoskeletal and connective tissue disorders Infections and infestations

Muscle spasms Arthropathy

21 13

0 0

Respiratory, thoracic and mediastinal disorders Nervous system disorders Neoplasms benign, malignant, and unspecified (including cysts and polyps)

Upper respiratory tract infection Sinusitis Pneumonia* Skin infection* Epistaxis Cough

19 19 14 14 19 13

0 0 6 2 0 0

Dizziness Headache Skin cancer*

14 13 11

0 0 0

The system organ class and individual ADR terms are sorted in descending frequency order. * Includes multiple ADR terms.

Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=63) All Grades Grade 3 or 4 (%) (%) 43 13 44 19 13 8

* Based on laboratory measurements.

Postmarketing Experience: The following adverse reactions have been identified during postapproval use of IMBRUVICA. 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.

Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported.

DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in Full Prescribing Information].

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in Full Prescribing Information].

CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in Full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.

Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.

Nursing Mothers: It is not known whether ibrutinib 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 IMBRUVICA, 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 effectiveness of IMBRUVICA in pediatric patients has not been established.

Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in Full Prescribing Information].

Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly patients.

® (ibrutinib) capsules IMBRUVICA PAGE 74

Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Hepatic Impairment: Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment.

Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing Information].

Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

Plasmapheresis: Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).

• Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions].

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions].

• Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions].

• Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

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

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions].

• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in Full Prescribing Information].

• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in Full Prescribing Information].

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions].

Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration.

Active ingredient made in China.

Distributed and Marketed by: Pharmacyclics LLC Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC © Pharmacyclics LLC 2015 © Janssen Biotech, Inc. 2015

| NOVEMBER 25, 2015 PAGE 74 The ASCO Post | NOVEMBER The ASCO Post 25, 2015

Announcements

The Bridge Project Receives $20 Million Gift From the Commonwealth Foundation for Cancer Research

T

he Commonwealth Foundation for Cancer Research has pledged $20 million to the Bridge Project, a collaborative research program of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) and Dana-Farber/ Harvard Cancer Center ( D F / H CC) , to accelerate the translation of interdisciplinary cancer solutions toward the clinic. Launched in 2011, the Bridge Project links the cancer research efforts of MIT and DF/HCC, Massachusetts’ two National Cancer Institute (NCI)designated cancer centers.

The Bridge Project funds cross-institutional and interdisciplinary teams of cancer scientists, engineers, and clinicians to solve longstanding problems in the most intractable cancers. The program was designed to integrate advanced cancer science research at both institutions by leveraging MIT’s strengths in basic cancer research and bioengineering and Harvard’s strengths in clinical cancer research and cancer care. As such, each team is co-led by at least one MIT investigator and one DF/HCC investigator.

The Commonwealth Foundation gift, which will be made over the next 5 years, will double the number of grants available to fund these multi-investigator teams each year. It also will create two new funding mechanisms that will extend the pipeline of collaboration and catalyze the translation of basic research toward clinical trials. “Footbridge Grants” will enable new teams to form and establish proof of concept.

“Expansion Grants” will provide followup funding to existing teams that are on the cusp of making significant advances toward clinical implementation.

This gift follows an initial investment of $4.5 million from the Commonwealth Foundation in 2012. To amplify the impact of this new gift, DF/HCC and MIT will raise matching

funds over the next 5 years, resulting in a combined $40 million expansion of the Bridge Project.

15 Teams Funded Since its inception, the Bridge Project has funded 15 teams that are pursuing clinical advances across a variety of cancer types that represent areas of great clinical need, including brain, lung, ovarian, pancreatic, and advanced prostate cancers. The work of these teams has led to publications in high-profile journals, the filing of invention disclosures and patent applications, the formation of new companies, and the initiation of clinical trials.

Tyler Jacks, PhD, Director of the Koch Institute and the David H. Koch Professor of Biology at MIT, and ­David Livingston, MD, Deputy Director of

Tyler Jacks, PhD

David Livingston, MD

DF/HCC and the Emil Frei Professor of Medicine at Harvard Medical School, lead the Bridge Project.

The new and expanded funding opportunities will be made available to DF/ HCC-MIT teams for the 2016–2017 funding cycle. n

ASCOPost.com | NOVEMBER 25, 2015

PAGE 75

Direct From ASCO

TAPUR: ASCO’s First Clinical Trial Addresses Critical Gaps in Understanding of and Access to Targeted Therapies

A

SCO is preparing to expand the boundaries of precision medicine with the launch of its first clinical trial. At a press briefing during the 2015 ASCO Annual Meeting, the Society formally announced its plans for the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

At a time when physicians are frequently confounded by how to act on

cord and share key clinical outcomes.

“Clinical reports, to date, suggest that 30% to 80% of advanced solid tumors harbor potentially actionable genomic variants, but the outcomes of patients treated based on such tests remain largely anecdotal or unknown,” said ASCO Chief Medical Officer ­Richard L. Schilsky, MD, FACP, FASCO, who is leading the study (see page 116).

We have a big knowledge gap and an unbelievable opportunity.

—Clifford A. Hudis, MD, FACP

teria. If and when a patient meets the defined trial criteria, the treating physician will select a drug from among those available in the TAPUR study protocol that targets the identified genomic variation in the patient’s tumor. If a relevant drug-target match is not described in the protocol, the physician may consult the TAPUR Molecular Tumor Board, which will review the clinical and genomic features of the case and suggest potential therapies on or off the study.

The primary endpoint of TAPUR is objective tumor response defined by RECIST or stable disease for at least 16 weeks; other endpoints include progression-free survival, overall survival, duration of treatment, and treatment-related serious adverse events.

Richard L. Schilsky, MD, FACP, FASCO

Edward S. Kim, MD

Practical Applications of TAPUR the results of genomic testing to benefit their patients, TAPUR and similar investigations are critical. “We have a big knowledge gap and an unbelievable opportunity,” said ASCO Past President Clifford A. Hudis, MD, FACP, of Memorial Sloan Kettering Cancer Center, who moderated the press conference.

Rationale and Design ASCO recognized two significant challenges slowing the pace of discovery in precision medicine: a lack of access to drugs prescribed off label and a lack of data collection on the safety and efficacy of such treatments. TAPUR has the potential to address both issues, by making targeted drugs available to participants at no cost and by creating a registry to re-

The prospective, nonrandomized TAPUR clinical trial will collect information on the antitumor activity and toxicity of commercially available targeted cancer drugs in a range of cancer types (including advanced solid tumors, multiple myeloma, and B-cell non-Hodgkin lymphoma) with a genomic variation known to be a drug target.

At its outset, TAPUR will evaluate 10 to 15 drugs contributed by five pharmaceutical companies, with cohorts of up to 35 patients defined by tumor type, genomic abnormality, and drug.

Patient enrollment is expected to open in early 2016.

Patients will be screened to determine if they are healthy enough to participate based on broad inclusion/exclusion cri-

TAPUR will harness information from discussions about molecular targets and potential treatments that are already happening in oncology practices every day—a source of knowledge that is currently lost, because there is no mechanism to learn from the experience of patients who use targeted drugs in off-label settings, Dr. Schilsky said.

Edward S. Kim, MD, confirmed that in his practice, patients and their family members frequently ask about the effectiveness of targeted therapies and request commercially available marker panels to assess their tumors.

“The truth is that scientists and clinicians don’t know what to do with many of these markers. We have no idea how impactful they are when applying a therapy.

Sometimes, physicians have to make in-

dependent decisions based on their own knowledge. Sometimes, there are opportunities to use a molecular tumor board to have a forum discussion about markers and treatments. But we’re all still learning.

There is no instruction booklet that tells us, ‘If A, use B.’ The levels of evidence vary, and there can be a lot of bias in the decision-making. Capturing this information prospectively and being able to analyze outcomes based on drug selection are the best ways to start making better informed decisions moving forward,” he said.

Dr. Kim is Chair of Solid Tumor Oncology and Investigational Therapeutics at Levine Cancer Institute, Carolinas HealthCare System, one of the three clinical sites at which TAPUR will launch. He is a veteran of personalized continued on page 76

Applications Open for ASCO’s New Policy Fellowship Program

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n October 15, ASCO launched a new fellowship program aimed at providing physicians with the necessary skills to shape cancer policy. ASCO is actively recruiting oncologists in the early phase of their careers that have leadership, civic, policy, or advocacy experience, and a keen interest in acquiring stronger health policy skills.

The ASCO Health Policy Fellowship application period closes December 15 for the July 1, 2016–July 1, 2017 program. Two participants will be selected.

“Sound public health policy is critical to improving the experiences of people living with cancer and reducing the impact of cancer in the United States,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO. “This program is designed to build a cadre of oncologists who can effectively develop and advocate for policies that support cancer research and delivery of high-quality cancer care.”

The ASCO fellowship program components will include active participa-

tion in policy development; small-group teaching sessions; training in communication, leadership skills, and advocacy strategies; and a mentored research project.

Applicants must be oncologists who have been working in any discipline for 10 years or less, or who have completed at least 2 years of an accredited United States clinical oncology training program. They also must be ASCO members.

Applications must be submitted online using ASCO’s Grants Portal at https://grants.conquercancerfoundation.

org. Paper applications or applications sent by e-mail will not be accepted. Applicants will be notified on January 29, 2016, via email.

Visit www.asco.org/policyfellowship for more details.

ASCO conducts and administers the fellowship, with funding support from the Conquer Cancer Foundation Mission Endowment. n © 2015. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | NOVEMBER 25, 2015

PAGE 76

Direct From ASCO ASCO’s First Clinical Trial continued from page 75

medicine studies, having served as lead investigator for the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial while at The University of Texas MD Anderson Cancer Center.

From a clinical perspective, he believes, the most exciting aspect of ­TAPUR is access. Too often, a panel will yield an interesting marker in a patient’s tumor for which there is a drug that may be effective, but the drug is not approved or indicated for that particular setting.

“The patient is put in an impossible position. Should they divest their life savings…and spend tens of thousands of dollars to try a drug for a few months? Should they appeal to the drug company and spend months trying to get access to the drug?” Dr. Kim explained. Because selected targeted therapies will be made available to TAPUR participants at no cost, “we don’t have to ask our patients to make that choice. That access is incredible.”

A Collaborative Effort Numerous partners have contributed knowledge, expertise, and resources to make TAPUR possible. ASCO will sponsor and organize the operational

aspects of the study, including the participation of multiple collaborators.

Cancer researchers and patient advocates are important partners in the study and will contribute to the plan-

Jane Perlmutter, PhD

ning and conduct of TAPUR, as well as assist in increasing public and patient awareness. Jane Perlmutter, PhD, a cancer survivor and nationally recognized patient advocate, is lending her expertise in trial development and will help coordinate patient advocate recruitment and training for the study.

TAPUR will launch at clinical sites within the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, the Levine Cancer Institute, and the Carolinas HealthCare System, with the goal of expanding nationally.

ASCO has invited a number of phar-

maceutical companies to provide marketed, targeted drugs and additional resources to support TAPUR. Five companies have signed memoranda of understanding agreeing to participate in the study as of July 2015: AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Genentech, and Pfizer.

“At least 13 drugs that target more than 20 unique genomic variants will be provided by these companies. We are extremely grateful for the generosity of these companies without whose support T ­ APUR would not be possible,” said ASCO Immediate Past President Peter Paul Yu, MD, FACP, FASCO. “We anticipate additional companies will sign on, and we are extremely encouraged by the level of interest we have received so far.”

Two technology companies will provide key support to the study’s data collection: Syapse and Illumina. Syapse will provide its Syapse Precision Medicine Data Platform to automate the study workflow (including the Molecular Tumor Board and the Data and Safety Monitoring Board) and capture structured data from participating practices. Illumina will provide its NextBio knowledge base platform to support and inform the case review by the Molecular Tumor Board, as well as to support anal-

Peter Paul Yu, MD, FACP, FASCO

ysis of TAPUR data by the study team.

ASCO will collaborate and share data from TAPUR with the Netherlands Center for Personalized Cancer Treatment, which is conducting a clinical trial using a very similar study protocol.

For more information on ASCO’s Targeted Agent and Profiling Utilization Registry, visit asco.org/TAPUR. Online resources include a fact sheet, frequently asked questions, tools for patients and patient advocates, and recent publications about the study. n Selected portions reprinted from ASCO Connection. © American Society of Clinical Oncology. “TAPUR: ASCO’s First Clinical Trial Addresses Critical Gaps in Understanding of and Access to Targeted Therapies.” connection.asco.org. 21 August 2015.

All rights reserved.

ASCO University® Offers Resources for Palliative and Team-Based Care

A

SCO University®, ASCO’s eLearning center, offers an array of courses and programs relevant to palliative care and multidisciplinary team–based cancer care. Below are descriptions of just a few of these offerings.

Pain Management Released in March 2015, ASCO University’s “Pain Management Program” provides an in-depth overview of pain assessment, opioid titration, management of adverse effects of opioid analgesics, and achievement of balance in the treatment of pain.

“Pain relief is an essential component of comprehensive oncology care,” said Judith A. Paice, PhD, RN, of Northwestern University Feinberg School of Medicine, who served as a faculty expert for the program. “The ASCO University Pain Management Course delivers content that addresses issues seen every day in oncology settings, including how to provide safe and effective care using complex therapies.”

Participants will explore case scenarios using an interactive question format to select a course of action in managing the patient’s pain with feedback pro-

vided within the selected response. The program features an interactive decision-branching component that allows users to navigate through three patient case scenarios and apply their knowledge by selecting options that lead to different patient outcomes.

Fatigue “Cancer-Related Fatigue” outlines the primary evaluation, as well as the management and treatment of this distressing, persistent subjective phenomenon related to cancer treatment.

“I was privileged to work with Paul Jacobsen, PhD, of the Moffitt Cancer Center, both as members of the ASCO cancer-related fatigue guideline panel and the subsequent ASCO University course on Cancer-Related Fatigue,” said Gary H. Lyman, MD, MPH, FASCO, FRCP (Edin), of Fred Hutchinson Cancer Research Center. “[In the course,] we attempted to provide practical recommendations for identifying and evaluating patients with cancer-related fatigue.”

The course also reviews current evidence and recommendations on pharmacologic and nonpharmacologic

management of cancer-related fatigue, discusses the importance of physician/ patient communication about fatigue, and identifies available resources to assist patients at risk for, or symptomatic from, cancer-related fatigue.

Cultural Competence “Cultural Competence for Oncology Practice” is a free eLearning course designed to help members of a multidisciplinary team in oncology care increase their knowledge of cultural ­competence.

Through three case studies, the course teaches participants how to describe the concept of cultural competence and how it enhances the patient experience throughout the cancer care continuum; how to demonstrate appropriate communication strategies to minimize and address cultural issues that may affect care; how to identify barriers within health care related to various aspects of cultural competency—specifically race, gender, religion, age, language, and culture; and how to apply knowledge of personal barriers to improve the care of diverse patient populations throughout the cancer care continuum.

“ASCO University’s Cultural Competence course provides health professionals with real-life scenarios demonstrating sources of disparities in [the treatment of] patients with cancer that help us recognize who is at risk and address issues that might otherwise go overlooked,” said Gretchen Kimmick, MD, of Duke University Health System, who served on the course’s planning group. “The three course sections contain information useful to the health care community, from nurses and clinic staff to hospital administrators.”

ASCO offers continuing medical education credit, as well as certificates of participation and completion. Certificates of Nursing Education and Pharmacy Education are also available for this course. For more information on these and other eLearning courses, visit university.asco.org. n Originally printed in Palliative Care in Oncology Daily News. © American Society of Clinical Oncology. “ASCO University® Offers Resources for Palliative and TeamBased Care” pallonc.org/dn. 9 October 2015. All rights reserved.

ASCOPost.com | NOVEMBER 25, 2015

PAGE 77

Direct From ASCO

Former Conquer Cancer Foundation Grant Recipients Present Research Advances and Share Impact of CCF Grants

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f the $150 million being raised through The Campaign to Conquer Cancer, a planned $56 million will support vital research grants such as the Young Investigator Award (YIA) and Career Development Award (CDA).

Over the past 30-plus years, the Conquer Cancer Foundation (CCF) has supported and launched the research careers of more than 1,000 physician

New ASCO Answers Guide to Caregiving

T

his new ASCO Answers guide helps family caregivers better understand their role in the cancer care team. While there is no one way to be a caregiver, ASCO Answers: Caregiving is designed to help caregivers provide ongoing support as the person with cancer’s needs change.

In addition to providing practical tips for supporting someone with cancer, it includes blank workbook pages for family caregivers to keep track of important information, like appointments, medication schedules, and household chores. By using this guide, caregivers are better able to meet the needs of their loved ones and work through some of the challenges of caring for someone with cancer.

The guide can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All patient education materials ship for free, and ASCO members receive a 20% discount. n © 2015. American Society of Clinical Oncology. All rights reserved.

scientists in at least 65 countries.

Former CCF grant recipients, many of whom presented research at the ASCO Annual Meeting, can attest to the transformative power of these awards. Notably,

former CCF grant recipients led three of the studies highlighted in the official ASCO Annual Meeting press program.

Gregory T. Armstrong, MD, MSCE, Pediatric Oncologist at St. Jude Chil-

dren’s Research Hospital, led an analysis of more than 34,000 participants in the federally funded Childhood Cancer Survivor Study, which showed improvement continued on page 78

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 Despite initial high response rates with frst-generation EGFR TKIs, many tumors will develop new mutations and become resistant.6,7 A major barrier to disease control is resistance to treatment. Resistance to frst-generation therapy will develop in most patients with EGFRm+ advanced NSCLC on a currently approved EGFR TKI.7 After disease progression, clinical guidelines recommend subsequent treatments including either continuing with an EGFR TKI therapy or beginning platinum-based chemotherapy.5

Nearly 2 out of 3 cases of progression with first-generation EGFR TKIs are related to the T790M mutation In patients with NSCLC who are EGFRm+, T790M is an acquired mutation and has been identifed as the most common mechanism of acquired resistance in nearly 2 out of 3 patients.1,2 Development of T790M mutation may confer resistance through several potential mechanisms, which may include8,9: - Steric hindrance, which reduces receptor binding of reversible EGFR TKIs - Increased binding affnity of EGFR for ATP, resulting in reduced TKI potency

T790M Is the Most Common Mechanism of Acquired Resistance to First-Generation EGFR TKI Therapy1

63%

T790M (98/155)

CI, (9555 –70 ) %

%

MET amplifcation (4/75)

5% (95% CI, 1%–13%)

HER2 amplifcation (3/24)

NEARLY 2 OUT OF 3

%

13% (95% CI, 3%–32%)

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

AstraZeneca is a leader in lung cancer research AstraZeneca is conducting ongoing research to understand the science of the T790M mutation as a driver of resistance.

Find out more at EGFRevolution.com.

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 | NOVEMBER 25, 2015

PAGE 78

Direct From ASCO Impact of CCF Grants continued from page 77

in late mortality achieved over 3 decades.

Among 5-year survivors, all-cause mortality at 15 years after diagnosis dropped from 12.4% to 6%. This improvement is attributed in part to changes in care that reduced the risk of mortality related to late effects of pediatric cancer treatment, such as subsequent malignancies and cardiac and lung diseases.

Dr. Armstrong received a 2008 Career Development Award CDA from CCF to evaluate the long-term effects of anthracycline-induced cardiotoxicity.

The CCF CDA “was my first grant, and gave me the money to do studies which

I could not have done otherwise,” Dr. Armstrong said.

A phase II study led by Dung T. Le, MD, Assistant Professor of Oncology at Johns Hopkins Kimmel Cancer Center, identified the first genomic marker—mismatch repair (MMR) deficiency—to predict response to the anti– PD-1 antibody pembrolizumab (Keytruda). This marker predicted responses across a range of cancers.

Dr. Le received a 2008 CDA from CCF, the results of which led to a phase II clinical trial that identified a promising vaccine combination for patients with metastatic pancreatic cancer and was labeled a “breakthrough

Gregory T. Armstrong, MD, MSCE

Dung T. Le, MD

therapy” by the U.S. Food and Drug Administration in July 2014.

“Awards such as the Conquer Cancer Foundation Career Development Award have definitely made it possible for me to dedicate time to push forward innovative programs,” said Dr. Le. Tanguy Seiwert, MD, Assistant Professor of Medicine at the University of Chicago, led a phase I study indicating that pembrolizumab immunotherapy is safe and possibly more effective than existing options for advanced head and neck cancer. Up to 23% of patients treated with the anti–PD-1 antibody experienced tumor shrinkage. The findings suggest that immunotherapy may fill a large unmet need for better treatments— importantly, responses were observed across a wide range of patient subgroups.

Dr. Seiwert received a 2006 YIA from CCF to investigate Heat

Tanguy Seiwert, MD

Shock Protein 27 as a promising novel target and prognostic marker in non– small cell lung cancer.

“I am extraordinarily thankful for having received the YIA, and it was very impactful,” Dr. Seiwert said. “This grant was extremely important, even more than many other grants I received later on, because of the pivotal time point in my career following residency and fellowship.”

Visit conquer.org for additional information about The Campaign to Conquer Cancer and join us as we work to take down cancer. n Originally printed in ASCO Connection. © American Society of Clinical Oncology.

“Former Conquer Cancer Foundation Grant Recipients Present Research Advances and Share Impact of CCF Grants.”

ASCO Connection, September 2015: 51.

All rights reserved.

Support the Conquer Cancer Foundation on Giving Tuesday

“G

iving Tuesday” is the perfect time to start your holiday giving and take part in a global movement to give back. Giving Tuesday has raised tens of millions of dollars for charities around the world since its start in 2012.

Donating to the Conquer Cancer Foundation (CCF) this Giving Tuesday—December 1—is your chance to keep growing the giving spirit and help create a world free from the fear of cancer. CCF has awarded more than $90

million dollars to cutting-edge research through more than 1,400 grants.

Your gift will not only help advance cancer research, but will also be tripled thanks to a matching gift grant. Your support will allow us to continue to provide funding that may remove the fear of cancer from future holidays.

Donate on December 1 at www .conquercancerfoundation.org/tap. n © 2015. American Society of Clinical Oncology. All rights reserved.

Save the Date

Genitourinary Cancers Symposium

Cancer Survivorship Symposium

January 7–9, 2016

January 15–16, 2016

Moscone West Building

San Francisco Marriott Marquis

San Francisco, California

San Francisco, California

ASCOPost.com | NOVEMBER 25, 2015

PAGE 79

Education in Oncology

How QOPI® Is Improving Oncology Care

A Conversation With Joseph V. Simone, MD, FASCO

By Jo Cavallo

L

aunched in 2002 as a pilot program to promote excellence in oncology care, the origins of ASCO’s Quality Oncology Practice Initiative (QOPI®) date as far back as 1997, when the Institute of Medicine (IOM) created a National Cancer Policy Board to assess the state of cancer care in the United States. The IOM’s findings, published in a report 2 years later,1 concluded that many patients with cancer did not receive highquality, evidence-based care, although there was not enough information at the time to actually measure quality of care, according to Joseph V. Simone, MD, FASCO, a coeditor of the report.

has grown from 100 to 1,000 oncology practices, and the number of quality metrics developed to assess quality of care has increased from 35 to 180, including more than 40 measures related to pain and symptom management, palliative care, and end-of-life care. Disease-specific modules include breast cancer management, colorectal cancer management, non-Hodgkin lymphoma management, and non–small cell lung cancer management.

In addition to providing individual oncology practices with the tools to improve the quality of patient care and keep current with national practice

I believe QOPI has contributed positively to the quality of cancer care over the past decade. The program will continue to evolve to provide both community and academic oncologists with the tools they need to have a positive impact on patient outcomes in the future.

—Joseph V. Simone, MD, FASCO

A pediatric oncologist and active ASCO member, Dr. Simone proposed that ASCO initiate a quality-assessment program with a volunteer group of oncologists to measure the quality of care they provided in their practices and to share the results with their colleagues. The goals of the program, said Dr. Simone, were to promote excellence in oncology care and improve patient outcomes, develop a method to measure progress, reward successful participants, and support ASCO’s mission to ensure access to quality cancer care for all patients.

After the completion of several feasibility studies in 2006, QOPI, a completely voluntary program, was made available to all ASCO members in community and academic practice in the United States, Puerto Rico, and Guam.

(Recently, ASCO began test piloting QOPI programs in some European countries as well as Brazil and plans to expand QOPI outside the United States based on level of interest.)

Growth of the Program Since the launch of QOPI nearly a decade ago, enrollment in the program

guidelines, QOPI also contributes to the performance improvement assessment of Continuing Medical Education activities and engagement of fellows in assessment and improvement activities during fellowship training.

In 2010, ASCO launched the QOPI Certification Program (QCP ™) to recognize medical oncology and hematology/oncology practices that are committed to delivering the highest quality of cancer care in several areas, including staffing-related standards, treatment planning and chart documentation standards, informed consent, administration, patient monitoring and assessment, chemotherapy-order standards, drug preparation, and patient education. In the future, QOPI reporting will be integrated into CancerLinQ™, ASCO’s health information technology platform, which will be implemented and used by practices starting in 2016.

During a special session at the 2010 ASCO Annual Meeting, Dr. Simone was recognized for the significant contributions he has made to the prevention and management of cancer and for his commitment to quality in oncology

with the ASCO/American Cancer Society Award.

The ASCO Post talked with Dr. ­Simone, President of the Simone Consulting Company, about the effect QOPI is having on the care of patients with cancer.

Origins of QOPI What was the impetus for your interest in developing QOPI? The idea was born out of the notion that oncologists had to be involved in changing the culture of medical practice to one in which they could selfcheck how well they were doing in terms of providing the highest quality of care for their patients and then to measure the care they provided against evidence-based and expert consensus care ­recommendations.

One of the novel measures we included early on was in pain control. At the minimum, you’ve got to ask patients if they are in pain and, if so, what grade of pain on a scale of 1 to 10. Then you have to show in the patient’s chart that you asked about pain. Getting physicians to do that was difficult.

The bedrock principles that the members of the QOPI steering committee felt were important were that it be a voluntary program, that the data generated would be managed by the participating physicians, that the deidentified data would be collected by the oncology practices and submitted to ASCO for data management, that the results would be returned to the participating practices showing performance compared to other practices, and that ASCO would provide some financial support (with no money accepted from the pharmaceutical industry).

Quality of Care How is QOPI evolving to address quality-of-care issues?

A study by Arif H. Kamal, MD, [Assistant Professor of Medicine at Duke University School of Medicine] and colleagues investigating quality measures for palliative care found that patient care is often focused on the physical manifestations of disease and the side effects of therapy, with little attention paid to the psychological, social, and spiritual distress of patients.2 In 2014, ASCO teamed up with the American Academy of Hospice and Palliative Care Medicine to establish the Virtual Learning Collaborative (asco.

Leora Horn, MD, MSc

E

GUEST EDITOR

ducation in Oncology focuses on faculty development, medical education curricula, fellowship training, and communication skills. The column is guest edited by ­Leora Horn, MD, MSc, Associate Professor of Medicine, Assistant Director of the Educator Development Program, and Clinical Director of the Thoracic Oncology Program at Vanderbilt University School of Medicine, Nashville. org/vlc), a Web-based technology platform. The goal was to disseminate evidence-based palliative care approaches and provide oncologists with a toolbox of evidence-based resources that would help them put the latest research into practice in such areas as improved symptom management, psychosocial issues, and discussions about goals of care. Practice teams from 26 medical oncology practices participating in the pilot program will report the data on palliative care quality using QOPI measures, and we should have results from the pilot study soon.

ASCO is also developing a QOPI module devoted to palliative care and improving quality of life for patients.

The main goal of QOPI is to provide oncology practices with a framework for improving patient care and to make the habit of practice self-examination routine, because that is the only way we become better physicians.

Measuring Results Are there data to quantify how successful QOPI is in improving patient care?

I was a coauthor of a study published in the Journal of Clinical Oncology in 2013, which analyzed self-reported data from 156 practice groups submitted between 2006 and 2010.3 Our findings continued on page 80

The ASCO Post | NOVEMBER 25, 2015

PAGE 80

Education in Oncology How QOPI® Is Improving Care continued from page 79

showed that there were significant improvements in performance on certain measures for quality oncology care.

Overall, mean normalized performance scores in these practices rose from 71% to 85%, and the practices reported 90% or higher rates of providing adjuvant chemotherapy for breast, colorectal, and non–small cell lung cancers, as recommended. Mean scores of measures related to new clinical practices rose from 5% to 69% overall over 4 years. These new clinical practices included genetic testing for tumor molecular markers that predict response to treatment in patients with metastatic colorectal cancer (eg, KRAS gene alterations before administering anti-EGFR

therapy), adequate lymph node examination after surgery in colorectal cancer, and testing for and use of the antinausea drug aprepitant when certain chemotherapy regimens are administered.

However, measures that assess smoking cessation and fertility preservation counseling did not improve.

A major weakness of QOPI—and we knew this from its inception—is its inability to tell both oncologists and patients what they really want to know.

For example, has QOPI changed patient outcome? Are patients living longer because of improvements in care? We just haven’t gotten there yet, because cancer is so unpredictable.

In the future, there will be new methodologies added to QOPI to improve quality and maximize outcomes

and value in oncology practice. For example, ASCO is developing a means of reducing or eliminating manual data abstraction that will allow data to be uploaded from electronic health record– generated reports directly into the QOPI system. In turn, QOPI reporting will be integrated into CancerLinQ, which is scheduled to be implemented and used by practices in 2016. As the genetic component of cancer risk is becoming better understood, ASCO is also developing QOPI measures to assess patient and family cancer risk.

I believe QOPI has contributed positively to the quality of cancer care over the past decade. The program will continue to evolve to provide both community and academic oncologists with the tools they need to have a positive impact

on patient outcomes in the future. n Editor’s Note: To learn more about participating in QOPI, e-mail qopi@ asco.org or visit qopi.asco.org.

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

References 1. Hewitt M, Simone JV (eds): Ensuring Quality Cancer Care. Washington, DC, National Academies Press, 1999.

2. Kamal AH, Gradison M, Maguire JM, et al: Quality measures for palliative care in patients with cancer: A systematic review. J Oncol Pract 10:281-287, 2014.

3. Neuss MN, Malin JL, Chan S, et al: Measuring the improving quality of outpatient care in medical oncology practices in the United States. J Clin Oncol 31:14711477, 2013.

2015 JADPRO Live at APSHO in Phoenix, Arizona

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The 2015 JADPRO Live at APSHO (Advanced Practitioner Society for Hematology and Oncology) took place earlier this month. More than 700 attendees participated in the 3-day event in Phoenix (see page 14). Here, we present some of the photos from this year’s meeting, co-chaired by Pamela Hallquist Viale, RN, MS, CNS, ANP, Heather M. Hylton, PA, and Sandra E. Kurtin, RN, MS, AOCN(R), ANP-C. 1.

Panel discussion. 2. Hands-on Skills Workshop. 3. JADPRO Editor-inChief Pamela Hallquist Viale, RN, MS, CNS, ANP, and her husband Gary Viale. 4. Panel discussion. 5. Conference co-chair Wendy Vogel, RN, MSN, FNP. 6. Attendees enjoy lunch symposium. 7.

Conference cofounder John A. Gentile, Jr, and his wife Gerry Gentile.

8. Laura Adams, President & CEO, Rhode Island Quality Institute, Keynote Speaker. 9. Satellite symposium faculty Sandra E. Kurtin, RN, MS, AOCN(R), ANP-C, Clinical Nurse Educator, Tanya Price, RN, BSN, MSN, CNS, OCN, and multiple myeloma patient, Patricia C. For more, see page 14 or visit APSHO.org.

NOW APPROVED

Visit IMLYGIC.com to learn more

Š 2015 Amgen Inc. All rights reserved. 09/15 USA-678-104478

The ASCO Post | NOVEMBER 25, 2015

PAGE 82

Journal Spotlight Cancer Screening

ACS Guideline Update on Breast Cancer Screening for Women at Average Risk

By Matthew Stenger

A

s reported in JAMA by Kevin C. Oeffinger, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues, the American Cancer Society (ACS) has issued an update to its 2003 guideline on breast cancer screening for women at average risk of breast cancer.1 Robert A. Smith, PhD, of the Cancer Control Department, ACS, is the corresponding author of the JAMA article.

In formulating the updated recommendations, an ACS guideline development group selected the Duke University Evidence Synthesis Group to conduct an independent systematic evidence review of the breast cancer screening literature. The ACS also commissioned the Breast Cancer Surveillance Consortium to update previously published analyses of mammography screening interval and outcomes, and the ACS Surveillance and Health Services Research Program contributed supplementary data on disease burden using Surveillance, Epidemiology, and End Results (SEER) program data.

The intention of this new guideline is to provide both guidance and flexibility for women about when to start and stop screening mammography and how frequently to be screened for breast cancer.

—Kevin C. Oeffinger, MD, and colleagues

cancer and for whom mammography screening alone may have reduced effectiveness, including those with significant family histories but who do not have a high probability of carrying identified risk mutations, those with a prior diagnosis of benign proliferative breast disease, and those with significant mammographic breast density.

The investigators noted: “At this time, there are no reliable estimates of the number of women who have one or more of these risk factors; nor are there widely accepted risk-based screening recommendations that differ for women in this intermediate-risk group compared with average-risk women.”

Evidence Synthesis

Robert A. Smith, PhD

Average Risk Women at average risk were defined as those without a personal history of breast cancer, a confirmed or suspected genetic mutation known to be associated with increased risk (eg, BRCA), or a history of radiotherapy to the chest at a young age. The authors acknowledged that there also are women outside of these higher-risk categories who are at higher-than-average risk of breast

Key points from the evidence synthesis follow: • Screening mammography in women aged 40 to 69 years is associated with reduction in breast cancer deaths across a range of study designs; inferential evidence supports breast cancer screening for women aged ≥ 70 years who are in good health.

• Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages, due to the greater number of mammograms as well as to the higher recall rate for younger women.

The quality of evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence.

• Analysis of the effects of the screening interval indicates more favorable tumor characteristics when premenopausal women are screened annually vs biennially.

• Evidence does not support routine clinical breast examination as a screening method for women at average risk.

Updated Recommendations The updated recommendations, designated as strong or qualified, are reproduced here. A strong recommendation indicates consensus that the benefits of adherence to an intervention outweigh the undesirable effects that may result from screening. A qualified recommendation indicates clear evidence of benefit of screening but less certainty about the balance of benefits and harms or about patient values and preferences, factors that could lead to different decisions about screening.

Women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years. (Strong Recommendation) 1a. Women aged 45 to 54 years should be screened annually. (Qualified Recommendation) 1b. Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually. (Qualified Recommendation) 1c. Women should have the opportunity to begin annual screening between the ages of 40 and 44 years.

(Qualified Recommendation) Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer. (Qualified Recommendation) The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age. (Qualified Recommendation) The authors concluded: “These updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer s­ creening.”

They continued: [T]he ACS recommendations are made in the context of maximizing reductions in breast cancer mortality and reducing years of life lost while minimizing the associated harms among the population of women in the United States. The ACS recognizes that the balance of benefits and harms will be close in some instances and that the spectrum of women’s values and preferences will lead to varying decisions. The intention of this new guideline is to provide both guidance and flexibility for women about when to start and stop screening mammography and how frequently to be screened for breast cancer.” n Disclosure: This work was supported by the ACS. For full disclosures of the study authors, visit www.jama.jamanetwork.com.

Further comments on page 83 (Therese Bevers, MD, and Mark Helvie, MD) and on page 84 (Ismail Jatoi, MD, PhD, FACS).

Reference 1. Oeffinger KC, Fontham ET, Etzioni R, et al: Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA 314:1599-1614, 2015.

More in This Issue on the Updated ACS Breast Cancer Screening Guidelines In a detailed interview with The ASCO Post (see page 148), Kevin C. Oeffinger, MD, Chair of the American Cancer Society (ACS) panel that updated the breast cancer screening guidelines, discusses the attention and media coverage that has been given to the subject of breast cancer screening. Dr. Oeffinger explains how the updated ACS guideline is especially designed for use in the context of the clinical encounter, and that it is the woman herself who should decide with her physician when to start and stop screening mammography.

ASCOPost.com | NOVEMBER 25, 2015

PAGE 83

Perspective

Getting the Content and the Message Right in Breast Cancer Screening Guidelines

By Therese Bevers, MD, and Mark Helvie, MD

A

ccording to recent national headlines, the American Cancer Society (ACS) now recommends that women at average risk of breast cancer should “screen later and less often.”1 While the new ACS recommendations (summarized on page 82 in this issue of The ASCO Post) might initially be taken as casting doubt on the value of “annual mammographic screening for women beginning at age 40,” when considering the nuances of the new ACS breast cancer screening guideline for women at average risk of the disease, the conflict is less pronounced than it appears in recent press coverage. As specialists in breast cancer screening, our concern is that the increasing number of differing recommendations creates confusion and a lack of clear direction for women— and their doctors—to effectively safeguard their breast health.

Qualified Recommendations The ACS issued a “strong recommendation” that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years. From the patient perspective, a “strong recommendation” means: “Most individuals in this situation would want the recommended course of action, and only a small proportion would not.”2 However, a number of qualified recommendations must be understood to fully appreciate the new guideline. In contrast to a strong recommendation, a “qualified recommendation” means: “The majority of individuals in this situation would want the suggested course of action, but many would not.” This “qualified recommendation” allows a great deal of latitude in the interpretation of the ACS recommendations.

Dr. Bevers is Professor, Clinical Cancer Prevention; Medical Director, Cancer Prevention Center, The University of Texas MD Anderson Cancer Center; Chair, Breast Cancer Screening and Diagnosis Guideline Panel, National Comprehensive Cancer Network. Dr. Helvie is Professor, Department of Radiology, Comprehensive Cancer Center, University of Michigan Health System; Vice-Chair, Breast Cancer Screening and Diagnosis Guideline Panel, National Comprehensive Cancer Network.

The ACS “qualified recommendations” include: • Women aged 45 to 54 years should be screened annually.

• Women should have the opportunity to begin annual screening between the ages of 40 and 44 years.

• Women 55 years and over should transition to biennial screening or have the opportunity to continue screening annually.

U.S. Preventive Services Task Force ­(USPSTF) grade B recommendations for routine mammographic screening to be done biennially beginning at age 50.3,4 Although the ACS recommends annual screening for women aged 45 to 54, the new guideline also allows the opportunity for women to begin annual screening mammograms at age 40 (qualified recommendation).

In addition, while the ACS notes that

As specialists in breast cancer screening, our concern is that the increasing number of differing recommendations creates confusion and a lack of clear direction for women—and their doctors—to effectively safeguard their breast health.

—Therese Bevers, MD, and Mark Helvie, MD

• Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or ­longer.

• The ACS does not recommend clinical breast examination for breast cancer screening among averagerisk women at any age.

Interpreting the Guidelines With these new recommendations, the ACS affirms that screening mammography saves lives. Specifically, fewer women will die of breast cancer as a result of early detection from routine screening mammography. Notably, and in contrast to recurring arguments against screening mammography, they did not find evidence that the value of mammographic screening has declined due to advances in breast cancer treatment.

Additionally, the new recommendations confirm the value of annual mammographic screening for women in their 40s. This is in direct contrast to the 2009 and 2015 draft

women may transition to biennial mammographic screening at age 55, they also note that women should have the opportunity to continue annual mammographic screening (qualified recommendation).

These last two qualified recommendations have been consistently missing in the media coverage. On first review, the new ACS recommendations appear to endorse fewer mammograms and less frequent screening, resulting in the previously mentioned headlines. However, when distilled to its simplest form, a recommendation of “annual mammographic screening for average-risk women beginning at age 40 years” is not in conflict with the ACS recommendations. This perspective on the ACS recommendations also aligns with the National Comprehensive Cancer Network’s (NCCN) recommendations for annual mammographic screening beginning at age 40 after women are counseled regarding potential benefits, risks, and limitations of breast screening.5

Benefits vs Harms The rationale for the qualified recommendations for annual screening of women aged 40 to 44 and women aged 55 and older (noted as “opportunities” for both age groups in the new guideline) relates to the perceived balance of benefits and harms. The ACS felt that this balance was less favorable for these women than for women aged 45 to 54. It is acknowledged that women at all of these ages are less likely to die of breast cancer if they undergo annual mammographic screening. However, the ACS identified concerns about the harms incurred as a result of screening mammography (largely false-positives), especially for women in their early 40s.

When considering the “harms” of false-positives of screening mammography, there are several perspectives to consider. First, there is no consensus on what constitutes “harm” and what value judgment women assign to the “harm” compared to the mortality reduction benefit. Many women who are called back for additional testing and for which the evaluation was benign feel reassured that every measure is being taken to ensure that there is no serious concern on their screening mammogram. These women do not label their call-back (a false-positive) as a “harm.”

In the ACS and USPSTF analyses, the harms of screening have been reported to be compared to the harms of “no screening.” However, the actual analysis has compared screening harms to the absence of harm among nonscreened women.

Nevertheless, nonscreened women frequently develop breast symptoms that require diagnostic evaluation and biopsy, many of which will be benign (false-positive). A more appropriate analysis would be the “net” harms of screening vs no screening.

The discussion of the benefits of mammographic screening (mortality reduction, less morbidity) should be balanced not only by the harms of screening (mostly false-positives) but also by the harms of not screening (cancers diagnosed at more advanced stages, increased mortality, and increased morbidity). continued on page 84

The ASCO Post | NOVEMBER 25, 2015

PAGE 84

Perspective

ACS Breast Cancer Screening Guidelines: Balancing the Benefits and Harms of Mammography

By Ismail Jatoi, MD, PhD, FACS

F

or the past 30 years, mammography screening has been one of the most contentious issues in medicine.

Controversy has generally centered on the age at which to begin mammography screening (40 vs 50 years) and also, to a lesser extent, on the age at which it should stop. The recent American Cancer Society (ACS) guidelines—summarized in this issue of The ASCO Post— are unlikely to quell such controversy.1 Two randomized trials have been specifically designed to assess the efficacy of mammography screening for women in their 40s: the Canadian National Breast Screening Study (CNBSS) I and the United Kingdom Age trial.2,3 In both trials, mammography screening for women in their 40s did not significantly reduce breast cancer mortal-

Dr. Jatoi is Dale H. Dorn Chair in Surgery, Professor and Chief, Division of Surgical Oncology and Endocrine Surgery, University of Texas Health Science Center, San Antonio.

Therese Bevers, MD Mark Helvie, MD continued from page 83

Clinical Breast Exam An unanticipated recommendation from the ACS is the “qualified recommendation” against clinical breast exam for average-risk women of any age, citing a lack of evidence of any benefit alone or in conjunction with screening mammography. However, two international studies have suggested that a clinical breast exam may have value in breast cancer screening.6,7 It is surprising that ACS made a strong negative recommendation absent new scientific evidence that benefits were lacking or the harms were significant. Of note, while the value of clinical breast exam remains to be determined, the clinical encounter provides an opportunity to evaluate a woman’s risk of breast cancer and have a discussion regarding risk reduction strategies, such as preventive therapies (eg, tamoxifen and raloxifene) and the importance of a healthy lifestyle.

After review of the new ACS Breast Cancer Screening recommendations,

ity. Although other trials have included women in their 40s, those trials were not specifically designed to assess the efficacy of screening younger women.

Moreover, meta-analyses of the screening trials show that, among women who initiate mammography screening at age > 50 years, the mortality benefit is evident within 7 to 9 years, whereas for those who initiate screening in their 40s, the benefit takes longer to emerge.4 Many investigators have argued that the delayed benefit of screening younger women is simply attributable to screening beyond age 50 years. Thus, the ACS recommendations for screening women in their 40s do not seem consistent with the best evidence at hand.

Overdiagnosis Problem The ACS guidelines do not specify the age at which mammography screening should stop. Yet of the nine randomized trials that have examined the efficacy of mammography screening,

the NCCN Breast Cancer Screening and Diagnosis guideline panel, noting that no new data were available since the last annual review, did not recommend any changes to their recommendations for breast cancer screening. The NCCN continues to recommend annual clinical breast examination and screening mammograms for women beginning at age 40 and continuing for as long as they have a 10-year life expectancy. Our mission is to save lives, and the data indicate that this is the best way to do just that.

Addressing the Confusion Women at average risk are now confronted with different guidelines, each suggesting screening mammograms beginning at different ages and at differing intervals. Subtle differences in the ACS affirmative recommendations between “most” and “majority” are very nuanced. However, in the end, the ACS guidelines support annual screening mammograms beginning at age 40.

In an attempt to address the confusion of these differing guidelines, a Consensus Conference is being convened by the American College of Obstetricians

Controversy has generally centered on the age at which to begin mammography screening and also, to a lesser extent, on the age at which it should stop. The recent ACS guidelines are unlikely to quell such controversy.

—Ismail Jatoi, MD, PhD, FACS

only the Swedish Two-County trial included women aged ≥ 70 years (women were aged 40–74 years at entry), but participation of this age group was low, and a subgroup analysis of four Swedish randomized trials found no mortality benefit for those aged 70 to 74 years at study entry.5 Without evidence of benefit, mammography screening in women aged ≥ 70 years is difficult to justify.

Indeed, older women are more vulnerable to the harms associated with mammography screening, particularly

the vexing problem of overdiagnosis.6 Overdiagnosis refers to the diagnosis of a cancer that, in the absence of screening, would never have been detected during a patient’s lifetime. A populationbased study has suggested that, in the United States, nearly one-third of all breast cancers would never have been diagnosed in the absence of screening.7 This substantial rate of overdiagnosis is partly due to the detection of ductal carcinoma in situ, which is rarely palpa-

and Gynecologists in January 2016.

Major organizations, including ACS, NCCN, and other providers of women’s health care will gather to evaluate and interpret the data with the intent of developing a consistent set of uniform guidelines for breast cancer screening that can be implemented nationwide.

We are appreciative that a national organization of primary care providers has identified the critical need for a uniform recommendation for breast cancer screening and taken action. This upcoming conference provides a beacon of hope that a number of major organizations can agree on breast cancer screening recommendations and provide unified guidance to women and their clinicians. n

from the American Cancer Society. JAMA 314:1599-1614, 2015.

3. U.S. Preventive Services Task Force: Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 151:716-726, 2009.

4. U.S. Preventive Services Task Force: Draft recommendation statement for breast cancer screening. Available at www .uspreventiveservicestaskforce.org/Page/ Document/RecommendationStatementDraft/breast-cancer-screening. Accessed November 10, 2015.

5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast cancer screening and diagnosis (version 1.2015). Available at NCCN.org. Accessed November 10, 2015.

6. Mittra I, Mishra GA, Singh S, et al: A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: Methodology and interim results after three rounds of screening. Int J Cancer 126:976-984, 2010.

7. Sankaranarayanan R, Ramadas K, Thara S, et al: Clinical breast examination: Preliminary results from a cluster randomized controlled trial in India. J Natl Cancer Inst 103:1476-1480, 2011.

Disclosure: Drs. Bevers reported no potential conflicts of interest. Dr. Helvie has received an institutional grant with GE Healthcare for tomosynthesis.

References 1. Cohen E: New breast cancer screening guidelines: Screen later, less often. CNN.com, October 22, 2015. Accessed October 28, 2015.

2. Oeffinger KC, Fontham ET, Etzioni R, et al: Breast cancer screening for women at average risk: 2015 guideline update

continued on page 86

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-40680 May 2015. Printed in USA.

The ASCO Post | NOVEMBER 25, 2015

PAGE 86

Perspective

Ismail Jatoi, MD, PhD, FACS continued from page 84

ble and almost exclusively detected with screening mammography. Many cases of ductal carcinoma in situ would likely never progress to invasive cancer, and when they do progress, the process un-

doubtedly takes many years. Thus, ductal carcinoma in situ is unlikely to pose a threat to the life of an elderly woman, and its detection triggers treatments (surgery, radiotherapy, and endocrine therapy) that could have been avoided in the absence of screening mammography.

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.

However, overdiagnosis is not simply attributable to the detection of ductal carcinoma in situ; it can also result from the detection of invasive cancers. Mammography screening preferentially detects indolent invasive cancers, whereas the more aggressive tumors are often de-

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-40580 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

tected in the intervals between screening sessions (length bias).6 Many indolent invasive cancers would pose no threat to the life of an elderly patient and might not be detected in the absence of mammography screening. As with ductal carcinoma in situ, detection of these cancers may trigger unnecessary treatments.

Thus, overdiagnosis of breast cancer may expose elderly women to the risk of unnecessary treatment-related morbidity and mortality.

Clinical vs Self Breast Exam The ACS recommendation against screening clinical breast examination is puzzling. Screening clinical breast examination is undertaken by trained health-care personnel and should be distinguished from screening breast self-examination, where women are instructed on self-breast examination.4 Two large randomized trials, undertaken in St. Petersburg, Russia, and Shanghai, China, have shown that screening breast self-examination does not reduce breast cancer mortality. However, screening clinical breast examination was incorporated into four of the nine mammography screening trials and showed promise.

In the Health Insurance Plan (HIP) trial of New York, women were randomized to mammography screening plus screening clinical breast examination vs usual care.

In the screening arm of the trial, 67% of the cancers were detectable by clinical breast examination and only 33%, by mammography alone.

In the Edinburgh trial, 74% of the cancers in the screening group were detectable by clinical breast exam and only 26% by mammography alone.

In the CNBSS I, women aged 40 to 49 years at study entry were randomized to screening with mammography and clinical breast examination vs no screening. There was no reduction in mortality attributable to screening, but clinical breast examination detected 59% of the cancers in the study arm, with 32% detected by clinical breast examination alone and 27% detected by clinical breast examination and mammography.

In the CNBSS II, women aged 50 to 59 years at study entry were randomized to receive either screening with clinical breast examination and mammography (study group) vs clinical breast examination alone continued on page 87

724-43396

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ASCOPost.com | NOVEMBER 25, 2015

PAGE 87

JCO Spotlight Thoracic Oncology

ASCO Clinical Practice Guideline Update: Systemic Therapy for Stage IV NSCLC

By Matthew Stenger

A

s reported in the Journal of Clinical Oncology by Gregory A. Masters, MD, and colleagues, ASCO has issued a clinical practice guideline update on systemic therapy for stage IV non– small cell lung cancer (NSCLC).1 Recommendations are based on an update committee systematic review of randomized controlled trials conducted between January 2007 and February 2014. The update committee was co-chaired by David H. Johnson, MD, of the University of Texas Southwestern Medical Center at Dallas, and Dr. Masters, of the Helen F. Graham Cancer Center, Newark, Delaware.

Gregory A. Masters, MD

•

David H. Johnson, MD

The basic recommendations are reproduced here. For all recommendations, benefits outweigh the harms. The type of recommendation is evidence based, except where otherwise noted.

•

Overall • There is no cure for patients with stage IV NSCLC. • Decisions on chemotherapy should not be made on the basis of age alone.

•

First-Line Treatment

•

• For patients without an epidermal growth factor receptor (EGFR)sensitizing mutation or ALK gene re­ arrangement and a performance status of 0 to 1 (or appropriate patients with a performance status of 2): A variety

Ismail Jatoi, MD, PhD, FACS continued from page 86

(control group). Whereas other trials have shown that mammography screening can effectively reduce breast cancer mortality in women older than 50 years, there was no difference in breast cancer mortality between the study and control groups of the CNBSS II trial. This finding might be interpreted to mean that mammography screening adds little benefit beyond that of screening clinical breast examination alone.

•

of combination cytotoxic chemotherapies are recommended. Platinumbased doublets are preferred, along with early concurrent palliative care and symptom management. Based on tumor histology (ie, squamous vs nonsquamous), there are some variations (evidence quality = high, strength of recommendation = strong).

Adding bevacizumab (Avastin) to carboplatin plus paclitaxel is recommended if there are no contraindications (evidence quality = intermediate, strength of recommendation = moderate).

For patients with a performance status of 2: Combination or single-agent chemotherapy or palliative care alone may be used (for chemotherapy: evidence quality = intermediate, strength of recommendation = weak; for palliative care: evidence quality = intermediate, strength of recommendation = strong).

For patients with sensitizing EGFR mutations: Afatinib (Gilotrif), erlotinib (Tarceva), or gefitinib is recommended (evidence quality = high, strength of recommendation = strong for each).

For patients with ALK gene rearrangements: Crizotinib (Xalkori) is recommended (evidence quality = intermediate, strength of recommendation = moderate).

For patients with ROS1 rearrangement: Crizotinib is recommended

Mammography screening is likely to remain a contentious issue. As breast cancer treatments continue to improve, the benefit of screening in reducing breast cancer mortality is likely to decline.8 Moreover, the impact of screening on quality of life needs to be thoroughly considered. The harms associated with screening are not insignificant, and greater emphasis should be placed on reducing these adverse effects. n Disclosure: Dr. Jatoi reported no potential conflicts of interest.

(recommendation type = informal consensus, evidence quality = low, strength of recommendation = weak).

• For patients with large cell neuroendocrine carcinoma: Platinum plus etoposide or the same treatment as other patients with nonsquamous carcinoma may be administered (recommendation type = informal consensus, evidence quality = low, strength of recommendation = weak).

• First-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients with nonresponsive stable disease (no change in recommendation).

• For patients with stable disease or response after four cycles of a first-line pemetrexed (Alimta)-containing regimen: Pemetrexed continuation maintenance may be used; if initial regimen does not contain pemetrexed, an alternative chemotherapy (switch) may be used, or a break from chemotherapy may be recommended until disease progression (for addition of pemetrexed: evidence quality = intermediate, strength of recommendation = moderate).

Second-Line Treatment • For patients with nonsquamous cell carcinoma: Docetaxel, erlotinib, gefitinib, or pemetrexed is acceptable (evidence quality = high, strength of recommendation = strong).

• For patients with squamous cell carcinoma: Docetaxel, erlotinib, or gefitinib is acceptable (evidence quality = high, strength of recommendation = strong).

• For patients with sensitizing EGFR mutations who did not respond to a first-line EGFR tyrosine kinase inhibitor: Combination cytotoxic chemotherapy is recommended for those with nonsquamous cell carcinoma, as listed

References 1. Oeffinger KC, et al: Breast cancer screening for women at average risk. JAMA 314:1599-1614, 2015.

2. Miller AB, et al: Twenty five year follow-up for breast cancer incidence and mortality of the CNBSS. BMJ 348:g366, 2014.

3. Moss SM, et al: Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years’ follow-up. Lancet Oncol 16:1123-1132, 2015.

4. Jatoi I, Anderson WF: Cancer screening. Curr Probl Surg 42:620-682, 2005.

under first-line treatment (recommendation type = informal consensus, evidence quality = intermediate, strength of recommendation = strong).

• For patients with sensitizing EGFR mutations who received a first-line EGFR tyrosine kinase inhibitor and experienced disease progression after an initial response: Regimen may be switched to chemotherapy or another EGFR tyrosine kinase inhibitor as second-line therapy (recommendation type = informal consensus, evidence quality = low, strength of recommendation = weak).

• For patients with ALK rearrangement and progression after first-line crizotinib: Chemotherapy or ceritinib (Zykadia) may be offered (for chemotherapy: evidence quality = high, strength of recommendation = strong; for ceritinib: evidence quality = intermediate, strength of recommendation = moderate).

Third-Line Treatment • For patients who have not received erlotinib or gefitinib and have a performance status of 0 to 3: Erlotinib may be recommended.

• Data are insufficient to recommend routine third-line cytotoxic drugs.

Additional information is available at http://www.asco.org/guidelines/nsclc.

Patient information is available at http:// www.cancer.net. n

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

Reference 1. Masters GA, Temin S, Azzoli CG, et al: Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 33:3488-3515, 2015.

See commentary by Heather A. W ­ akelee, MD, on page 90.

5. Nyström L, et al: Long-term effects of mammography screening. Lancet 359:909919, 2002.

6. Jatoi I, Miller AB: Breast cancer screening in elderly women. JAMA Surg.

October 14, 2015 (early release online).

7. Bleyer A, Welch HG: Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 367:1998-2005, 2012.

8. Jatoi I: The impact of advances in treatment on the efficacy of mammography screening. Prev Med 53:103-104, 2011.

i am proof of extended survival in newly diagnosed GBM

Actor portrayal

Optuneâ&#x201E;˘ is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM).

Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy.

Optune was studied in the EF-14 trial, a prospective, international, multicenter, open-label, randomized, controlled, phase 3 trial in newly diagnosed GBM patients comparing Optune + TMZ with TMZ alone (N=700). The prespecified interim analysis occurred when the first 315 patients completed 18 months of follow-up. The primary endpoint was PFS (ITT); OS (per protocol) was a powered secondary endpoint; 1- and 2-year survival rates, PFS6, QoL, and radiological response rates, along with safety, were also secondary endpoints. The final analysis included all patients randomized to EF-14 who had CRF information available at the database cutoff of December 3, 2014. This included 695 of the 700 patients randomized at that time: 466 patients in the Optune + TMZ arm and 229 patients in the TMZ-alone arm.1,2

Please see the following Summary of Important Safety Information for Optune and visit www.Optune.com/IFU for Optune Instructions for Use for complete information regarding the deviceâ&#x20AC;&#x2122;s indication, contraindications, warnings and precautions.

CI, confidence interval; CRF, case report form; GBM, glioblastoma; HR, hazard ratio; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; PFS6, progression-free survival at 6 months; QoL, quality of life; TMZ, temozolomide.

References: 1. Optune Instructions for Use. Novocure 2015. 2. Novocure Data on File. OPT-103.

Optune + TMZ significantly extended median overall survival by 4.9 months and median PFS by 3.2 months 1 20.5 months median OS with Optune + TMZ1

Fraction Survival

Overall Survival (interim analysis)1 1.0

Median OS from randomization (months)1

0.9

Log-rank P-value1

0.0042

HR (95% CI)1

0.666 (0.495-0.898)

0.8

Optune + TMZ

0.7

20.5 MONTHS

0.6 0.5

20.5

Median OS from diagnosis (months)2

Median OS

24.4

15.6

19.4

Per Protocol population

0.4

TMZ alone

Optune + TMZ (n=196)

0.3

15.6

TMZ alone (n=84)

MONTHS

0.2 0.1 + Censored

0.0 0

6

12

18

24

30

36

42

48

54

60

Overall Survival (months)

* In the final analysis (n=695), Optune + TMZ extended median OS by 4.4 months, and this was consistent with the interim analysis (n=315).1

Overall Survival (months)

Median PFS improved by >3 months with Optune + TMZ1

Fraction Survival

Progression-free Survival (interim analysis)1 1.0

Median PFS from randomization (months)1

7.2

0.9

Log-rank P-value1

0.0013

HR (95% CI)1

0.621 (0.468-0.823)

0.8

Optune + TMZ

0.7

7.2 MONTHS

0.6 0.5

Median PFS from diagnosis (months)2

Median PFS

0.4

TMZ alone

0.3

4.0

11.0

4.0

Median time from diagnosis to randomization was

7.8

3.8 months1

ITT population

Optune + TMZ (n=210) TMZ alone (n=105)

MONTHS

0.2 0.1

â&#x20AC;

+ Censored

0.0 0

3

6

9

12

15

18

21

Progression-free Survival (months)

24

In the final analysis (n=695), Optune + TMZ extended median PFS by 2.9 months, and this was consistent with the interim analysis (n=315).1

Progression-free Survival (months)

SELECTED SAFETY INFORMATION Do not use Optune in patients with an active implanted medical device, a skull defect (such as, missing bone with no replacement), or bullet fragments. Use of Optune together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of Optune together with skull defects or bullet fragments has not been tested and may possibly lead to tissue damage or render Optune ineffective.

Learn more at Optune.com Š2015 Novocure. All rights reserved. Optune and Novocure are trademarks of Novocure. OPT-117

PAGE 90

The ASCO Post | NOVEMBER 25, 2015

Perspective INDICATIONS FOR USE Optune™ is intended as a treatment for adult patients (22 years of age or older) with histologicallyconfirmed glioblastoma multiforme (GBM).

Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy.

SUMMARY OF IMPORTANT SAFETY INFORMATION Contraindications Do not use Optune in patients with an active implanted medical device, a skull defect (such as, missing bone with no replacement), or bullet fragments. Use of Optune together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of Optune together with skull defects or bullet fragments has not been tested and may possibly lead to tissue damage or render Optune ineffective.

Do not use Optune in patients that are known to be sensitive to conductive hydrogels. In this case, skin contact with the gel used with Optune may commonly cause increased redness and itching, and rarely may even lead to severe allergic reactions such as shock and respiratory failure.

Warnings and Precautions Optune can only be prescribed by a healthcare provider that has completed the required certification training provided by Novocure (the device manufacturer).

Do not prescribe Optune for patients that are pregnant, you think might be pregnant or are trying to get pregnant, as the safety and effectiveness of Optune in these populations have not been established.

The most common (≥10%) adverse events involving Optune in combination with temozolomide were thrombocytopenia, nausea, constipation, vomiting, fatigue, medical device site reaction, headache, convulsions, and depression.

Use of Optune in patients with an inactive implanted medical device in the brain has not been studied for safety and effectiveness, and use of Optune in these patients could lead to tissue damage or lower the chance of Optune being effective.

If the patient has an underlying serious skin condition on the scalp, evaluate whether this may prevent or temporarily interfere with Optune treatment.

Please see the Optune Instructions for Use (IFU) for complete information regarding the device’s indication, contraindications, warnings, and precautions at Optune.com/IFU.

Updated Guidelines for Treating Stage IV NSCLC: Trying to Keep Up

By Heather A. Wakelee, MD

I

n late August 2015, Gregory A. Masters, MD, and colleagues published an update to the ASCO guidelines for systemic therapy for stage IV non–small cell lung cancer (NSCLC), summarized in this issue of The ASCO Post.1 This builds on the full guidelines published in 20092 and the additional switch maintenance published in 2011.3

Heather A. Wakelee, MD

In the rapidly changing world of lung cancer, it is important to highlight the fact that this update is based on reports from 73 phase III randomized controlled trials published through February 2014 and was approved for publication in February 2015. The recommendations focus on the paradigm shift that has occurred in lung cancer therapy since 2009 and thus refer specifically to decisions based on histology and molecular subtype. The guidelines do not yet reflect the approvals of the first wave of checkpoint inhibitors, specifically the programmed cell death protein 1 (PD-1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) as second-line treatment options for advanced NSCLC.4,5 Discussions of these agents are included in the text of the update but not in “The Bottom Line” summary of the guidelines.

The guidelines reflect the highest level of evidence and have been developed through a rigorous ASCO Clinical Practice Guideline Committee review process. In the rapidly changing oncology landscape, such a rigorous process serves an important role in establishing standards at a set period of time but cannot always be nimble enough to reflect all relevant changes in practice. Clinical guidelines

help to improve the consistency of care and set benchmarks for providers, patients, policymakers, and insurance carriers6 but will by necessity lag behind “real time” given the time necessary to go through the rigorous process involved.

First-Line Options The current guidelines remain unchanged in recommending combination cytotoxic (preferably platinum-based) chemotherapy for untreated patients without EGFR-sensitizing mutations or ALK rearrangements and a good performance status (0–1 and select patients with performance status 2). They include a mention that bevacizumab (Avastin) may be considered with carboplatin/ paclitaxel for nonsquamous histology but provide no significant comment on the use of bevacizu­ mab with platinum/pemetrexed (Alimta), given insufficient evidence for or against that combination.

Use of first-line targeted therapy in molecular subtypes of NSCLC is emphasized with a focus on EGFR-activating mutations treated with erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif) and on ALK-translocated tumors treated with crizotinib (Xalkori), with a strong recommendation rating for these agents. Though many other molecular subsets of NSCLC are now identified in addition to the EGFR and ALK subsets, only ROS1 rearrangements are mentioned, with a suggestion to use crizotinib in that setting but only as an informal consensus.

The guidelines appropriately refer to differences by histology for adenocarcinoma and squamous cell carcinoma and additionally mention, with an informal consensus, consideration of platinum plus etoposide as an option in patients with large-cell neuroendocrine carcinoma. Maintenance therapy recommendations include stopping first-line cytotoxic chemotherapy at progression or after four cycles, with the options of continuation maintenance for those on firstline pemetrexed-containing regimens

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or switch maintenance utilizing pemetrexed (or less preferably erlotinib) for those on a nonpemetrexed regimen (assuming nonsquamous histology for use of pemetrexed).

The first-line options thus have not significantly changed but emphasize consideration of histology and, in particular, molecular subtypes when making first-line treatment decisions.

Readers are referred to other ASCO guidelines specifically addressing molecular markers7 and palliative care.8 Mention is made of the importance of palliative care and that chemotherapy selection decisions should not be made or altered based on age alone; however, individual care plans taking comorbidities into account are critical.

Second- and Third-Line Options The guidelines for second-line therapy also include reference to approvals of docetaxel, erlotinib, gefitinib, or pemetrexed for nonsquamous disease and docetaxel, erlotinib, or gefitinib for squamous cell carcinoma. There is a brief discussion of ramucirumab (Cyramza) with a statement that “the role for vascular endothelial growth factor inhibitor therapy in the secondline setting is not clear.”

Use of cytotoxic combination chemotherapy for patients previously treated with a first-line EGFR or ALK inhibitor is endorsed, as is the use of ceritinib (Zykadia) for patients who have previously received crizotinib for ALK-positive NSCLC. Based on the timing of guideline development, the recent approvals of nivolumab and pembrolizumab as second-line therapeutic options are not included in the recommendations. Thus, the second-line recommendations must be viewed in this context.

The new ASCO guidelines note that “data are not sufficient to make a recommendation for or against using cytotoxic drugs as third-line therapy; patients should consider experimental treatment, clinical trials, and continued best supportive (palliative) care (no change from previous recommendations).” Erlotinib “may be recommended” for patients with performance status 0–3 who had not previously received erlotinib or gefitinib.

However, with the recent approvals of nivolumab as a second-line option for nearly all NSCLC patients or pembrolizumab for patients with tumor PD-1 ligand (PD-L1) expression, the use of

third-line therapy will increase.

The future directions section of the guidelines emphasize these pending changes and also mention newer agents that will likely be available shortly, including next-generation therapy for patients with disease progression on first-generation EGFR inhibitors and currently available ALK inhibitors.

Important Considerations As outlined in the “Limitations of Research” section, this is a rapidly evolving world, and data to support clinical practice patterns can evolve to such an extent as to limit the utility of the guidelines in a short period of time.

As the authors stated, “With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence.”

Importantly, the guidelines do emphasize the communication between the patient and physician about goals of care and treatments and, in particular, the noncurative nature of currently available options. Given the limitations of trying to set standards based on a snapshot in time in a world of rapid change, the current ASCO guidelines of systemic therapy for stage IV NSCLC do an outstanding job of compiling existing high-level data to support first-line therapeutic decisions and clearly defining treatment standards for second- and third-line therapy in the preimmunotherapy era. n

27:6251-6266, 2009.

3. Azzoli CG, Temin S, Aliff T, et al: 2011 focused update of 2009 American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non–smallcell lung cancer. J Clin Oncol 29:38253831, 2011.

4. 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.

5. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.

6. Woolf SH, Grol R, Hutchinson A, et al: Clinical guidelines: Potential benefits, limitations, and harms of

clinical guidelines. BMJ 318:527-530, 1999.

7. Leighl NB, Rekhtman N, Biermann WA, et al: Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/ International Association for the Study of Lung Cancer/Association for Molecular Pathology guideline. J Clin Oncol 32:3673-3679, 2014.

8. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol 30:880887, 2012.

Moment in History

Disclosure: Dr. Wakelee has had a consulting or advisory role with Peregrine, ACEA Biosciences, Pfizer, Helsinn, Novartis (uncompensated), Clovis Oncology (uncompensated), and Genentech/Roche (uncompensated) and has received research funding (paid to Stanford University) from Genentech/Roche, Novartis, Clovis, Exelixis, Celgene, Bristol-Myers Squibb, AstraZeneca/ Medimmmune, Gilead, Pfizer, and Xcovery.

References 1. Masters GA, Temin S, Azzoli CG, et al: Systemic therapy for stage IV non– small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 33:34883515, 2015.

2. Azzoli CG, Baker S Jr, Temin S, et al: American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol

Treatment in a Tumor Clinic: A physician and a nurse are dressing a wound after the removal of a tumor on a patient’s neck at the U.S. Health Service Marine Hospital in Bethesda, Maryland. Creator: Roy Perry.

Source: National Library of Medicine.

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Limitation of Use: Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Giant Cell Tumor of Bone Xgeva is indicated for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Hypercalcemia of Malignancy Xgeva is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

DOSAGE AND ADMINISTRATION: Important Administration Instructions Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.

Recommended Dosage: Bone Metastasis from Solid Tumors: The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Giant Cell Tumor of Bone: The recommended dose of Xgeva is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Hypercalcemia of Malignancy: The recommended dose of Xgeva is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.

CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva.

Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva.

WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia.

Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently.

Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels, throughout Xgeva therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) has been reported in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure. Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Consider temporary discontinuation of Xgeva therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating physician should guide the management plan of each patient based on individual risk/benefit assessment.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis.

EMBRYO-FETAL TOXICITY: Xgeva can cause fetal harm when administered to a pregnant woman.

Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time.

ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia • Osteonecrosis of the Jaw The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

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 other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental

procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female.

Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3) Zoledronic Acid Xgeva n = 2836 Body System n = 2841 % % GASTROINTESTINAL 32 31 Nausea 19 20 Diarrhea GENERAL Fatigue/ Asthenia 45 46 IN VESTIGATIONS Hypocalcemiab 9 18 20 32 Hypophosphatemiab NEUROLOGICAL Headache 13 14 RESPIRATORY 18 21 Dyspnea 15 15 Cough Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes.

• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53).

Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva.

Giant Cell Tumor of Bone The safety of Xgeva was evaluated in two single arm trials (Trials 4 and 5) in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of Xgeva. Patients received 120 mg Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Trial 5. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

Of the 304 patients who received Xgeva, 145 patients were treated with Xgeva for ≥ 1 year, 44 patients for ≥ 2 years, and 15 patients for ≥ 3 years. The median number of doses received was 14 (range: 1 to 60 doses) and the median number of months on study was 11 (range: 0 to 54 months).

Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33 years (range: 13 to 83 years); a total of 10 patients were skeletally mature adolescents (13 to 17 years of age).

The adverse reaction profile of Xgeva in patients with giant cell tumor of bone was similar to that reported in Trials 1, 2, and 3. The most common adverse reactions in patients (per-patient incidence ≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis (per-patient incidence of 0.7%).

The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis of the jaw (per-patient incidence of 0.7%), and tooth abscess or tooth infection (per-patient incidence of 0.7%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.

Hypocalcemia and Hypophosphatemia • Moderate hypocalcemia (corrected serum calcium less than 8 to 7 mg/dL or less than 2 to 1.75 mmol/L) occurred in 2.6% of patients treated with Xgeva.

• Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) occurred in 29 patients (9.5%).

Osteonecrosis of the Jaw (ONJ) In Trials 4 and 5, ONJ was confirmed in 4 of 304 (1.3%) patients who received Xgeva. The median time to ONJ was 16 months (range: 13 to 20 months) [see Warnings and Precautions (5.4)].

Hypercalcemia of Malignancy Xgeva was evaluated in an open-label, single-arm trial (Trial 6) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled.

The adverse reaction profile of Xgeva in patients with hypercalcemia of malignancy was similar to that reported in Trials 1, 2, 3, 4, and 5. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on study were related to Xgeva therapy.

Postmarketing Experience. Because postmarketing 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.

The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases.

• Hypersensitivity, including anaphylactic reactions.

• Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported.

Immunogenicity.

As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years and none of the 304 patients with giant cell tumor of bone in Trials 4 and 5 tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as a

assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result 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 antibodies to denosumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect.

Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy and/or hormone therapy.

USE IN SPECIFIC POPULATIONS: Pregnancy: Category D. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva.

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation.

Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated.

Pediatric Use. The safety and efficacy of Xgeva have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone. Xgeva is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone.

Xgeva was studied in an open-label trial that enrolled a subset of 10 adolescent patients (aged 13-17 years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus), and had a body weight ≥ 45 kg. A total of two of six (33%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/ kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth.

Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Renal Impairment. Two clinical trials were conducted in patients without cancer and with varying degrees of renal function. In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation.

Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and, calcium and vitamin D intake.

Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk.

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Perspective Genitourinary Oncology

Changing Landscape in the Treatment of Metastatic Renal Cell Carcinoma: Findings With Nivolumab and Cabozantinib

By Brian I. Rini, MD, FACP

In the October 25 issue of The ASCO Post (pages 50–57), we presented two important studies in previously treated advanced renal cell carcinoma, including the paper

by Motzer et al “Nivolumab versus everolimus in advanced renal-cell carcinoma” (CheckMate 025), published in The New England Journal of Medicine, September 25, 2015 (early release online), and that by Choueiri et al on “Cabozantinib versus everolimus in advanced renal-cell carcinoma” (METEOR trial), also in The New England Journal of Medicine, September 25, 2015 (early release online). Here, Brian I. Rini, MD, FACP, of the Cleveland Clinic Taussig Cancer Institute shares his personal perspective on the impact of these important studies on clinical care. To view the paper published in October 25, visit http://bit.ly/1MDGrH3.

T

he landscape of treatment for metastatic renal cell carcinoma has again shifted. Built upon a foundation of therapy targeting the vascular endothelial growth factor (VEGF) pathway with a small subset of patients benefitting from immunotherapy (high-dose interleukin-2 [Proleukin]), recent data have expanded the therapeutic armamentarium while simultaneously raising new questions. The most impressive new data have come from the CheckMate 025 trial—reported by Motzer and colleagues and summarized in this issue of The ASCO Post—in which the anti–programmed cell death protein 1 (PD-1) antibody nivolumab (Opdivo) Dr. Rini is Professor of Medicine, Lerner College of Medicine, Leader, GU Program, Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute.

While several questions remain as to how to optimally incorporate and sequence new and existing agents, the prognosis for metastatic renal cell carcinoma patients continues to improve.

—Brian I. Rini, MD, FACP

was compared to everolimus (Afinitor), an oral mammalian target of rapamycin (mTOR) inhibitor, in patients with refractory metastatic renal cell carcinoma.1 An overall survival advantage was demonstrated with a very tolerable safety profile.

Emerging Questions Assuming U.S. Food and Drug Administration approval, these data make nivolumab likely the predominant standard of care in refractory renal cell carcinoma. One perspective is to ask the question of which refractory renal cell carcinoma patients should not get nivolumab? Aside from those with contraindications such as autoimmune disease, the answer to this question is not clear.

Disappointingly, tumor expression of the ligand for PD-1 (PD-L1), while prognostic, did not predict for or against response to nivolumab and thus is not presently of clinical utility.

Whether this will hold true for other drugs in this class in renal cell carcinoma or whether using alternative antibodies or staining other cell populations (eg, infiltrating immune cells) will permit prediction of response awaits further investigation.

Of note, in CheckMate 025, there was no progression-free survival difference between the arms, and a substantial percentage of patients in the nivolumab arm (35%) had a best response of progressive disease. Although

this subset likely includes patients with disease worsening before subsequent improvement, there are likely patients (eg, those with bulky, symptomatic disease) in whom subsequent VEGFtargeted therapy may be a better choice for initial disease control.

Several other questions also emerge.

The complete response rate was identical (1%) in both arms of CheckMate 025, as was the duration of response (12 months), and thus, the potential of immunotherapy to induce durable and deep remissions is not yet realized—at least at this point in patient follow-up.

Further, whether continuous therapy (as was employed in this study) is needed in patients with durable disease control will require additional investigation but has important cost and toxicity implications.

Role of Cabozantinib Additional data in this setting have been presented on cabozantinib (Cometriq). This agent inhibits not only the VEGF receptor but other potentially biologically relevant receptors such as c-met and AXL, which have been shown in preclinical models to be associated with VEGF resistance.

In the METEOR trial, reported by Choueiri and colleagues and summarized in this issue of The ASCO Post, cabozantinib demonstrated a progression-free survival and objective response rate advantage over everolimus

in refractory renal cell carcinoma.2 Whether this benefit simply reflects an advantage of VEGF targeting over mTOR targeting in this setting or is a result of targeting of additional receptors is unclear. A smaller randomized trial of cabozantinib vs sunitinib in front-line renal cell carcinoma is awaited to provide further insight.

This efficacy benefit came at a cost of toxicity, however, with 68% of cabozantinibtreated patients experiencing a grade 3 or higher adverse event and 60% requiring dose reductions.

As the dosing of cabozantinib has varied considerably among trials in different cancers, the optimal dosing strategy for this compound in renal cell carcinoma requires further study.

Nonetheless, the progression-free survival observed with cabozantinib in this setting is impressive and provides a new option for this group of patients.

Closing Thoughts Thus, just when the existing targeted therapies had likely been maximized in terms of patient benefit, these new treatment options emerge. Ongoing studies are moving checkpoint inhibitors into the front-line setting, and additionally combining immunotherapeutics and VEGF-targeted agents. While several questions remain as to how to optimally incorporate and sequence new and existing agents, the prognosis for metastatic renal cell carcinoma patients continues to improve. n

Disclosure: Dr. Rini is a consultant for and has received research funding from BristolMyers Squibb and Exelexis.

References 1. Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803-1813, 2015.

2. Choueiri TK, Escudier B, Powles T, et al: Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1814-1823 2015.

Nivolumab and Cabozantinib Improve Outcomes vs Everolimus in Previously Treated Advanced Renal Cell Carcinoma

Robert J. Motzer, MD Toni K. Choueiri, MD

See the October 25 issue of The ASCO Post for a summary of the CheckMate 025 and METEOR trials as reported recently in The New England Journal of Medicine by Robert J. Motzer, MD, and colleagues and Toni K. Choueiri, MD, and colleagues, respectively, or visit http://bit.ly/1MDGrH3.

The ASCO Post | NOVEMBER 25, 2015

PAGE 96

Book Review

A Shrink Tells the Inside Story of Psychiatry

By Ronald Piana

J

effrey A. Lieberman, MD, is the Lawrence C. Kolb Professor and Chairman of Psychiatry at the Columbia University College of Physicians and Surgeons. Along with a host of other notable credentials in the world of psychiatry, Dr. Lieberman is the Past President of the American Psychiatric Association.

He recently added author to his hefty CV with the publication of his book, Shrinks: The Untold Story of Psychiatry, which he wrote with the help of journalist Ogi Ogas.

The book has been well received. In fact, Pulitzer Prize winner Siddhartha Mukherjee, MD, called it “astonishing.”

The Era of Lobotomies One skeleton in the psychiatric closet that Dr. Lieberman reveals is the era of lobotomies, which were pioneered in America by Walter J. Freeman, MD, PhD. Lobotomies first sprang on the psychiatric scene

Bookmark Title: Shrinks: The Untold Story of Psychiatry Author: Jeffrey A. Lieberman, MD, with Ogi Ogas Publisher: Little, Brown and Company Publication date: March 10, 2015 Price: $28.00, hardcover; 352 pages

in Europe when Antonio Moniz, MD, a Portuguese neurologist, convinced the medical community that mental illness was a neural condition that could be cured by inflicting per-

manent damage to the frontal lobe of the brain. Astonishingly, Dr. Moniz won the Noble Prize for his brain mutilation treatment.

Dr. Freeman led the charge in the

United States, actually traveling the country doing icepick lobotomies in what he affectionately called the “lobotomobile.” A 30-year-old woman with postpartum depression and an

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Book Review

unruly fifth-grade boy were among his thousands of “patients.”

Well-Organized Narrative Shrinks, with the help of the talented writer Ogi Ogas, is well written and organized in a linear way that gives the narrative a clear trajectory. The book begins with a section

called “The Story of Diagnosis,” in which the author rolls out some of the eccentric quacks in psychiatry’s history. He writes with frankness: “Psychiatry has trumpeted more illegitimate treatments than any other field of medicine, in large part because —until quite recently—psychiatrists could never agree on what

actually constituted a mental disorder, much less how best to treat it.”

Naturally, “The Story of Diagnosis” is loaded with tales of Sigmund Freud, and the author does a good job filling in many of the blank spaces in Freud’s complicated life and career.

Freud’s work held enormous sway on the sociopolitical landscape of West-

ern Europe, and eventually, America.

The author writes, “German fascism roused psychoanalysts from its American slumber and invigorated a new Freudian force in North America that would systematically take over every institution of American psychiatry— and soon beget the shrink.” continued on page 98

The ASCO Post | NOVEMBER 25, 2015

PAGE 98

Book Review Untold Story of Psychiatry continued from page 97

Dr. Lieberman is at his best when analyzing his predecessors and their impact on people. He writes, “Starting in the late 1950s and early ’60s, the psychoanalysts set out to convince the public that we were all walking wounded, normal neurotics,

functioning psychotics … and that Freud’s teachings contained the secrets to eradicating inner strife and reaching our full potential as human beings.”

While oncologists have a battery of cutting-edge tools to help make precise cancer diagnoses, psychiatry does not possess such technology.

Dr. Lieberman admits that reading the highly subjective Diagnostic and Statistical Manual of Mental Disorders (DSM) is a mind-numbing exercise.

There is such overlap in the multitude of disorders that it becomes a psychiatric stew of mental illnesses and complexes for the various “schools” of psychiatry to sort out.

As he notes, a lot of harm was done during its various iterations.

Misguided Views The most tarnished psychoanalytic diagnosis was undoubtedly homosexuality. In the 1950s, the prevailing thought among psychiatrists was that a controlling mother and weak-kneed father

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Book Review

“caused” homosexuality. American psychiatry had long considered homosexuality to represent deviant behavior, and generations of practitioners had labeled it a mental disorder, one that needed fixing. In fact, the first volume of the manual (DSM-I) described homosexuality as a “sociopathic personality disturbance.”

That misguided view carried on well

into the 1960s, without any rigorous scientific methodology to back up the claim. As a mea culpa to the malpractice of his profession, Dr. Lieberman offers this, “This unfounded and immensely destructive attribution of unconscious conflicts in homosexual persons illustrates the broad fallibility and potential for misuse of the psychoanalytic ap-

proach to diagnosis. In the absence of a rigorous scientific methodology, therapists were prone to projecting their own values and intuitions onto the mental lives of their patients.”

Public Backlash Given the arbitrary nature of psychiatry and many of the crude meth-

ods for “curing” the mentally ill, it’s not surprising that the profession suffered a backlash from the public. In 1961, Hungarian-born psychiatrist Thomas Szasz, MD, published The Myth of Mental Illness, which won him instant fame and ignited the antipsychiatry movement. “Szasz’s ideas helped give birth to an organized activist movement that questioned the very existence of the profession of psychiatry, and called for its eradication,” writes Dr. Lieberman.

He does a thorough job giving the historical context of the public’s growing dissatisfaction at what many felt was a highly subjective profession populated by quacks and opportunists. Psychiatry went through a long and bumpy period before being resurrected by pharmacology.

In one of the book’s best chapters, “Mother’s Little Helper: Medicine at Last,” Dr. Lieberman treats the readers to a lively discussion about the early days of the medication revolution in psychiatry, some of the unfortunate missteps—such as high doses of morphine to treat sleep disorders—and the eventual success stories of medications that truly improved the lives of people with life-altering psychiatric conditions.

But, as he asserts, “Before the psycho-pharmacologists could permanently tip the balance away from the ivory-tower psychoanalysts, one final revolution was still necessary … pioneering the frontiers of the human brain.” With the advent of highly sensitive imaging technology, neuropsychologists could explore the inner workings of the brain. “As a result of these magnificent new technologies, psychiatrists could finally examine the brain of a living person in all its exquisite splendor.”

Remaining Honest Psychiatric conditions such as manic depression and bipolar disorders have been stigmatized, and Dr. Lieberman ends with a compassionate discussion about these disorders and the crippling effect they have unless treated.

Despite a few areas where the book bogs down, this is a first-rate and enjoyable read. At the end, Dr. Lieberman remains honest about his profession: “I am under no illusion that the specters of psychiatry’s past have vanished, or that my profession has freed itself from suspicion … but psychiatry has arrived at a pivotal moment in its evolution, and it is an opportunity to reflect on the work that lies ahead.” n

The ASCO Post | NOVEMBER 25, 2015

PAGE 100

Integrative Oncology Graviola

By Jyothirmai Gubili, MS

T

he use of dietary supplements by patients with cancer has increased significantly over the past 25 years despite insufficient evidence of safety and effectiveness.

Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information.

The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. We chose graviola for this issue because of the growing interest of cancer patients in the herb’s anticancer potential.

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.

Graviola Scientific name: Annona muricata Common names: Guanabana, soursop, custard apple, Brazilian pawpaw

Overview

A small, evergreen tree that belongs to the custard apple family, graviola is a native of the tropical areas in Central and South Americas and the Caribbean. Graviola produces heart-shaped edible fruits, the pulp of which is used to make drinks and sherbets.

Graviola also has a long history of medicinal use for treating inflamma-

tory conditions, diabetes, hypertension, insomnia, parasitic infections, and cancer. All parts of the tree including the bark, leaves, fruits, and roots are used in herbal medicine.

Jyothirmai Gubili, MS

Interest in graviola as a potential anticancer agent surged following the discovery of its cytotoxic property in a 1976 plant-screening program by the National Cancer Institute. Annonaceous acetogenins, extracted from different parts of the tree, were found to have cytotoxic effects. These observations have yet to be confirmed in clinical trials. Nevertheless, despite lack of substantial evidence, graviola is heavily promoted as a cancer-fighting herb.

Products containing graviola are available in health food stores and via the Internet in the form of capsules, liquid extracts, juice blend, teas, and tinctures.

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.

In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. the expression of hypoxia-inducible factor 1-alpha, nuclear factor kappaB, glucose transporters, and glycolytic enzymes, resulting in decreased glucose uptake and adenosine triphosphate production in pancreatic cancer cells11 as well as downregulated epidermal growth factor receptor expression in breast cancer cells.8

The Science

Graviola exerts antiviral,1 antiparasitic,2 cytotoxic,3 anti-inflammatory,4 antiplatelet,5 antidiabetic,6 antihyperglycemic,7 and anticancer effects8,9 in vitro and in vivo.

Mechanistic studies revealed the effectiveness of graviola extracts against the growth of doxorubicinresistant human mammary adenocarcinoma (MCF-7/Adr) cells by blocking access of cancer cells to adenosine triphosphate and by inhibiting the actions of plasma membrane glycoprotein.10 They also inhibited

cies production, and expression of the apoptosis regulator Bax and the Bax/Bcl-2 ratio.12 Phenolic compounds of graviola also demonstrated free-radical scavenging potential against human breast carcinoma cells.13 However, human data are lacking.

Of concern are findings that alkaloids extracted from graviola can cause neuronal dysfunction and degeneration.14,15 Graviola also may decrease the uptake of radiopharmaceuticals used in nuclear imaging.16

Adverse Reactions

Repeated consumption of graviola resulted in movement disorders and myeloneuropathy with symptoms mimicking Parkinson’s disease.14,15

In a rodent model of hepatic cancer, bullatacin, an acetogenin derived from graviola, caused hepato- and nephrotoxicity by increasing calcium concentration, reactive oxygen spe-

Herb-Drug Interactions

Antidiabetics and antihypertensives: Graviola may have additive ­effects.7,17 n

Disclosure: Ms. Gubili reported no potential conflicts of interest.

Learn More About

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

www.mskcc.org/cancer-care/ integrative-medicine/herbs/graviola

ASCOPost.com | NOVEMBER 25, 2015

PAGE 101

Integrative Oncology References 1. Padma P, Pramod NP, Thyagarajan SP, et al: Effect of the extract of Annona muricata and Petunia nyctaginiflora on Herpes simplex virus. J Ethnopharmacol 61:81-83, 1998.

2. dos Santos AF, Sant’Ana AE: Molluscicidal properties of some species of Annona. Phytomedicine 8:115-120, 2001.

3. Liaw CC, Chang FR, Lin CY, et al: New cytotoxic monotetrahydrofuran annonaceous acetogenins from Annona muricata. J Nat Prod 5:470-475, 2002.

4. de Sousa OV, Vieira GD, de Jesus RGdPJ, et al: Antinociceptive and antiinflammatory activities of the ethanol extract of Annona muricata L. leaves in animal models. Int J Mol Sci 11:20672078, 2010.

5. Awodele O, Ishola IO, Ikumawoyi VO, et al: Toxicological evaluation of the lyophilized fruit juice extract of Annona muricata Linn. (Annonaceae) in rodents.

J Basic Clin Physiol Pharmacol 18:1-11, 2013.

6. Florence NT, Benoit MZ, Jonas K, et al: Antidiabetic and antioxidant effects of Annona muricata (Annonaceae), aqueous extract on streptozotocin-induced diabetic rats. J Ethnopharmacol 151:784790, 2014.

7. Adeyemi DO, Komolafe OA, Adewole OS, et al: Antihyperglycemic activities of Annona muricata (Linn). Afr J Tradit Complement Altern Med 6:62-69, 2008.

8. Dai Y, Hogan S, Schmelz EM, et al: Selective growth inhibition of human breast cancer cells by graviola fruit extract in vitro and in vivo involving downregulation of EGFR expression. Nutr Cancer 63:795-801, 2011.

9. Hamizah S, Roslida AH, Fezah O, et al: Chemopreventive potential of Annona muricata L leaves on chemically-induced skin papillomagenesis in mice. Asian Pac J Cancer Prev 13:2533-2539, 2012.

10. Oberlies NH, Chang CJ, McLaughlin JL: Structure-activity relationships of diverse Annonaceous acetogenins against multidrug resistant human mammary adenocarcinoma (MCF-7/Adr) cells. J Med 40:2102-2106, 1998.

11. Torres MP, Rachagani S, Purohit V, et al: Graviola: A novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Lett 323:29-40, 2012.

12. Chen Y, Chen JW, Zhai JH, et al: Antitumor activity and toxicity relationship of annonaceous acetogenins. Food Chem Toxicol 58:394-400, 2013.

13. George VC, Kumar DR, Rajkumar

V, et al: Quantitative assessment of the relative antineoplastic potential of the n-butanolic leaf extract of Annona muricata Linn. in normal and immortalized human cell lines. Asian Pac J Cancer Prev 13:699-704, 2012.

14. Lannuzel A, Michel PP, CaparrosLefebvre D, et al: Toxicity of Annonaceae for dopaminergic neurons: Potential role

in atypical parkinsonism in Guadeloupe.

Mov Disord 17:84-90, 2002.

15. Lannuzel A, Hoglinger GU, Champy P, et al: Is atypical parkinsonism in the Caribbean caused by the consumption of Annonacae? J Neural Transm Suppl (70):153-157, 2006.

16. Holanda CM, Barbosa DA, Demeda VF, et al: Influence of Annona muri-

cata (soursop) on biodistribution of radiopharmaceuticals in rats. Acta Cir Bras Mar 29:145-150, 2014.

17. Nwokocha CR, Owu DU, Gordon A, et al: Possible mechanisms of action of the hypotensive effect of Annona muricata (soursop) in normotensive SpragueDawley rats. Pharm Biol 50:1436-1441, 2012.

ADVERTORIAL

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SIGNALING PATHWAYS

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Cancer Stem Cells and Their Role in Recurrence and Metastasis Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 Cancer stem cells are a subset of the total cancer cell population that is highly tumorigenic.2,3 Chemotherapy and radiation have been shown to affect the primary tumor, but not the cancer stem cell.4 Many patients with cancer, even though diagnosed early, succumb to the disease because of recurrence and metastasis.5,6 Cancer stem cells are thought to contribute to this recurrence and metastasis.7

Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stem cell pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis.

Another characteristic of cancer stem cells is that they possess stemness. Stemness distinguishes cancer stem cells by their ability to continually self-renew, differentiate into cancer cells, migrate, and regrow the tumor.7,8 Most chemotherapeutic strategies target actively proliferating cancer cells, resulting in bulk tumor shrinkage. Cancer stem cells, however, are highly resistant to these therapies and may not be eradicated during treatment, resulting in recurrence and metastasis.4,7 Moreover, chemotherapy and radiation have the potential to induce stemness properties in non-stem cancer cells.2,9 Several signaling pathways are involved in the induction and maintenance of stemness in cancer stem cells, including JAK/ STAT, Wnt/β-catenin, Hedgehog, Notch, and Nanog.10-12 Targeting these aberrant signaling pathways may result in cancer stem cell apoptosis, while reducing the toxicity to normal tissues that is associated with chemotherapy.4

EDU-NPS-0027

8/2015

©2015 Boston Biomedical

Learn more at www.bostonbiomedical.com References: 1. Li Y, Rogoff HA, Keates S, et al. Supression of cancer relapse and metastasis by inhibiting cancer stemness.

Proc Natl Acad Sci. 2015;112(6):1839-1844. 2. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer stemness by chemotherapy.

Cell Cycle. 2012;11(14):2691-2698. 3. Clarke MF. Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant. 2005:11(2 suppl 2):14-16. 4. Boman BM, Huang E. Human colon cancer stem cells: A new paradigm in gastrointestinal oncology. J Clin Oncol.

2008;26(17):2828-2838. 5. Ahmad A. Pathways for breast cancer recurrence. ISRN Oncol. 2013;2013:290568. doi: 10.1155/2013/290568.

6. Hung JH, Wu YC. Stage I non-small cell lung cancer: recurrence patterns, prognostic factors and survival. In: Cardoso P, ed. Topics in Thoracic Surgery. Shanghai, China: InTech; 2012:285-292. http:// www.intechopen.com/books/topics-in-thoracic-surgery/stage-inon-smallcell-lung-cancer-recurrence-patterns-prognostic-factorsand-survival. Accessed May 8, 2015. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261.

8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 9. Ghisolfi L, Keates AC, Hu X, Lee D, Li CJ. Ionizing radiation induces stemness in cancer cells.

PLOS ONE. 2012;7(8):1-11. 10. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549-1554. 11. Bourguignon LYW, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149160. 12. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-tomesenchymal transition. Onco Targets Ther. 2013;6:1249-1259.

The ASCO Post | NOVEMBER 25, 2015

PAGE 102

Journal Spotlight Thoracic Oncology

Checkmate 057: Nivolumab Improves Survival vs Docetaxel in Advanced Nonsquamous Non–Small Cell Lung Cancer

By Matthew Stenger

I

n the phase III CheckMate 057 trial, reported in The New England Journal of Medicine by Hossein Borghaei, DO, of Fox Chase Cancer Center, and colleagues, the programmed cell death protein 1 (PD-1) inhibitor nivolumab (Opdivo) improved overall survival vs docetaxel in patients with advanced nonsquamous non–small cell lung cancer (NSCLC).1 (A phase III trial reported earlier this year by Julie Renee Brahmer, MD, of Sidney

Julie Renee Brahmer, MD

Kimmel Comprehensive Cancer Center, and colleagues showed survival improvement with nivolumab vs docetaxel in advanced squamous NSCLC.2)

Study Details In this open-label international trial, 582 patients with nonsquamous NSCLC progressing during or after platinum-based doublet chemotherapy were randomly assigned between November 2012 and December 2013 to receive intravenous nivolumab at 3 mg/ kg every 2 weeks (n = 292) or intravenous docetaxel at 75 mg/m2 every 3 weeks (n = 290). Nivolumab patients could receive the drug beyond disease progression.

The primary endpoint was overall survival. Formal testing for the primary endpoint was based on a prespecified interim analysis; the current report provided an updated P value

based on data from a July 2, 2015, database lock.

The nivolumab and docetaxel groups were generally balanced for all patient characteristics that were ­assessed.

Among patients with advanced nonsquamous NSCLC that had progressed during or after platinumbased chemotherapy, overall survival was longer with nivolumab than with docetaxel.

Overall Survival Minimum follow-up for overall survival was 13.2 months. Median overall survival was 12.2 months (95% confidence interval [CI] = 9.7–15.0 months) in the nivolumab group vs 9.4 months (95% CI = 8.1–10.7 months) in the docetaxel group (hazard ratio [HR] = 0.73, P = .002). Overall survival rates were 51% (95% CI = 45%–56%) vs 39% (95% CI = 33%–45%) at 1 year. With additional follow-up, median overall survival was 12.2 months (95% CI = 9.7–15.1 months) vs 9.4 months (95% CI = 8.1–10.7 months; HR = 0.72, P < .001), and overall survival at 18 months was 39% (95% CI = 34%–45%) vs 23% (95% CI = 19%–28%).

Subgroup analysis showed that hazard ratios favored nivolumab in most subgroups, except among 66 patients receiving third-line therapy, 98 patients in the “rest of the world” geographic subgroup (South America, Asia, and Australia), 68 patients with central nervous system metastases, 118 neversmokers, and 82 patients with an epidermal growth factor receptor (EGFR) mutation; none of the hazard ratios for these subgroups was significant. Subsequent systemic cancer therapy was received by 42% of the nivolumab group (23% docetaxel, 29% taxanes) and 50% of the docetaxel group (27% antimetabolites, 2% immunotherapy).

Response Rate The overall response rate was 19% with nivolumab vs 12% with docetaxel (P = .02). Median duration of response was 17.2 vs 5.6 months.

Nivolumab in Nonsquamous NSCLC ■■ Nivolumab significantly improved overall survival vs docetaxel in platinumpretreated patients.

■■ Nivolumab was associated with increased efficacy in subgroups defined according to prespecified PD-L1 levels of ≥ 1%, ≥ 5%, and ≥ 10%.

—Hossein Borghaei, DO, and colleagues

Among 71 patients in the nivolumab group (24%) who continued treatment after initial progression, 16 (23%) exhibited a nonconventional pattern of benefit.

Outcomes by PD-L1 Level PD-1 ligand (PD-L1) expression was quantifiable in 455 patients (78%).

A test for interaction at interim analysis indicated significant associations between treatment effect and PD-L1 expression level. The hazard ratio for overall survival was 0.59 (95% CI = 0.43–0.82) among 123 nivolumab and 123 docetaxel recipients with levels ≥ 1%, 0.43 (95% CI = 0.30–0.63), among 95 nivolumab and 86 docetaxel recipients with levels ≥ 5%, and 0.40 (95% CI = 0.26-0.59) among 86 nivolumab and 79 docetaxel recipients with levels ≥ 10%. The corresponding hazard ratios for progression-free survival were 0.70 (95% CI = 0.53–0.94), 0.54 (95% CI = 0.39–0.76), and 0.52 (95% CI = 0.37–0.75).

Adverse Events The most common treatment-related adverse events of any grade were fatigue (16%), nausea (12%), decreased appetite (10%), and asthenia (10%) in the nivolumab group and neutropenia (31%), fatigue (29%), nausea (26%), and alopecia (25%) in the docetaxel group. Treatment-related grade 3 or 4 adverse events occurred in 10% (most common = fatigue, nausea, and diarrhea in 1% each) vs 54% (most common = neutropenia in 27%, febrile neutropenia in 10%). Treatment-related serious adverse events occurred in 7% vs 20%.

Treatment-related adverse events led

to discontinuation of study drug in 5% vs 15%, with the most common causes being pneumonitis in the nivolumab group (1%) and fatigue in the docetaxel group (3%). Dose delay occurred in 39% of the nivolumab group (45% due to adverse events) and 37% of the docetaxel group (46% due to adverse events). One death in the nivolumab group (due to encephalitis) and one in the docetaxel group (due to febrile neutropenia) were considered related to study treatment.

The most frequently reported treatment-related select adverse events, including immune-related events, of any grade were rash (9% of the nivolumab group vs 3% of the docetaxel group), pruritus (8% vs 1%), erythema (1% vs 4%), diarrhea (8% vs 23%), hypothyroidism (7% vs 0%), increased alanine transaminase (3% vs 1%), increased aspartate transaminase (3% vs 1%), infusion-related reaction (3% vs 3%), and pneumonitis (3% vs < 1%).

The investigators concluded: “Among patients with advanced nonsquamous NSCLC that had progressed during or after platinumbased chemotherapy, overall survival was longer with nivolumab than with docetaxel.” n Disclosure: The study was funded by BristolMyers Squibb. For full disclosures of the study authors, visit www.nejm.org.

References 1. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.

N Engl J Med 373:1627-1639, 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.

TheWe’ve We’ve Got It Covered The Coveredprogram programisisan anall-in-one all-in-one resource that that provides provides information resource informationabout aboutAFINITOR AFINITOR access, fifinancial nancial assistance, access, assistance,and andsupport supportprograms programs available to to eligible eligible patients. available patients.

Features of the program include: Features of the program include: 14-Day Free Trial 14-Day Free Trial • Free 14-day supply of AFINITOR® (everolimus) Tablets at treatment initiation,

• Free 14-day supplytoofget AFINITOR® (everolimus) Tablets treatment allowing patients on therapy promptly while ourat experts assistinitiation, them allowing patients to get onneeds therapy promptly while our experts assist them with financial or coverage with financial or coverage needs

Getting Insurance on Board Getting Insurance onin:Board • Our experts are trained

— Routine such • Our experts processes are trained in: as benefits verifications and prior authorization (PA) assistance* — Routine processes such as benefits verifications and prior authorization (PA) —assistance* Assisting with many of the possible complications that sometimes arise when trying secure coverage, includingthat denied or appealed — Assisting withtomany ofinsurance the possible complications sometimes arise insurance claims when trying to secure insurance coverage, including denied or appealed *PA assistance available to eligible patients. insurance claims

Making It Affordable • $25 AFINITOR Co-Pay Card Making It Affordable

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• Referrals to independent charitable organizations and government-funded † • $25 AFINITOR Co-Pay Card programs • • Referrals to independent charitabletoorganizations and government-funded Therapy-specifi c support programs cover out-of-pocket costs programs † Limitations apply. See Program Terms and Conditions. Up to $6350 per month; • Therapy-specific support programs to cover out-of-pocket costs patient responsible for any difference above $6350 per month. This offer is not † Limitations See Medicaid, Program Terms Conditions.

Up toprogram. $6350 per month; valid underapply.

Medicare, or any and other federal or state Novartis patient responsible any diff erence per month.

Thisnotice. offer is not reserves the right tofor rescind, revoke, orabove amend$6350 this program without valid under Medicare, Medicaid, or any other federal or state program. Novartis Coverage for the Uninsured reserves the right to rescind, revoke, or amend this program without notice.

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To find out more about these and other programs, contact sales specialist, visit www.AFINITOR.com, Toyour findNovartis out more about these and other programs, contact orspecialist, call 1-877-433-8067. your Novartis sales visit www.AFINITOR.com,

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The ASCO Post | NOVEMBER 25, 2015

PAGE 104

Through the Lens of Oncology History

A Century of Progress The text and photographs on this page are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD, FACS. The photos below are from the volume titled “The X-ray Era: 1901–1915.” To view additional photos from this series of books, visit burnsarchive.com.

THE X-RAY Era: 1901–1915 Submammilary Infusion, Chicago, 1907

T

he length and complexity of surgical procedures increased as anesthesia and antisepsis became the standard of care. It seemed the only limiting factors to complete success were anesthesia complications and blood loss.

The prime disaster and cause of immediate death in cancer surgery, especially resections of vascular tumors, large sarcomas, and breast and prostate cancers, is significant blood loss. Patients were monitored by pulse rate as well as respiration and skin color.

William Halsted, MD

When William Halsted, MD, transfused his own blood into his sister, it was recognized as the first successful human transfusion. At that time, the medical community still had no knowledge of blood types and factors, so there was an inherent danger of death to the recipient of a person-to-person transfusion.

Alternate means of preserving blood and fluids were needed.

Autotransfusion, the temporary intravascular displacement of the blood to the essential organs by mechanical means, was recognized as one of the most important and valuable. It was easy to perform and its effects were immediately achieved; simply raising the legs caused the blood to flow back into the body. The backbone of autotransfusion was alternately restricting the blood flow to an extremity. It was thought to be perfectly safe to exclude blood from a limb

August Nélaton, MD

for at least 2 hours. Several surgeons over the centuries recognized the procedure as a life-saving necessity. French master surgeon ­August Nélaton, MD (1807–1873), and English master surgeon John Hunter, MD, advocated the procedure. However, it was Johann F.A. von ­Esmarch (1823–1908), already famous for introducing the first-aid bandage on the battlefield, who perfected the technique. In 1873, he described a method of bandaging for surgical hemostasis by elevating the leg vertically, waiting a few minutes for the blood to drain out and then wrapping the entire leg starting at the foot. His methods simply shifted the available blood in severe hemorrhage, but fluid replacement was still needed. In the 1890s, mechanisms for the delivery of body hypertonic fluid were developed, with normal saline solution used as the blood substitute. It was a significant step forward in medical treatment to realize that circulation could be maintained and blood loss replaced with an equivalent quantity of normal salt solution.

Nicholas Senn, MD, in 1901, noted, “The solution used is a 6/10 of 1 percent solution of chemically pure sodium chloride…. In emergencies it is prepared by dissolving a teaspoon of salt in a pint of water. The solution is administered at a temperature of about 120 degrees… by three different routes, according to the urgency of the

symptoms — by the rectum, hypodermically, and directly into larger veins … in the rectum…. From one to two quarts of the solution can be given every 2 or 3 hours until the necessary degree of intravascular tension has been reached. In graver cases the solution is administered subcutaneously, infusing from a pint to a quart at a time, and repeating the procedure every hour or two…. All that is necessary for making the subcutaneous infusion are a small trocar and an irrigator. For the puncture, localities are selected where the subcutaneous tissue is abundant and loose, as the mammary and interscapular regions, the abdomen, or the inner surface of the thigh.”

This photograph, taken for Carl Beck, MD’s 1907 text, Surgical Diseases of the Chest, shows a typical hypodermoclysis. While the patient was on the operating table, a hypodermic needle was placed beneath the breast and the fluid run in. When necessary, this procedure could also be performed at the bedside. Hypodermoclysis remained a standard procedure for at least two more decades.

In 1908, a year after this photograph appeared, the modern era of blood transfusion began when Alexis Carrel, MD, sutured a father’s artery to a dying baby’s vein. Cleveland’s George W. Crile, MD (1864–1943), developed a cannula to attach blood vessels and this method, aptly named “direct blood transfusion,” became the procedure of choice for blood transfusion. It was the method of blood replenishment used for decades. In 1900, Karl Landsteiner, MD (1868–1943), discovered the blood groups A, B, and O, and published his findings. Unfortunately, few physicians paid attention to his discovery and for years performed direct blood transfusions hoping there would be no reaction.

Dr. Landsteiner did win the 1930 Nobel Prize in Medicine for his work.

By 1915, Dr. Crile and others developed detailed protocols for dealing with surgical shock from blood loss.

Dr. Crile also developed a rubber surgical suit for the patient that proved a more effective method for auto­ transfusion. n

ASCOPost.com | NOVEMBER 25, 2015

PAGE 105

Announcements

American Board of Internal Medicine Names Richard G. Battaglia, MD, FACP, Chief Medical Officer

T

he American Board of Internal Medicine (ABIM) announced that Richard G. Battaglia, MD, FACP, has joined the senior leadership team of the organization and will serve as Chief Medical Officer, leading ABIM’s effort to incorporate feedback from practicing physicians and key stakeholders into clinical aspects of all ABIM activities, including certification and maintenance of ­certification.

centers, health systems, community hospitals, medical groups, payers, and national physician certification ­organizations.

Dr. Battaglia received his medical

degree from the University of Rochester School of Medicine and Dentistry. He completed his residency through the University of Rochester Primary Care Program in internal

medicine, and also served as Chief Resident of the University’s Primary Care Program in Internal Medicine.

Dr. Battaglia is a Fellow of the American College of Physicians. n

NOW ENROLLING Rociletinib Expanded Access Program

Richard G. Battaglia, MD, FACP

Dr. Battaglia served as a primary care internist with Health Care Plan/ Univera, a multispecialty physician group in Western New York, before transitioning into leadership roles. At ABIM, he reports to President and Chief Executive Officer Richard J. Baron, MD.

New Role Dr. Battaglia assumed his new position in October. As Chief Medical Officer, he will build and lead ABIM’s Clinical Affairs efforts to support the organization’s work in defining and assessing physician competencies.

Going forward, the department will more fully integrate physician voices into the design and operation of ABIM activities to ensure that all products and services, including certification and maintenance of certification, contribute to the highestquality practice of medicine and better outcomes for patients.

Dr. Battaglia has participated in national initiatives at the Group Practice Improvement Network and The HMO Group, which focused on improving the quality of health-care delivery. He worked with the National Committee for Quality Assurance for 10 years, including a term as Chairman of the committee charged with accreditation decision-making.

Most recently, he was a consultant for national and international organizations, including academic medical

For patients with previously treated EGFR mutation– positive NSCLC and the T790M resistance mutation Access for eligible patients in the US who have no other available rociletinib clinical trial options Key inclusion criteria • Documented evidence of a tumor with the T790M mutation • Prior treatment with an approved or experimental EGFR-directed therapy • Central nervous system metastases, other than leptomeningeal disease, are permitted if asymptomatic and stable • Prior chemotherapy is permitted if the last treatment occurred >14 days prior to the first dose of rociletinib

Key exclusion criteria • EGFR exon 20 insertion activating mutation • Prior participation in a rociletinib clinical trial or eligibility for a current rociletinib clinical trial Upon FDA approval of rociletinib, patients will be transitioned to the commercially available drug.

Visit TIGERtrials.com to learn more

Copyright © 2015 Clovis Oncology. All rights reserved. NP-ROCI-US-0028 10/15

The ASCO Post | NOVEMBER 25, 2015

PAGE 106

Journal Spotlight Breast Cancer

Mediterranean Diet Supplemented With Extra-Virgin Olive Oil Reduces Risk for Invasive Breast Cancer

By Matthew Stenger

A

s reported in JAMA Internal Medicine by Estefania Toledo, MD, MPH, PhD, and colleagues, a large Spanish primary prevention nutrition intervention trial in patients at high cardiovascular risk (PREDIMED) showed a large reduction in the risk for invasive breast cancer among women 60 to 80 years of age whose Mediterranean diet was supplemented with

with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet with advice to reduce dietary fat. Participants in the two intervention groups were given supplementary foods for free, consisting of 1 L/wk of extra-virgin olive oil for participants and their families or mixed nuts (30 g/d; 15 g of walnuts, 7.5 g of hazelnuts, and 7.5 g of almonds). At baseline

with nuts, and 1,391 received the control diet. The three groups were generally balanced for age (mean 67 to 68 years), smoking status (never for 87% in each), body mass index, hypertension, type 2 diabetes, dyslipidemia, family history of premature coronary heart disease or cancer, use of hormone therapy, age at menopause, and alcohol consumption.

Breast Cancer Incidence

Our results suggest a beneficial effect of a Mediterranean diet supplemented with extra-virgin olive oil in the primary prevention of breast cancer.

—Estefania Toledo, MD, MPH, PhD, Miguel A. Martínez-González, MD, PhD, and colleagues

extra-virgin olive oil.1 Dr. Toledo and the corresponding author of this article, Miguel A. Martínez-González, MD, PhD, are both from the University of Navarra School of Medicine, in Pamplona, Navarra, Spain.

Study Details The PREDIMED trial included 7,447 men aged 55 to 80 years or women aged 60 to 80 years (n = 4,282) with no cardiovascular disease at entry but considered to be at high cardiovascular risk. High-risk cardiovascular disease was defined as type 2 diabetes or three risk factors from among smoking, hypertension, elevated low-density lipoprotein (LDL) cholesterol, low highdensity lipoprotein (HDL) cholesterol, overweight or obesity, or a family history of premature coronary heart disease.

Patients were randomized between October 2003 and June 2009 to receive a Mediterranean diet supplemented

and once a year during follow-up, participants were administered a validated 14-item Mediterranean diet screener, a general medical questionnaire, a 137item validated food-frequency questionnaire, and the Minnesota LeisureTime Physical Activity Questionnaire.

The incidence of breast cancer was a prespecified secondary outcome of the trial among women with no history of breast cancer (n = 4,152).

Among these women, 1,476 received the Mediterranean diet with olive oil, 1,285 received the Mediterranean diet

After a median follow-up of 4.8 years, there were 35 confirmed incident cases of invasive breast cancer. Among patients with available receptor-status information, 31 of 33 had estrogen receptor–positive disease, 21 of 27 had progesterone receptor–positive disease, and 12 of 21 had HER2-positive disease.

The incidence rates were 8 of 7,031 person-years in the Mediterranean diet with extra-virgin olive oil group, 10 of 5,492 person-years in the Mediterranean diet with nuts group, and 17 of 5,829 person-years in the control group, yielding rates per 1,000 personyears of 1.1, 1.8, and 2.9, respectively.

On multivariate analysis adjusting for age, study site, body mass index, waistto-height ratio, use of hormone therapy, leisure-time physical activity, total energy intake, alcohol consumption, age at menopause, and baseline adherence to the Mediterranean diet, hazard ratios for invasive breast cancer were 0.32 (95% confidence interval [CI] = 0.13–0.79) for the Mediterranean diet with extra-virgin olive oil group and 0.59 (95% CI = 0.26–1.35) for the Mediterranean diet with nuts group compared with the control group. After excluding women with follow-up of less than 1 year (including one patient who developed breast cancer in the

Dietary Intervention and Breast Cancer ■■ Use of the Mediterranean diet supplemented with extra-virgin olive oil was associated with a significantly reduced risk for invasive breast cancer, according to the results of a large Spanish primary prevention nutrition intervention trial in patients at high cardiovascular risk.

■■ Higher consumption of extra-virgin olive oil was associated with a greater risk reduction in invasive breast cancer.

olive oil group, one in the nuts group, and two in the control group), hazard ratios were 0.33 (95% CI = 0.13–0.85) and 0.65 (95% CI = 0.27–1.53) vs the control group.

In analyzed subgroups, hazard ratios for the olive oil group vs the control group were similar to those in the overall population and were significant among women aged ≤ 67 years, never smokers, those with type 2 diabetes, nonusers of hormone therapy, those with no family history of cancer, and those with low baseline adherence to the Mediterranean diet.

Risk and Olive Oil Consumption In a per-protocol analysis in the combined-study groups, participants who had higher extra-virgin olive oil consumption during follow-up had the lowest risk for breast cancer (hazard ratio = 0.18, 95% CI = 0.06–0.57, for 5th vs 1st quintile). In analysis with yearly cumulative updated dietary exposures, the hazard ratio was 0.72 (95% CI = 0.57–0.90) for each additional 5% of calories from extra-virgin olive oil.

The investigators concluded: “This is the first randomized trial finding an effect of a long-term dietary intervention on breast cancer incidence. Our results suggest a beneficial effect of a Mediterranean diet supplemented with extravirgin olive oil in the primary prevention of breast cancer. These results come from a secondary analysis of a previous trial and are based on few incident cases and, therefore, need to be confirmed in longer-term and larger studies.” n

Disclosure: The PREDIMED trial was supported by Instituto de Salud Carlos III and by the National Institutes of Health, Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional, Consejería de Salud de la Junta de Andalucía, and Generalitat Valenciana.

For full disclosures of the study authors, visit www.jama.jamanetwork.com.

Reference 1. Toledo E, Salas-Salvadó J, DonatVargas C, et al: Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: A randomized clinical trial. JAMA Intern Med 175:1752-1760, 2015.

Diet and Cancer: How Will We Make Progress?

Clifford A. Hudis, MD, shares his perspective on the PREDIMED study discussed above. See page 110 in this issue of The ASCO Post.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR TREANDA® (bendamustine hydrochloride) injection, for intravenous use TREANDA® (bendamustine hydrochloride) for injection, for intravenous use 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

2 DOSAGE AND ADMINISTRATION 2.1 Selection of TREANDA Formulation to Administer TREANDA is available in two formulations, a solution (TREANDA Injection) and a lyophilized powder (TREANDA for Injection).

Do not use TREANDA Injection if you intend to use closed system transfer devices (CSTDs), adapters and syringes containing polycarbonate or acrylonitrilebutadiene-styrene (ABS) prior to dilution in the infusion bag [see Dosage and Administration (2.4)].

If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag. Polypropylene syringes are translucent in appearance.

TREANDA Injection and the reconstituted TREANDA for Injection have different concentrations of bendamustine hydrochloride. The concentration of bendamustine hydrochloride in the solution is 90 mg/mL and the concentration of bendamustine hydrochloride in the reconstituted solution of lyophilized powder is 5 mg/mL. Do not mix or combine the two formulations.

TREANDA Injection must be withdrawn and transferred for dilution in a biosafety cabinet (BSC) or containment isolator using a polypropylene syringe with a metal needle and a polypropylene hub.

If a CSTD or adapter that contains polycarbonate or ABS is used as supplemental protection prior to dilution, only use TREANDA for Injection, the lyophilized powder formulation [see How Supplied/Storage and Handling (16.1)].

2.2 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [see Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.

Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.

Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.

2.4 Preparation for Intravenous Administration TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures.

TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) TREANDA Injection must be diluted in a biosafety cabinet (BSC) or containment isolator.

• When preparing and transferring the concentrated TREANDA Injection solution into the infusion bag, do not use devices that contain polycarbonate or ABS. However, after dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used. TREANDA Injection contains N,N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices, including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA which is present in the product. This incompatibility leads to device failure (e.g., leaking, breaking, or operational failure of CSTD components), possible product contamination, and potential serious adverse

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

health consequences to the practitioner, including skin reactions; or to the patient, including but not limited to, the risk of small blood vessel blockage if they receive product contaminated with dissolved ABS or polycarbonate. Devices that are compatible for use in dilution of TREANDA Injection are available.

• If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and a polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag.

• Each vial of TREANDA Injection is intended for single dose only.

• Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution using a polypropylene syringe with a metal needle and a polypropylene hub.

• Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.7 mg/mL. • After dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used.

• Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear colorless to yellow solution.

Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) If a closed system transfer device or adapter that contains polycarbonate or ABS is to be used as supplemental protection during preparation, only use TREANDA for Injection, the lyophilized formulation.

• Each vial of TREANDA for Injection is intended for single dose only.

• Aseptically reconstitute each TREANDA for Injection vial as follows: ◦ 25 mg TREANDA for Injection vial: Add 5 mL of only Sterile Water for Injection, USP. ◦ 100 mg TREANDA for Injection vial: Add 20 mL of only Sterile Water for Injection, USP. • Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not be used.

• Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag.

• Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear and colorless to slightly yellow solution.

Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

General Information Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

2.5 Admixture Stability TREANDA Injection and TREANDA for Injection contain no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature (15°-30°C or 59°86°F) and room light. Administration of diluted TREANDA Injection must be completed within this period.

TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (3647°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of reconstituted and diluted TREANDA for Injection must be completed within this period.

4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [see Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4).

Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [see Dosage and Administration (2. 2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports,

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.

In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes.

The relationship to TREANDA cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.

5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

6.1 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.

Chronic Lymphocytic Leukemia The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days.

Adverse reactions were reported according to NCI CTC v.2.0. Non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).

Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.

Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.

The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%).

Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class All Grade All Grade Preferred term Grades 3/4 Grades 3/4 Total number of 121 (79) 52 (34) 96 (67) 25 (17) patients with at least 1 adverse reaction Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class All Grade All Grade Preferred term Grades 3/4 Grades 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study Laboratory TREANDA Chlorambucil Abnormality N=150 N=141 All Grade All Grade Grades 3/4 Grades 3/4 n (%) n (%) n (%) n (%) Hemoglobin 134 (89) 20 (13) 115 (82) 12 (9) Decreased Platelets 116 (77) 16 (11) 110 (78) 14 (10) Decreased Leukocytes 92 (61) 42 (28) 26 (18) 4 (3) Decreased Lymphocytes 102 (68) 70 (47) 27 (19) 6 (4) Decreased Neutrophils 113 (75) 65 (43) 86 (61) 30 (21) Decreased In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.

Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [see Warnings and Precautions (5.5)]

7 DRUG INTERACTIONS No formal clinical assessments of pharmacokinetic drug-drug interactions between TREANDA and other drugs have been conducted.

Bendamustine’s active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of bendamustine and decrease plasma concentrations of active metabolites.

Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites. Caution should be used, or alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed.

The role of active transport systems in bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in bendamustine transport.

Based on in vitro data, bendamustine is not likely to inhibit metabolism via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes.

8.6 Renal Impairment No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild or moderate renal impairment. TREANDA should not be used in patients with CrCL < 40 mL/min.

8.7 Hepatic Impairment No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild hepatic impairment. TREANDA should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures. Care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection and TREANDA for Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If gloves come in contact with TREANDA Injection prior to dilution, remove gloves and follow disposal procedures. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water.

16.3 Storage TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) TREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F). Retain in original package until time of use to protect from light.

TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) TREANDA for Injection may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2015 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates.

All rights reserved.

Brief Summary of TREANDA Prescribing Information TRE-011

TRE-40554

The ASCO Post | NOVEMBER 25, 2015

PAGE 110

Perspective

Diet and Cancer: How Will We Make Progress?

By Clifford A. Hudis, MD

N

ot only is breast cancer among the most common cancers in women, but it is also one of the most common causes of premature death.

Rates of death from the disease vary widely around the world, reflecting variations in risk, screening, and access to highest quality treatment.

Although female gender and age are the most constant risk factors, they are not modifiable. Among the modifiable risk factors, obesity is now emerging as key. Apart from just breast cancer, obesity is poised to replace tobacco use— because of slow and steady progressive control of the latter—as the leading modifiable risk factor for cancer in the United States and possibly other higher-income countries.

It is difficult to talk about obesity without considering energy balance, including exercise and other activity, as well as dietary composition, the latter relating to both total caloric content and also specific components.

At the same time, many “healthier” diets may be so because of many factors, not all of which are understood or studied.

More Than Just a Low-Fat Diet For example, consider a low-fat diet.

If proven healthier for some diseases, we are often forced to at least note that it is generally a lower-calorie diet as well.

An earlier randomized study of a very low–fat diet in the adjuvant treatment setting for breast cancer demonstrated this: The low-fat diet was also associated with weight loss.1 Hence, its clinical benefits might be partially attributed to Dr. Hudis is Chief, Breast Medicine Service; Vice President for Government Relations; Chief Advocacy Officer, Memorial Sloan Kettering Cancer Center; and Professor of Medicine, Weill Cornell Medical College.

lower calorie consumption and weight loss (as was seen in the study), in addition to the specific benefits of lower fat consumption.

Diet and Breast Cancer In a recent issue of JAMA Internal Medicine, Toledo and colleagues attempted to study the risk of developing invasive breast cancer among women enrolled in a cardiac diet

cases of breast cancer were identified.

The method of detection (screening as opposed to clinical presentation) is not clear, nor is the staging presented.

Nonetheless, these factors should not be different across the three arms.

It is interesting to note that almost all cases (33 of 35) were hormone receptor–positive disease, and about onethird (12 of 35) were HER2-positive disease. For each of these biomarkers,

Despite some limitations— albeit fewer than many other diet intervention trials—the data from the trial provide a good argument for a Mediterranean diet enriched by extra-virgin olive oil.

—Clifford A. Hudis, MD

study2; the study is summarized in this issue of The ASCO Post. The women in the study were not “average” women, in the sense that they had a high cardiovascular risk, and this, in many settings, is associated with both obesity and components of the metabolic syndrome, as well as diabetes and a sedentary lifestyle.

Acknowledging that this group was perhaps at higher risk, we should also note that these risk factors are common in the United States and elsewhere, and these patients may be more typical than we wish.

The subjects who enrolled were randomized to follow a Mediterranean diet supplemented with extravirgin olive oil, one supplemented with mixed nuts, or a control group that was simply advised to reduce their dietary fat consumption. More than 4,000 patients participated, and with nearly 5 years of follow-up, 35

the incidence is normally a bit lower, but this may be a reflection of the age of the patients or other factors. Hormone receptor–positive breast cancer is the most common subtype in high-income countries, and there is a plausible link to the chronic white adipose inflammation that is commonly associated with elevated body mass index.3 In the study, the incidence of breast cancer appears to have been greatest among participants on the control diet, lower with the nut-supplemented Mediterranean diet, and lowest with the extra-virgin olive oil.

However, the numbers are small, and only the latter achieved statistical significance vs the control.

Limitations yet a Good Argument This study has some limitations.

The endpoint (breast cancer incidence) was secondary, the overall

incidence was low, and standard clinical approaches to ascertainment (mammograms and clinical exams at regular intervals) were not described.

It appears that the daily caloric intake for all three diets was initially about the same, but by the end of 3 years, the control group actually seemed to have slightly lower daily kilocalorie intake. Unfortunately, weight and body mass index were not described at the 3-year time point. If they remained stable, this study would gain even more utility, as this would suggest more clearly that a specific diet has an impact.

Despite some limitations—albeit fewer than many other diet intervention trials—the data from the trial provide a good argument for a Mediterranean diet enriched by extravirgin olive oil. The potential risk reductions for breast cancer represent a bonus, given that it generally tastes great anyway! n

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

References 1. Chlebowski RT, Blackburn GL, Thomson CA, et al: Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 98:1767-1776, 2006.

2. Toledo E, Salas-Salvado J, DonatVargas C, et al: Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: A randomized clinical trial. JAMA Intern Med 175:1752-1760, 2015.

3. Morris PG, Hudis CA, Giri D, et al: Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 4:1021-1029, 2011.

2015 San Antonio Breast Cancer Symposium Watch upcoming issues of The ASCO Post for reports from the San Antonio Breast Cancer Symposium, being held December 8–12, 2015.

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The ASCO Post | NOVEMBER 25, 2015

PAGE 112

Physiatry in Oncology Head and Neck Cancer

The Role of Botulinum Toxin in Head and Neck Cancer

By Michael D. Stubblefield, MD

H

ead and neck cancer and its treatment can result in a variety of neuromuscular and musculoskeletal pain and functional sequelae. Commonly seen conditions in patients with the disease include neck pain and spasm, hemifacial spasm, trismus, dysphonia, dysarthria, neuropathic pain, and salivary disorders, such as first bite syndrome, which can sometimes occur after surgery.

fibrotic tissue sclerosis. Radiation fibrosis syndrome can affect any organ, system, or bodily function with potentially devastating implications for function and quality of life.

Surgical techniques for head and neck cancer have also evolved over the past few years, and while surgery now generally results in less morbidity, critical neuromuscular structures are often adversely

As the number of head and neck cancer survivors surges in the coming years, it is essential that we continue to investigate and optimize treatments for the multitude of neuromuscular, musculoskeletal, pain, and functional disorders that will afflict this population.

—Michael D. Stubblefield, MD

Physical medicine and rehabilitation physicians are able to use their knowledge of the musculoskeletal and neurologic systems and management of functional impairment to address these symptoms. The causes of these ailments vary but may include tumors in key neuromuscular structures in the head or neck, surgery, radiation, neurotoxic chemotherapy, or a combination of these factors. Preexisting disorders, such as diabetes or cervical spinal stenosis, may also adversely impact the manifestation of many disorders resulting from head and neck cancer and its treatment.1

Treatment Side Effects Radiation is used extensively in the treatment of many types of head and neck cancers. Despite the continued evolution of radiation techniques intent upon providing maximal antineoplastic benefit with minimal damage to normal tissues, late effects from the treatment still develop.

The term radiation fibrosis describes the insidious pathologic fibrotic tissue sclerosis that occurs in response to radiation exposure, and radiation fibrosis syndrome describes the clinical manifestations that result from progressive Dr. Stubblefield is National Medical Director of Cancer Rehabilitation at Select Medical Corporation in Mechanicsburg, Pennsylvania, and Medical Director of Cancer Rehabilitation at Kessler Institute for Rehabilitation in West Orange, New Jersey.

affected. Among these is the spinal accessory nerve, which innervates the sternocleidomastoid and trapezius muscles and is occasionally subject to resection or damage from the tumor itself, surgery, and/or radiation therapy. Compromise of the spinal accessory nerve often leads to pain and spasm in the sternocleidomastoid and trapezius muscles with perturbation of shoulder function due to loss or dysfunction of the trapezius muscles as an important shoulder stabilizer.

Injecting the neurotoxic protein botulinum toxin into these muscles provides multiple therapeutic benefits owing to the presynaptic inhibition of the release of acetylcholine and other neurotransmitters. Approved by the U.S. Food and Drug Administration (FDA) in the treatment of cervical dystonia, blepharospasm, primary axillary hyperhidrosis, chronic migraine, and strabismus, botulinum toxin is often used off-label for treating pain, abnormal muscle spasm, and excessive glandular secretions.

A role for the agent in the treatment of patients with head and neck cancer and associated disorders is also beginning to emerge. In addition to botulinum toxin, physiatrists may prescribe a combination of other medications, splints/braces, and exercises to mitigate pain in this setting.

Abnormal Muscle Spasm Cervical dystonia, or neck spasm, is common in survivors of head and neck cancer as a result of neck dissection surgery and radiation therapy as well as tu-

mors located in proximity to key structures such as the spinal accessory nerve.

Ectopic activity in the spinal accessory nerve, which may occur as a result of surgery, radiation therapy, and/or chemotherapy, can cause pathologic and often painful spasm in the sternocleidomastoid and trapezius muscles. The scalene and other muscles, including flaps, are also commonly affected by surgery and/or radiation. Dysfunction of these muscles may lead to acquired cervical dystonia.

For patients complaining of pain, neck tightness, or loss of neck or shoulder range of motion, botulinum toxin is diluted with normal saline to the desired concentration and injected directly into the affected muscle. FDA-approved for the treatment of cervical dystonia in the general population, botulinum toxin has also shown efficacy in the treatment of muscle spasms after radiotherapy in survivors of head and neck cancer.1-3 Trismus, or impaired mouth opening, results in multiple medical and social complications, including decreased oral intake, impaired speech, compromised oral intimacy, inability to maintain oral hygiene and dental care, and reduced ability to visually survey for cancer recurrence. Although botulinum toxin injection has not been demonstrated to improve the oral opening when used in isolation, it has been shown to improve pain scores and oromandibular dystonia.4,5 Inhibiting pathologic masticator muscle spasm may be inadequate to improve mouth opening when the supporting tissues are also affected by radiation and surgical changes. The use of physical therapy and a jaw-stretching device such as the Dynasplint Trismus System following botulinum toxin injection may help improve this condition.6 The anti–muscle spasm effect of botulinum toxin injection may also be beneficial in treating synkinesis, hemifacial spasm, blepharospasm, pharyn-

GUEST EDITOR

Sean Smith, MD

P

hysiatry in Oncology explores the benefits of cancer rehabilitation in oncology clinical practice to screen survivors for physical and cognitive impairments along the care continuum to minimize survivors’ disability and maximize their quality of life. The column is guest edited and occasionally written by Sean Smith, MD, Director of the Cancer Rehabilitation Program at the University of Michigan Department of Physical Medicine and Rehabilitation in Ann Arbor. goesophageal muscle spasms, and other disorders of pathologic muscle spasm resulting from malignant tumors, surgery, or radiation therapy.7-9

Pain Disorders In addition to the inhibition of acetylcholine release, botulinum toxin is thought to inhibit the release of other neurotransmitters involved in the generation of pain. This effect was likely evident in the prospective facial pain and trismus trial by Hartl et al,4 which demonstrated improved pain scores but not trismus.

While botulinum toxin injections can cause systemic effects, the treatment does not generally spread far beyond the injection site, making it ideal for focal pain disorders. Injections of botulinum toxin have been shown to be beneficial

Role of Physiatry in Head and Neck Cancer ■■ With expertise in the musculoskeletal system and late effects of cancer treatment, physiatrists are uniquely qualified to address issues related to head and neck cancer and its treatment.

■■ The late effects of radiation therapy on the musculoskeletal components and peripheral nerves of the head and neck continue to evolve, so physiatric assessment of this dynamic process may be beneficial.

■■ Botulinum toxin injection is a valuable treatment for a number of disorders related to head and neck cancer due to the agent’s ability to focally inhibit muscle spasm, pain transmission, and glandular secretion.

ASCOPost.com | NOVEMBER 25, 2015

PAGE 113

Physiatry in Oncology in reducing chronic neuropathic pain in the head, neck, and shoulder following treatment of several tumor types.10,11

Abnormal Secretion Disorders Botulinum toxin injection is FDAapproved for use in primary axillary hyperhidrosis, a disorder of abnormal glandular secretion. The ability of botulinum toxin to inhibit glandular secretion has applications in survivors of head and neck cancer as well. Botulinum toxin has emerged as a useful treatment for first bite syndrome12 and has demonstrated efficacy in reducing saliva flow temporarily with subsequent reductions in saliva-related complications and improved healing following surgery for certain types of head and neck cancer.13,14

neck cancer patients. Curr Opin Otolaryngol Head Neck Surg 15:112-116, 2007.

8. Behbehani R, Hussain AE, Hussain AN: Parotid tumor presenting with hemifacial spasm. Ophthal Plast Reconstr Surg 25:141-142, 2009.

9. Hoffman HT, Fischer H, VanDenmark D, et al: Botulinum neurotoxin injection after total laryngectomy. Head Neck 19:92-97, 1997.

10. Wittekindt C, Liu WC, Preuss SF, et al: Botulinum toxin A for neuropathic pain after neck dissection. Laryngoscope 116:1168-1171, 2006.

11. Mittal S, Machado DG, Jabbari B: OnabotulinumtoxinA for treatment of focal cancer pain after surgery and/or radiation.

Pain Med 13:1029-1033, 2012.

12. Laccourreye O, Werner A, Garcia D, et

al: First bite syndrome. Eur Ann Otorhinolaryngol Head Neck Dis 130:269-273, 2013.

13. Steffen A, Hasselbacher K, Heinrichs S, et al: Botulinum toxin for salivary disorders in the treatment of head and neck cancer. Anticancer Res 34:6627-6632, 2014.

14. Corradino B, Di Lorenzo S, Moschella F: Botulinum toxin A for oral cavity cancer patients. Toxins (Basel) 4:956-961, 2012.

Closing Thoughts Only a few studies are currently available to test the safety and efficacy of botulinum toxin injection in patients with head and neck cancer. As the number of head and neck cancer survivors surges in the coming years, it is essential that we continue to investigate and optimize treatments for the multitude of neuromuscular, musculoskeletal, pain, and functional disorders that will afflict this population. n

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

References 1. Stubblefield MD: Radiation fibrosis syndrome: Neuromuscular and musculoskeletal complications in cancer survivors.

PM R 3:1041-1054, 2011.

2. Bach CA, Wagner I, Lachiver X, et al: Botulinum toxin in the treatment of postradiosurgical neck contracture in head and neck cancer. Eur Ann Otorhinolaryngol Head Neck Dis 129:6-10, 2012.

3. Van Daele DJ, Finnegan EM, Rodnitzky RL, et al: Head and neck muscle spasm after radiotherapy. Arch Otolaryngol Head Neck Surg 128:956-959, 2002.

4. Hartl DM, Cohen M, Julieron M, et al: Botulinum toxin for radiation-induced facial pain and trismus. Otolaryngol Head Neck Surg 138:459-463, 2008.

5. Lou JS, Pleninger P, Kurlan R: Botulinum toxin A is effective in treating trismus associated with postradiation myokymia and muscle spasm. Mov Disord 10:680-681, 1995.

6. Stubblefield MD, Manfield L, Riedel ER: A preliminary report on the efficacy of a dynamic jaw opening device (dynasplint trismus system) as part of the multimodal treatment of trismus in patients with head and neck cancer. Arch Phys Med Rehabil 91:1278-1282, 2010.

7. Laskawi R, Ellies M: The role of botulinum toxin in the management of head and

In EGFRm+ advanced NSCLC,

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

NEARLY 2 OUT OF 3

CASES ARE RELATED TO T790M

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

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

as a driver of resistance.

References: 1. Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19: 2240-2247. 2. Arcila ME, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay.

Clin Cancer Res. 2011;17:1169-1180. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. ©2015 AstraZeneca. All rights reserved. 3140405 6/15

The ASCO Post | NOVEMBER 25, 2015

PAGE 114

In the Clinic Sarcoma

Trabectedin in Unresectable or Metastatic Liposarcoma or Leiomyosarcoma

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

How It Works Trabectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix toward the major groove. Adduct formation triggers events that can affect the subsequent activity of DNA-binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.

upper limit of normal; decreased left-ventricular ejection fraction to less than the lower limit of normal or if there is clinical evidence of cardiomyopathy; and grade 3 or 4 nonhematologic adverse events.

Dose reduction is recommended for platelet count < 25,000/µL, absolute neutrophil count < 1,000/µL with fever/infection or < 500/µL lasting > 5 days, total bilirubin greater than the upper limit of normal, AST or ALT more than five times the upper limit of normal, ALP more than 2.5 times the upper limit of normal, creatine phosphokinase more than five times the upper limit of normal, decreased left-ventricular ejection fraction with absolute decrease of ≥ 10% and less than the lower limit of normal or if there is clinical evidence of cardiomyopathy, and grade 3 or 4 nonhematologic adverse events. The first dose reduction is to 1.2 mg/m2 every 3 weeks, and the second, is to 1.0 mg/m2 every 3 weeks.

Coadministration of strong CYP3A

n October 23, 2015, trabectedin (Yondelis) was approved for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma after a prior anthracycline-­ How It Is Used The recommended dose of trabectcontaining regimen.1,2 edin is 1.5 mg/m2 via intravenous infuSupporting Efficacy Data sion over 24 hours through a central Approval of trabectedin was based venous line every 21 days until disease on improvement in progression-free progression or unacceptable toxicity in survival in an open-label phase III trial patients with normal bilirubin and asparin which 518 anthracycline-pretreated tate aminotransferase (AST) or alanine patients were randomly assigned 2:1 aminotransferase (ALT) ≤ 2.5 times the to receive trabectedin at 1.5 mg/m2 as upper limit of normal. There is no recoman intravenous infusion over 24 hours mended dose of trabectedin in patients once every 3 weeks (n = 345) or dacarbazine at 1,000 mg/m2 as an intraveTrabectedin for Soft-Tissue Sarcoma nous infusion over 20 to 120 minutes 3 once every 3 weeks (n = 173).

■■ Trabectedin (Yondelis) was approved to treat patients with unresectable The trial excluded patients with central or metastatic liposarcoma or leiomyosarcoma after a prior anthracyclinenervous system metastasis, elevated secontaining regimen. rum bilirubin or significant chronic liver ■■ The recommended dose of trabectedin is 1.5 mg/m2 via intravenous disease (eg, cirrhosis or active hepatitis), infusion over 24 hours every 21 days until disease progression or history of myocardial infarction within 6 unacceptable toxicity. months, history of New York Heart Association class II to IV heart failure, or abnormal left-ventricular ejection fraction. with serum bilirubin levels above the in- inhibitors (eg, ketoconazole, itraconazole, Patients randomized to the dacarbazine stitutional upper limit of normal. Patients posaconazole, voriconazole, clarithromyarm were not offered trabectedin at the should be premedicated with intravenous cin, telithromycin, indinavir, lopinavir, time of disease progression. dexamethasone (20 mg) 30 minutes pri- ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) Patients had a median age of 56 years or to each dose. (range = 17 to 81 years); 70% were feTrabectedin should be permanently and grapefruit/grapefruit juice should be ­ YP3A inhibitor for male; 76% were white, 12% were black, discontinued for persistent adverse reac- avoided. If a strong C and 4% were Asian; 73% had leiomyo- tions requiring a delay in dosing of more short-term use (< 14 days) must be used, sarcoma and 27% had liposarcoma; than 3 weeks, adverse reactions requiring it should be given 1 week after trabectedin 49% had Eastern Cooperative Oncol- further dose reduction following dose infusion and discontinued the day prior ogy Group performance status of 0; reduction to 1.0 mg/m2, and severe liver to the next infusion. Coadministration and 89% had received at least two prior dysfunction indicated by bilirubin at least of strong CYP3A inducers (eg, rifampin, chemotherapy regimens. The most two times the upper limit of normal and phenobarbital, St. John’s wort) should be common prior drugs were doxorubicin AST or ALT at least three times the upper avoided.

(90%), gemcitabine (81%), docetaxel limit of normal with alkaline phosphatase (74%), and ifosfamide (59%), with ap- (ALP) less than two times the upper limit Safety Profile In the phase III trial, the most comproximately 10% of patients having re- of normal in the prior treatment cycle.

Treatment should be withheld for mon adverse events of any grade in the ceived pazopanib (Votrient).

Median investigator-determined pro- grade ≥ 2 neutropenia, severe or life- trabectedin group were nausea (75% vs gression-free survival was 4.2 months threatening increases in creatine phospho- 50% with dacarbazine), fatigue (69% vs in the trabectedin group vs 1.5 months kinase, and left-ventricular dysfunction. 52%), vomiting (46% vs 22%), constipain the dacarbazine group (hazard ratio Dose delay of up to 3 weeks is recom- tion (37% vs 31%), decreased appetite [HR] = 0.55, P < .001). Median overall mended for platelet count < 100,000/µL; (37% vs 21%), and diarrhea (35% vs survival was 13.7 vs 13.1 months (HR = absolute neutrophil count < 1,500/µL; 23%). The most common grade 3 or 4 0.93, P = .49). Objective response rates total bilirubin greater than the upper limit adverse events were fatigue (8% vs 1.7%), were 7% vs 6%, with median durations of of normal; AST, ALT, ALP, or creatine nausea (7% vs 1.7%), and vomiting (6% phosphokinase more than 2.5 times the vs 1.2%). The most common grade 3 or 4 response of 6.9 vs 4.2 months.

OF NOTE Trabectedin carries warnings/precautions for neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and embryofetal toxicity.

laboratory abnormalities were neutropenia (43% vs 26%), increased ALT (31% vs 0.6%), thrombocytopenia (21% vs 20%), and increased AST (17% vs 1.2%).

Adverse events led to dose reduction in 42% of patients in the trabectedin group, due to increased liver function tests in 24%, neutropenia in 8%, thrombocytopenia in 4.2%, fatigue in 3.7%, increased creatine phosphokinase in 2.4%, nausea in 1.1%, and vomiting in 1.1%, and to dose interruption in 52%, due to neutropenia in 31%, thrombocytopenia in 15%, increased liver function tests in 6%, fatigue in 2.9%, anemia in 2.6%, increased creatinine in 1.1%, and nausea in 1.1%. Adverse events led to permanent discontinuation of treatment in 26%, due to increased liver function tests in 5.6%, thrombocytopenia in 3.4%, fatigue in 1.6%, increased creatine phosphokinase in 1.1%, and decreased left-ventricular ejection fraction in 1.1%.

Trabectedin carries warnings/precautions for neutropenic sepsis, including fatal cases, rhabdomyolysis, hepatotoxicity, cardiomyopathy, including fatal cases, and embryofetal toxicity. Neutrophil counts and liver function tests should be monitored during treatment. The drug is contraindicated in patients with known hypersensitivity to trabectedin. Breastfeeding is not recommended in women receiving trabectedin. n References 1. U.S. Food and Drug Administration: Trabectedin. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm468914.htm. Accessed November 4, 2015.

2. Yondelis® (trabectedin) for injection for intravenous use prescribing information, Janssen Products, LP, October 2015.

Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl. pdf. Accessed November 4, 2015.

3. Demetri GD, von Mehren M, Jones RL, et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol.

September 14, 2015 (early release online).

Learn more

The ASCO Post | NOVEMBER 25, 2015

PAGE 116

Expert’s Corner Precision Medicine

ASCO Launches TAPUR to Assess the Off-Label Use of Targeted Therapies for Patients With Advanced Cancers A Conversation With Richard L. Schilsky, MD, FACP, FASCO

By Jo Cavallo

Richard L. Schilsky, MD, FACP, FASCO

T

wo years ago, Richard L. ­Schilsky, MD, FACP, FASCO, Chief Medical Officer of ASCO, proposed a unique clinical trial concept during an educational session on the challenges of delivering precision medicine services in a community setting at ASCO’s Annual Meeting. The idea was to design a clinical study that would serve two purposes: match commercially available targeted therapies to the genomic profile of patients’ tumors to determine the activity of the drugs when used off label and simplify patients’ access to the drugs, providing patients with truly personalized cancer care. After presenting the concept to ASCO’s Cancer Research Committee, Dr. Schilsky received approval and funding from ASCO to proceed with the development of the Targeted Agent and Profiling Utilization Registry (TAPUR) study, a prospective, nonrandomized clinical trial, which is slated to launch at the beginning of 2016.

The main objective of TAPUR is to collect information on the antitumor activity and toxicity of commercially available, targeted cancer therapies for advanced solid tumors and for two types of blood cancer, multiple myeloma and B-cell nonHodgkin lymphoma. Patients who are no longer benefitting from standard treatment, are healthy enough to participate in the study, and have a genomic variation in the tumor that can be targeted with a study drug are eligible to enroll in TAPUR. Currently, five pharmaceutical companies— AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, and Pfizer—are contributing drugs to the TAPUR trial, and ASCO is in discussions with other pharmaceutical companies in-

terested in participating, according to Dr. Schilsky.

To ensure that TAPUR follows the best clinical trial practices, ASCO has established three oversight committees: a Steering Committee to oversee study operations; a Molecular Tumor Board to review the proposed drug-target match; and a Data and Safety Monitoring Board to review study results, monitor for unexpected adverse events, and determine when to release data.

The ASCO Post talked with Dr. Schilsky, who is the principal investigator of TAPUR, about ASCO’s decision to launch its first-ever clinical investigation and how it will advance precision medicine in cancer care.

Trial Objectives Why did ASCO decide to launch TAPUR? We recognized that we have an opportunity to learn in a scientific setting what we are increasingly seeing in oncology practice in this era of genomic profiling. Patients with advanced cancer who have no other treatment options see the potential of getting a genomic profile of their tumor, which could possibly reveal an abnormality in the cancer that could be targeted with a drug that they otherwise might never have received or their doctor might never have thought about trying.

Genomic profiling is happening more and more frequently because the testing is more widely available, and there are many targeted drugs that are already approved by the U.S. Food and Drug Administration (FDA) and available for off-label prescribing. The problem is that patients often can’t get access to these drugs or reimbursed for them because they are being used off-label and there is no proof of benefit. Most importantly, even if patients do get access to the treatment, nobody outside of the patients’ medical teams ever learn what the patients’ outcomes are or whether this is a worthwhile strategy.

TAPUR is a focused effort to learn from real-world clinical practice in a very well delineated area. You can almost think of TAPUR as a microcosm of what we hope to accomplish with CancerLinQ™, the Society’s health information technology platform. CancerLinQ will allow us to learn about all

the dimensions of real-world clinical practice, and TAPUR will allow us to learn about this very specific dimension of clinical practice: the off-label prescribing of targeted drugs.

We feel that the timing is right to capture this information, and it is central to ASCO’s view that we can learn from observing real-world clinical practice.

TAPUR will also provide opportunities and mechanisms to help oncologists, particularly in the community setting, to learn more about how to utilize genomic testing in their practices and how to prescribe targeted therapies.

Study Design What is the endpoint and duration of the study?

Right now, the study is set for a 3-year duration. We think that by the end of 3 years, we will learn whether TAPUR can generate useful information. If it does, then we hope to continue it beyond that 3-year point.

The endpoint is to find persuasive evidence that these targeted drugs prescribed off-label are or are not active in particular tumor types with particular genomic variations. This is a type of investigation that is often called a signal-finding or hypoth-

We are continuously peeling the cancer onion, and every time we do, we find out how much more complex the situation is than we initially thought. But we will eventually get to the place where we have the right pieces of information to optimize treatment for each patient.

—Richard L. Schilsky, MD, FACP, FASCO

By having a research protocol that provides guidance to doctors on how to match drugs to gene mutations, we will be able to achieve a certain educational function as well as the research objectives of the study. And in the long run, that may be among the most valuable assets we provide oncologists who are not working in the major academic medical centers, so their patients can benefit from these precision medicine approaches.

Hematologic Targets The cancer types in TAPUR include advanced solid tumors, multiple myeloma, and B-cell non-Hodgkin lymphoma. Why did you choose those two blood cancers?

We choose those two because they are the most common blood cancers that occur in adults, and there are already targeted therapies for them that have shown effectiveness. And we are beginning to see some crossover effects, meaning that some targeted therapies that are effective in solid tumors are also showing effectiveness in some of these blood cancers, so we thought that we would be likely to get a sufficient number of patients with myeloma or non-Hodgkin lymphoma and a sufficient number of drug matches to learn something.

esis-generating study. We are not trying to prove anything in a definitive way, but we are trying to get a sense of whether a targeted drug used off-label in a specific patient population is sufficiently active to warrant further study of that drug in that patient population.

Improved Care How will this study advance precision medicine in oncology care?

We hope it will advance precision medicine in a number of ways. First and foremost, we hope it will generate important signals of drug activity or signals that suggest using a drug in a particular population might not be useful. Both of those would be important to know because if we find a new signal of activity, then there is an opportunity for the drug manufacturer or other researchers to pursue that further and maybe develop the drug in a new indication, which would give new treatment options to patients. If we don’t find any activity of a drug in a certain population, we would want to discourage the off-label prescribing of that drug and encourage patients to go on clinical trials or find other kinds of treatment options.

In a broader sense, we hope TAPUR will give us a much better understanding of how to interpret clinical genomic tests at the point of care and the best way to

ASCOPost.com | NOVEMBER 25, 2015

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Expert’s Corner

use that information to guide a doctor and patient to a particular therapeutic approach. Hopefully, we will also learn about the effectiveness of a molecular tumor board, which we will conduct in conjunction with TAPUR. We will be able to report on how it operates and how often it recommends a treatment approach that is different from what the treating physician is proposing.

Finally, I think we will learn a lot about the infrastructure necessary for precision medicine care and research to inform further advancement of the whole field.

Anticipated Time Line When do you expect to have some early results from TAPUR? It depends on the frequency of the genomic abnormalities we see in the patients enrolled in the study. If we see fairly common abnormalities and can enroll patients into the various cohorts pretty quickly, I think we will be able to generate some useful information within the first year. If all of the variations we see are very rare, then it’s going to take more time to fill those cohorts with a sufficient number

of patients to do an analysis of the study.

Our hope is that prior to the 3-year mark, we will be able to assess whether we are generating useful information often enough to justify continuing ­TAPUR or whether it needs to be modified in some way. Or we might conclude that TAPUR is not the right approach to gathering this information and that we should do something different.

Future Study Design Is TAPUR an example of how clinical studies will be designed in the future?

There is no doubt about that. We are already seeing that this design is the only way to proceed in order to obtain some kinds of information. The real struggle going forward will be in understanding the full complexity of a patient’s tumor.

TAPUR is designed to match a drug to an abnormality in the cancer genome based upon a single abnormality—a specific mutation in a single gene. We know that the cancer genome is much more complicated than that, so we have to figure out how to design studies that allow us to match a drug to a genetic signature that we determine based on an analysis

of multiple genes in the tumor specimen or in multiple pathways that are activated due to those genetic abnormalities.

Of course, the problem is not just in gene mutations. The cancer can be driven by genetic amplification, the translocation of genes, or the epigenetic modification of genes that can activate a pathway. Biologists will say it is not all just in the genome, because the genome only provides the basic information that operates the molecular pathways inside the cell, and it is the pathways that actually produce the malignant phenotype.

We will need to get even more sophisticated in our thinking about how to ascertain pathway activation and use that information as a basis for drug matching.

We are continuously peeling the cancer onion, and every time we do, we find out how much more complex the situation is than we initially thought. But we will eventually get to the place where we have the right pieces of information to optimize treatment for each patient.

Study Expansion Plans Currently, TAPUR is being launched in just two states, Michigan and North Caro-

lina. Do you have plans to expand the study to other states?

Yes. Initially, we are expecting to offer TAPUR in about 40 sites throughout Michigan and North Carolina. We have limited it to two states primarily to ensure that we have constructed TAPUR properly and that it functions the way we need it to function, because this is ASCO’s first clinical trial, and we need to have our infrastructure right.

As quickly as possible after the launch, we plan to expand the study to other states, and we are already accepting statements of interest from other sites. Any center interested in participating in the TAPUR study should email us at TAPUR@asco.org. n

For more information about the TAPUR study, see page 75 or visit asco.org/practice-research/ targeted-agent-and-profiling-utilization-registry-study; for questions, e-mail TAPUR@asco.org.

News Neuro-oncology

Pilot Study: Research Team Used Focused Ultrasound to Open Blood-Brain Barrier in Patient With Malignant Brain Tumor

A

team at Sunnybrook Health Sciences Centre in Toronto has used focused ultrasound to enable temporary and targeted opening of the blood-brain barrier, allowing the more effective delivery of chemotherapy into a patient’s malignant brain tumor.

This is the first known report of the noninvasive opening of the bloodbrain barrier in a patient, according to a news release announcing the team’s achievement.

Doxorubicin Infused Into Bloodstream With Microbubbles The team, led by neurosurgeon Todd Mainprize, MD, FRCSC, and physicist Kullervo Hynynen, MSc, PhD, infused the chemotherapy agent doxorubicin, along with tiny gas-filled bubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the bubbles to vibrate, loosening the tight junctions of the cells comprising the blood-brain barrier and allowing

high concentrations of chemotherapy to enter the targeted tissues.

“The blood-brain barrier has been a persistent impediment to delivering valuable therapies to treat tumors,” said Dr. Mainprize. “We are encouraged that we were able to open this barrier to deliver chemotherapy directly into the brain, and we look forward to more opportunities to apply this revolutionary approach.”

Pilot Study This patient treatment is part of a pilot study of up to 10 patients to establish the feasibility, safety, and preliminary efficacy of focused ultrasound to temporarily open the blood-brain barrier to deliver chemotherapy to brain tumors. The Focused Ultrasound Foundation is currently funding this trial through its Cornelia Flagg Keller Memorial Fund for Brain Research.

“Breaching this barrier opens up a new frontier in treating brain disorders,” said Neal Kassell, MD, Chair-

man of the Focused Ultrasound Foundation. “We are encouraged by the momentum building for the use of focused ultrasound to noninvasively deliver therapies for a number of brain disorders.”

Opening the blood-brain barrier in a localized region to deliver chemotherapy to a tumor is a predicate for utilizing focused ultrasound for the delivery of other drugs, DNA-loaded nanoparticles, viral vectors, and antibodies to the brain to treat a range of neurologic conditions, including various types of brain tumors, Parkinson’s, Alzheimer’s and some psychiatric ­diseases.

While the current trial is a firstin-human achievement, Dr. Hynyen, Senior Scientist at the Sunnybrook Research Institute, has been performing similar preclinical studies for about a decade. His research has shown that the combination of focused ultrasound and microbubbles may not only enable drug delivery, but might also stimulate the brain’s natural responses to fight

disease. For example, the temporary opening of the blood-brain barrier appears to facilitate the brain’s clearance of a key pathologic protein related to Alzheimer’s disease and improves cognitive function.

A recent study by PhD student Gerhard Leinenga and Jürgen Götz, PhD, from the Queensland Brain Institute in Australia further corroborated Dr. Hynynen’s research, demonstrating that opening the blood-brain barrier with focused ultrasound reduced brain plaques and improved memory in a mouse model of ­Alzheimer’s disease.1 Based on these two preclinical studies, a pilot clinical trial using focused ultrasound to treat Alzheimer’s disease is being organized. n Reference 1. Leinenga G, Götz J: Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer’s disease mouse model. Sci Transl Med 7:278ra33, 2015.

APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS* mCRC

VECTIBIX

®

FOLFOX In an exploratory analysis of the PRIME† study, Vectibix® improves median OS in the first line by 4.4 months vs FOLFOX alone in WT KRAS mCRC1

+4.4 MONTHS MEDIAN OS1

• Phase

3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC

• Vectibix®

+ FOLFOX extended the prespecified major efficacy measure of PFS vs FOLFOX alone (9.6 months vs 8.0 months, respectively)

• In

an exploratory analysis of OS, median OS in Vectibix® -treated patients was 23.8 months vs 19.4 months with FOLFOX alone

• No

benefits in OS or PFS were observed in patients with mutant RAS mCRC

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

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

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

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®.

Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).

Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

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

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

• Retrospective subset analyses across several randomized clinical trials

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

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

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

• Progressively

decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment.

Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

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

patients experienced severe infusion reactions (NCI-CTC grades 3–4).

Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe

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

• Fatal

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

• In

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

• Exposure

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

• Keratitis

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

• NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate

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

• As

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

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

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

• Because

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

• Women

who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program.

Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

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

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

• In

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

• In an interim analysis of an open-label, multicenter, randomized clinical

trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

Visit VectibixData.com to learn more

mCRC = metastatic colorectal cancer; OS = overall survival; PFS = progression-free survival; WT = wild type. *Exon 2 on codons 12 or 13. † PRIME = The Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy.

Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen.

Please see Brief Summary of full Prescribing Information on adjacent pages.

©2015 Amgen Inc. All rights reserved. 04/15 USA-945-103252

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

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

VECT15CDLA0437_B_Vectibix_BS_9.25x13_v23_Mar2015_r11_MBS.indd 1

Study 1

SYSTEM ORGAN CLASS Preferred Term

Vectibix® Plus Best Supportive Care (N = 229)

Best Supportive Care (N = 234)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

1 (< 1)

EYE DISORDERS Growth of eyelashes

13 (6)

GASTROINTESTINAL DISORDERS Nausea

52 (23)

2 (< 1)

37 (16)

Diarrhea

49 (21)

4 (2)

26 (11)

Vomiting

43 (19)

6 (3)

28 (12)

Stomatitis

15 (7)

2 (< 1)

2 (< 1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue

60 (26)

10 (4)

34 (15)

Mucosal inflammation

15 (7)

1 (< 1)

2 (< 1)

57 (25)

4 (2)

7 (3)

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

41 (18)

12 (5)

30 (13)

Cough

34 (15)

1 (< 1)

17 (7)

Erythema

150 (66)

13 (6)

2 (< 1)

Pruritus

132 (58)

6 (3)

4 (2)

Acneiform dermatitis

131 (57)

17 (7)

2 (< 1)

Rash

51 (22)

3 (1)

2 (< 1)

Skin fissures

45 (20)

3 (1)

1 (< 1)

Exfoliative rash

41 (18)

4 (2)

Acne

31 (14)

3 (1)

Dry skin

23 (10)

Nail disorder

22 (10)

Skin exfoliation

21 (9)

2 (< 1)

Skin ulcer

13 (6)

1 (< 1)

8 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).

In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].

In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix ®-treated patients [see Dosage and Administration (2.3)].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.

Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®.

Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3) Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

58 (18)

5 (2)

10 (3)

Diarrhea

201 (62)

59 (18)

169 (52)

29 (9)

Stomatitis

87 (27)

15 (5)

42 (13)

1 (< 1)

EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation

82 (25)

14 (4)

53 (16)

1 (< 1)

Asthenia

79 (25)

16 (5)

62 (19)

11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

Anorexia

116 (36)

14 (4)

85 (26)

6 (2)

INFECTIONS AND INFESTATIONS Paronychia

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

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

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

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

24 (7)

1 (< 1)

10 (3) 4 (1)

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

30 (9)

4 (1)

9 (3)

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

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).

Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix ® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)].

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.

Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.

In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix ®.

Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

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

Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)].

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

Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.

Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy.

Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Hypomagnesemia

96 (30)

21 (7)

26 (8)

1 (< 1)

Hypokalemia

68 (21)

32 (10)

42 (13)

15 (5)

Dehydration

26 (8)

8 (2)

10 (3)

5 (2)

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

46 (14)

30 (9)

This brief summary is based on the Vectibix ® Prescribing Information v23, 03/15.

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

4/27/15 6:12 PM

S:13”

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)].

• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)].

Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)].

DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes.

Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].

Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.

Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose.

• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose.

• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.

• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®.

Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.

Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®.

Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)].

Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS ” [see Indications and Usage (1.1), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)].

Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage (1.1), and Clinical Pharmacology (12.1)].

Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone [see Indications and Usage (1.1)].

Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).

Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)].

Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

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

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

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

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

Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

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

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.1) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)]

• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).

For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks).

Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

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Women in Oncology Professional Development

The Importance of Supporting the Role of Women Leaders in Oncology

By Julie M. Vose, MD, MBA, FASCO

Julie M. Vose, MD, MBA, FASCO

I

am honored to be the 52nd President of ASCO and thrilled to have followed in the steps of six remarkable women to hold this important leadership position in a professional Society that represents nearly 40,000 oncologists around the world caring for people with cancer. My six female predecessors are: Rose Ruth Ellison, MD, FASCO (1974–1975); Karen H. Antman, MD, FASCO (1994–1995); Margaret A. Tempero, MD, FASCO (2003–2004); Sandra J. Horning, MD, FASCO (2005–2006); Nancy E. Davidson, MD, FASCO (2007–2008); and Sandra M. Swain, MD, FASCO (2012–2013).

In the coming years, I am hoping there will be many more women elected to the office of President of ASCO, but I know that female oncologists have not risen to the top ranks of leadership in academic medicine as quickly as have our male counterparts. We need to do more to enhance and support the role of women leaders in oncology.

Helping Women Succeed in Oncology According to ASCO’s 2015 report The State of Cancer Care in America,1 the proportion of women in medical oncology continues to grow, with women now accounting for slightly more than 30% of practicing oncologists in the United States. And although women comprise 47% of medical school graduates, their numbers dwindle in academic faculty positions (38%); full professorship positions (21%); and leadership positions, such as department chairs or deans (between 15% and 16%).2 Dr. Vose is President of ASCO; the Neumann M. and Mildred E. Harris Professional Chair; and Chief, Oncology/Hematology Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha.

Recognizing the challenges women in oncology often encounter as they progress in their careers, at the 2013 Annual Meeting, ASCO launched Women in Oncology: Challenges and Keys to Success, an educational session exploring gender trends in the oncology and physician workforce; barriers to career development and professional satisfaction; and strategies to successfully develop and mentor young female oncologists. At the 2015 Annual Meeting, we expanded the session to include the Women’s Networking Center, a program focused on professional development. There will be additional programs to support women in their careers during the 2016 Annual Meeting, including expanded small-group networking sessions bringing together women oncology leaders and young female oncologists to enhance education, career opportunities, and mentorship.

Supporting the career development of women in oncology was also a major topic during the 2015 European Cancer Congress (ECC) this past September.

Two years ago, the European Society for Medical Oncology (ESMO) started shedding light on the limited presence of women oncologists in leadership positions compared to the increasing number of women in medical school

oncology needs to start early in their medical education. Here are some ways we can help women attain the leadership skills necessary to reach their career goals: • Urge female medical school students to get involved in ASCO-sponsored cancer interest groups, which help connect medical students with resources and information about careers in oncology. For information visit, asco.org/professional-development/resources-medical-students.

• Match medical students, residents, and fellows with research opportunities— ranging from both clini-

Let’s all do our share to support the development of women oncologists in leadership positions in their careers. We will all benefit from their accomplishments, especially our patients.

—Julie M. Vose, MD, MBA, FASCO

•

•

Enriqueta Felip, MD, PhD

and working in the field of oncology. So ESMO launched its Women for Oncology initiative to support the professional development of women oncologists and their access to leadership positions.

At this year’s ECC meeting, ESMO presented its inaugural Women for Oncology Award to Enriqueta Felip, MD, PhD, Head of the Lung Cancer Unit in the Oncology Department at Vall d’Hebron University Hospital in Barcelona, Spain, for her contribution to the career development of female oncologists.

Steps to Attaining Leadership Positions The process to enhance and support women in attaining leadership roles in

they face enhance the educational process for women and present new career opportunities.

• Recommend that early-career oncologists obtain additional leadership training with an advanced degree, such as an MBA, with a focus on health care or participate in the Hedwig van Ameringen Executive Leadership in Academic Medicine (ELAM), a year-long, part-time fellowship program for women faculty in schools of medicine and public health offered at Drexel University College of Medicine (drexel.edu/ medicine/Academics/Womens-

•

•

•

cal and basic research—to enhance their career goals.

Champion early-career mentorships.

Mentoring represents one of the most critical opportunities for shaping a woman’s career in oncology. Matching mentees with the right mentor (male or female) can focus the mentees’ goals and help them succeed.

Promote the development of students,’ residents,’ and fellows’ leadership skills through professional leadership programs at home institutions or through ASCO’s Leadership Development Program (asco .org/professional-development/ leadership-development-program).

Connect promising early-career oncologists with a career sponsor, a medical professional beyond a mentor, who can offer advice on networking opportunities and provide professional introductions.

Introduce young oncologists to key role models who can demonstrate how to work productively and as a collaborative team member.

Encourage young oncologists to get involved in professional societies, such as ASCO. Volunteering to serve on a committee; applying for participation in a leadership program, such as ASCO’s Leadership Development Program; and learning from seasoned oncologists from across the country and around the world about the oncology issues

Health-and-Leadership/ELAM).

• Support women in oncology through programs such as Women Who Conquer Cancer (conquercancerfoundation.org/womenwho-conquer-cancer), a Conquer Cancer Foundation initiative that funds research by female physicianscientists through ASCO’s Young Investigator Awards.

Although the future looks very bright for women leaders in oncology, improving their number in leadership positions within their home institutions, practices, and national societies will take active engagement by all oncology professionals, including trainees, early-career oncologists, mentors, and sponsors. Let’s all do our share to support the development of women oncologists in leadership positions in their careers. We will all benefit from their accomplishments, especially our patients. n Disclosure: Dr. Vose reported no potential conflicts of interest.

References 1. ASCO: The State of Cancer Care in America, 2015: A report by ASCO. J Oncol Pract 11:79-113, 2015.

2. Association of American Medical Colleges: The State of Women in Academic Medicine: The Pipeline and Pathways to Leadership, 2013-2014. Available at https://www.aamc.org/members/gwims/ statistics/. Accessed November 3, 2015.

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Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Hodgkin Lymphoma, Non-Hodgkin Lymphoma, and Myeloma

By Liz Janetschek

T

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with Hodgkin lymphoma, non-Hodgkin lymphoma, and myeloma. The trials are investigating combination treatments; modified chemotherapy regimens; autologous hematopoietic cell transplantations; and pediatric-specific cancers. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

PILOT Study Type: Pilot/interventional/ single-group assignment Study Title: Pilot Study of Rituximab and Brentuximab Vedotin With Deferred BMT for Relapsed Classical Hodgkin Lymphoma Study Sponsor and Collaborators: Sidney Kimmel Comprehensive Cancer Center Purpose: To study a combination of brentuximab vedotin and rituximab for the treatment of relapsed Hodgkin lymphoma Primary Outcome Measures: 1-year failure free survival [time frame: 1 year] Principal Investigator: Richard Jones, MD, The Johns Hopkins University; 443-287-7104, rjjones@jhmi.edu For More Information: Use ClinicalTrials.gov Identifier NCT01900496

PHASE I Study Type: Phase I/interventional/ single-group assignment Study Title: Phase I Study of ­Yttrium-90 Labeled Anti-CD25 Monoclonal Antibody Plus Standard BEAM Conditioning for Autologous Hematopoietic Cell Transplantation in Patients With Mature T-Cell Non-Hodgkin Lymphoma: The aTAC BEAM ­Regimen

Study Sponsor and Collaborators: City of Hope Medical Center, National Cancer Institute Purpose: To study the side effects and best dose of yttrium Y 90 basiliximab when given together with standard combination chemotherapy before a stem cell transplant in treating patients with mature T-cell non-Hodgkin lymphoma Primary Outcome Measures: MTD of yttrium Y 90 basiliximab defined as the highest dose in which fewer than 33% of patients experience dose-limiting toxicity attributable to study treatment, among those evaluable for toxicity [time frame: 30 days post-transplant], Incidence of toxicities assessed using National Cancer Institute (NCI) CTCAE version 4.03 [time frame: Up to 100 days post-transplant] Principal Investigator: Jasmine Zain, MD, City of Hope Medical Center; 800-826-4673, jzain@coh.org For More Information: Use ClinicalTrials.gov Identifier NCT02342782

PHASE I/II Study Type: Phase I/II/interventional/single-group assignment Study Title: A Phase I/II Study of Gemcitabine and Bendamustine in Patients With Relapsed or Refractory Hodgkin Lymphoma Study Sponsor and Collaborators: Ohio State University Comprehensive Cancer Center Purpose: To study the side effects and best dose of bendamustine hydrochloride when given together with gemcitabine hydrochloride and to see how well it works in treating patients with relapsed or refractory Hodgkin lymphoma Primary Outcome Measures: Adverse events in terms of dose-limiting toxicity (DLT) and MTD of bendamustine hydrochloride (phase I) [time frame: up to 5 years] Principal Investigator: Kristie Blum, MD, Ohio State University Comprehensive Cancer Center; 614-293-

4590, kristie.blum@osumc.edu For More Information: Use ClinicalTrials.gov Identifier NCT01535924

PHASE II Study Type: Phase II/Interventional/Parallel Assignment Study Title: Multicenter Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib After Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Multiple Myeloma Study Sponsor and Collaborators: National Heart, Lung, and Blood Institute; Blood and Marrow Transplant Clinical Trials Network; National Cancer Institute Purpose: To compare progression-free survival from randomization among patients randomized on the BMT CTN 1302 protocol, “Multicenter Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib after Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Multiple Myeloma.” It is hypothesized that ixazomib maintenance therapy will result in improved progression-free survival in patients with high-risk multiple myeloma following allogeneic hematopoietic stem cell transplantation.

Primary Outcome Measures: Progression-free survival [time frame: 2 years postrandomization] Principal Investigator: Mary Horowitz, MD, Center for International Blood and Marrow Transplant Research; contact Heather Wittsack, hwittsack@emmes.com.

For More Information: Use ClinicalTrials.gov Identifier NCT02440464

PHASE III Study Type: Phase III/interventional/parallel assignment Study Title: A Randomized Phase III Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed HighRisk Classical Hodgkin Lymphoma (cHL) in Children and Adolescents

Study Sponsor and Collaborators: National Cancer Institute Purpose: To study brentuximab vedotin and combination chemotherapy to see how well they work compared to combination chemotherapy alone in treating younger patients with newly diagnosed Hodgkin lymphoma Primary Outcome Measures: Event-free survival, where events include disease progression or relapse, second malignancy, or death [time frame: up to 48 months] Principal Investigator: Sharon Castellino, MD, Children’s Oncology Group; multiple study locations, see clinicaltrials.gov for respective contact information.

For More Information: Use ClinicalTrials.gov Identifier NCT02166463 Study Type: Phase III/interventional/parallel assignment Study Title: Tandem Autologous Hematopoietic Stem Cell Transplant With Melphalan Followed by Melphalan and Bortezomib in Patients With Multiple Myeloma Study Sponsor and Collaborators: Hackensack University Medical Center Purpose: To evaluate the use of melphalan in bone marrow transplant recipients Primary Outcome Measures: To determine the progression-free survival of patients with multiple myeloma treated with tandem cycles of high-dose melphalan followed by high-dose melphalan in combination with bortezomib with autologous hematopoietic stem cell transplantation [time frame: 3 years] Principal Investigator: Michele Donato, MD, John Theurer Cancer Center at Hackensack University Medical Center; mdonato@humed.com.

For More Information: Use ClinicalTrials.gov Identifier NCT01241708 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.

More on NCI Sponsored Clinical Trials For more on federally funded clinical research, visit https://ccr.cancer.gov/clinical-trials/

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Expert’s Corner Cancer Registries

Engaging Clinicians in the Collection of Cancer Registry Data to Improve Clinical Research A Conversation With Frederick L. Greene, MD, FACS

By Jo Cavallo

Frederick L. Greene, MD, FACS

I

n June, the Commission on Cancer of the American College of Surgeons published a revision of its Facility Oncology Registry Data Standards (FORDS) manual, which contains all the data items, codes, and rules to abstract data into cancer registries at the more than 1,500 Commission on Cancer–accredited hospitals in the United States. First developed in 2003, the updated manual, FORDS: Revised for 2015,1 contains revisions in clinical and pathologic TNM staging, clarification for coding biopsies followed by surgery, clarification for reporting dosages for proton treatment, and new sex codes to include transsexual natal male and natal female, among others.

A more comprehensive revision of the manual led by Frederick L. Greene, MD, FACS, Chair of the FORDS Revision Task Force, Medical Director of Cancer Data Registry at the Levine Cancer Institute, Charlotte, North Carolina, and Clinical Professor of Surgery at the University of North Carolina School of Medicine, Chapel Hill, is underway and projected to be completed in 2018.

Changes in the FORDS manual also affect other registry groups, including the North American Association of Central Cancer Registries, the National Cancer Data Base of the Commission on

Cancer, the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, and the Centers for Disease Control and Prevention National Program of Cancer Registries.

According to Dr. Greene, the FORDS manual is an important and relevant tool for clinicians and researchers because it determines what information is abstracted into the National Cancer Data Base and other cancer registries and influences the scope and quality of clinical studies.

The ASCO Post talked with Dr. Greene about the importance of the FORDS manual in clinical research and why every clinician/scientist should be aware of its content.

Shared Data Collection Please talk about the importance of the FORDS manual.

The FORDS manual is important because it contains all the data items on patient care that are collected and coded by hospital registrars, which can then be used as a source for answering research questions. Most clinicians have no idea what hospital registrars do

never had input from clinicians on the pertinent variables of clinical care that provide insight into outcomes of current treatment strategies.

To ensure effective revision of all data codes, clinicians will be invited to participate through membership in expert panels that have been created for the development of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, which will be completed in the fall of 2016.

I have contacted individual clinician leaders in the steering committee and have asked them to tell us what new codes are needed for surgery, drugs, and diagnostic studies, because if we don’t have the codes to capture this information in the hospital setting, we won’t be able to put them into the National Cancer Data Base, which is jointly sponsored by the American College of Surgeons and the American Cancer Society.

Research Applications How are the data contained in the FORDS manual used as a research tool?

The National Cancer Data Base has served as a source of data for many peer-

The large sample size of data and the range of hospital types make the information contained in the FORDS manual a viable alternative to institutional or clinical trial data as a source of information for answering some research questions.

—Frederick L. Greene, MD, FACS

or how this information is compiled.

About a year and a half ago, I was asked to lead a multidisciplinary steering committee of oncology experts, including ASCO members, to revise all of the data codes in the FORDS manual, which is an ongoing process. We hadn’t had a revision in 12 years, and we’ve

reviewed studies. Approximately 70% of all newly diagnosed cancers from the more than 1,500 Commission on Cancer–accredited hospitals in the United States are captured in this database. The large sample size of data and the range of hospital types make the information contained in the FORDS manual a vi-

able alternative to institutional or clinical trial data as a source of information for answering some research questions.

My goal is to inform physicians about the registry process so they have an understanding of its purpose. Most clinicians have no idea how the data are collected in any of the registries. They use the data in SEER, for example, but they have no idea how the data got there, and they have never been involved in the data-collection process.

Clinician Involvement How would you like ASCO members to get involved in the FORDS data revision project?

In general, I would just like physicians to be aware of the importance of the FORDS manual and the collection of data for the various registries and to let us know what significant changes in clinical care, such as new surgical procedures and new drugs, we need to collect and include to keep the data current and relevant. They are doing that through the steering committee we established.

The FORDS revision process is an important project to ensure that the surveillance and collection of data relating to the treatment of patients with cancer continue. n

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

Editor’s Note: To view a webinar on the FORDS Revision Project and the AJCC 8th Edition Expert Panels, go to https://www. youtube.com/watch?v=iTa_Vs5XBWs. Reference 1. American College of Surgeons Commission on Cancer: Facility Oncology Registry Data Standards (FORDS): Revised for 2015. Available at https://www.facs. org/quality-programs/cancer/ncdb/registrymanuals/cocmanuals/fordsmanual. Accessed November 3, 2015.

Download The ASCO Post iPad App FREE from iTunes today!

Š 2015 Celgene Corporation

03/15

US-CELG140284

IN MULTIPLE MYELOMA

RESIDUAL DISEASE AND IMMUNE DYSFUNCTION FORM A GROWING RISK OF RELAPSE An increased understanding of multiple myeloma has helped advance myeloma care over the past several decades.1,2 Despite a significant improvement in 5-year relative survival rates, patients still experience multiple periods of relapse and remission.2,3 Do residual disease and immune dysfunction form a cycle that complicates our strategies?

EVEN WITH THE ACHIEVEMENT OF A COMPLETE RESPONSE, 100 MILLION MYELOMA CELLS MAY REMAIN.4

~

The majority of patients with multiple myeloma have persistent levels of residual disease (minimal residual malignant cells) that are below the sensitivity of most protein and bone marrow diagnostic tests.5-7 Even in patients who achieve a complete response (by current International Myeloma Working Group criteria), residual disease may persist.4 In addition, dominant and minor clones continue to evolve, putting the patient at increased risk for relapse.8,9

IMMUNE DYSFUNCTION ALLOWS RESIDUAL DISEASE TO PROLIFERATE, FURTHER WEAKENING THE IMMUNE SYSTEM, AND MAY CAUSE A CYCLE OF DISEASE THAT RESULTS IN RELAPSE.5, 9-14 Myeloma tumor cells crowd out healthy cells in the bone marrow, leading to a compromised immune system and decreased immune surveillance—the immune system’s ability to identify and eliminate tumor cells.9-13 When immune surveillance is impaired, residual cells may proliferate and evolve, permitting a cycle that can lead to relapse.9,10,13

CONTINUOUS SUPPRESSION OF RESIDUAL DISEASE AND SUPPORT OF IMMUNE FUNCTION ARE IMPORTANT CONSIDERATIONS WHEN CREATING A LONG-TERM STRATEGY.13,15,16 Visit mmrelapserisk.com to learn more.

References: 1. Kumar SK, et al. Leukemia. 2014;28:1122-1128. 2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER cancer statistics review 1975-2011. Available at http://www.seer.cancer.gov. Accessed October 22, 2014. 3. Hajek R. Multiple myeloma – a quick reflection on the fast progress. InTech; 2013. Available at http://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-onthe-fast-progress. Accessed December 12, 2014. 4. Poon ML, et al. Cancer Therapy. 2008;6:275-284. 5. Hart AJ, et al. Biol Blood Marrow Transplant. 2012;18:1790-1799. 6. Rajkumar SV, et al. Blood. 2011;117:4691-4695. 7. Martinez-Lopez J, et al. Blood. 2014;123:30733079. 8. Keats JJ, et al. Blood. 2012;120:1067-1076. 9. Morgan GJ, et al. Nat Rev Cancer. 2012;12:335-348. 10. Katodritou E, et al. Am J Hematol. 2011;86:967-973. 11. Braga WM, et al. Clin Dev Immunol. 2012;2012:Mar 27 EPub. 12. Kyle RA, et al. N Engl J Med. 2004;351:18601873. 13. Pratt G, et al. Br J Haematol. 2007;138:563-579. 14. Favaloro J, et al. Leuk Lymphoma. 2014. May 12:1-8. [Epub ahead of print].

15. Roschewski M, et al. Blood. 2013;122:486-490. 16. Pessoa de Magalhães RJ, et al. Haematologica. 2013;98:79-86.

The ASCO Post | NOVEMBER 25, 2015

PAGE 126

Reflections

Cancer Cured My Life

Being a cancer survivor has made me a better physician.

By Richard M. Levine, MD The following essay by Richard M. Levine, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which is coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and the bigcasino.org.

exhausted and sometimes resentful of the additional time I’d have to spend after the hospital rounds and a full office schedule.

Today, I recognize the importance of each and every encounter that I have with patients and their caregivers. I make a determined effort to return every phone call, review every diagnostic report, and follow up with patients on a daily basis. I feel it is a privilege to have an individual place his or her trust and life in my hands—particularly a patient with a serious and potentially life-threatening condition. This is a responsibility that each physician (and everyone working in health care) should understand.

feel a sense of loss that we could not have done more for him in his fight against leukemia.

Christina was a patient of mine diagnosed with recurrent Hodgkin lymphoma. During my fellowship in medical oncology, I helped supervise her treatment and follow-up. Her husband and parents were very supportive and

lationship with each and every patient.

A few years ago, Dawn, a patient recently diagnosed with breast cancer, called our office requesting to be seen as soon as possible. We scheduled her appointment for the next day. Fortunately, she had a potentially curable breast cancer and completed treatment while working full time. Her personal

If you survive cancer, or any major challenge or life-threatening event, it can provide insight and open a new window in life. I know that firsthand.

—Richard M. Levine, MD

Keeping Patients in My Mind and Heart

I

’m a cancer survivor. I’m fortunate to have been in remission since 2000. I remember desperately waiting for the results of my biopsy. When informed that I had cancer, I went into emotional shock for several days. As a physician and oncologist, I was familiar with the healthcare system and was able to navigate through its complexities with success.

Today, I remain acutely aware of how dependent individuals are when seeking medical care. Just waiting for a phone call to be returned, waiting for an appointment to be scheduled, or waiting to receive state-of- the-art medical recommendations in a technically correct but easily understood manner can be very stressful.

Being a cancer survivor has made me a better physician. Prior to my diagnosis, I remember having 10 to 20 phone calls to return at the end of the day. I was emotionally and physically Dr. Levine is a medical oncologist at Space Coast Cancer Center in Merritt Island, Florida.

Over the years, certain patients and their stories have stayed in my mind and heart because of the powerful examples and lessons they’ve provided. Virgil was the first cancer patient I cared for as a physician. He was diagnosed with acute myelogenous leukemia (AML) and was an inpatient when I started my first week of internship in internal medicine in July 1977.

To this day, I remember the dignity and respect that Virgil always conveyed for himself and others. Every day when the medical team visited him during our hospital rounds, he was showered, shaved, dressed in clean pajamas, and sitting upright in bed. His room was clean, and his bed was always straightened. He answered our questions thoughtfully, shared how he was feeling, and always had a positive disposition. He treated everyone with the utmost courtesy and consideration.

When the hematology fellow explained to Virgil that his leukemia was refractory to treatment and terminal, he responded in a calm and understanding manner. Family and friends truly admired this man and shared stories of his kindness and leadership in the community. It was a privilege to know him and to have the opportunity to participate in his medical care. I still

Save the Date

friendly. Christina responded well to therapy, and I continued to monitor her in the outpatient clinic. She and her husband invited my fiancée and me to a Bruce Springsteen concert. We enjoyed the evening, and I had the privilege of getting to know her better as a person, not just as a patient.

She accepted the challenges and toxicity of her medical care, always following my recommendations with grace and a positive attitude. Christina did well throughout the remainder of my fellowship, and we remained in touch after I started my private practice in Florida. Unfortunately, she subsequently relapsed and passed away.

Cancer Dictates Patients’ Fate Christina’s parents sent me a very kind note thanking me for the professional and personal care that I’d provided, expressing their feelings that she had remained in remission for so long because she had such a strong belief and confidence that I could cure her.

Of course, I know better. The disease decides what the future will hold.

Nonetheless, I felt very fortunate to have a patient place such trust in me, even when I was a fellow in training.

Christina reinforced in me the importance of having an open and honest re-

life was very challenging in that Dawn was in a difficult marriage and had initiated divorce proceedings. She’d recently changed employment and was in a job she did not enjoy. She had no insurance and had additional stressful personal and economic issues.

Each time Dawn came into the cancer center, she was pleasant and professional. She wished to be informed and participate as best she could in getting better. After completing therapy, she changed careers and found enjoyable and fulfilling employment. She finalized her divorce and has since remarried a man who is very supportive and loving.

New Insight Into Life One day Dawn informed me that “cancer cured my life.” I’d never heard that expression before, but I thought it was true for Dawn and possibly many others. If you survive cancer, or any major challenge or life-threatening event, it can provide insight and open a new window in life. I know that firsthand.

After 30 years as a practicing oncologist, I continue to enjoy my career immensely. I look forward to the next generation of physicians continuing to improve and advance the medical care patients receive, and helping provide them with the best care possible. n

2016 Cancer Survivorship Symposium, January 15–16, San Francisco Marriott, San Francisco The Cancer Survivorship Symposium is the product of a unique collaboration among the American Academy of Family Physicians, the American College of Physicians, and the American Society of Clinical Oncology. The Symposium will provide information about survivorship issues that both primary care physicians and oncologists are faced with throughout the cancer care continuum. The Symposium represents an innovative approach to education and patient care. For more information, visit http://survivorsym.org/about.

ASCOPost.com | NOVEMBER 25, 2015

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Art of Oncology A Selfless Act

By Susan L. Cohn, MD

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

W

ithin minutes after opening the e-mail from ASCO on March 10, 2015, announcing the U.S. Food and Drug Administration (FDA) approval of dinutuximab (chimeric MAb ch14.18 or Unituxin), I contacted Amy’s mother (names have been changed). Amy was referred to our hospital in 2007, when she was 3 years old, after being diagnosed with high-risk neuroblastoma. She had developed a limp and leg pain, and an evaluation at another hospital revealed an adrenal mass and metastatic disease in multiple bones and the bone marrow.

I met Amy and her parents in our clinic to discuss the diagnosis, prognosis, and treatment plan.

Although I have been caring for children with cancer for more than 30 years, I still find it difficult to break the news to a parent that his or her child has a potentially terminal illness. For children with some types of cancers, I am able to emphasize that the prognosis is excellent and that the treatment is well tolerated. This is not the case, however, for high-risk neuroblastoma. I told Amy’s parents that, with current treatments, approximately 40% of children are cured. I also stated, “Although this number may be difficult to hear, please remember it is just a statistic. Right now, I am only concerned about one patient, and my intention is to cure Amy.”

Planned Therapy Because there were no open clinical trials at the time for patients with newly diagnosed neuroblastoma, I rec-

ommended treatment that was based on the best arm of a completed randomized, pediatric cooperative group clinical trial. I explained that this study showed better outcomes with myeloablative therapy followed by bone marrow transplantation than with chemotherapy.1 Amy’s parents had tears in their eyes as I reviewed the intensive, multimodal therapy and the expected toxicities. I also informed Amy’s parents that, even if their daughter had no evidence of disease after she completed the planned therapy, the neuroblastoma could return and that cure after relapse remains elusive.

Amy tolerated her induction chemotherapy well. However, she developed high fevers and severe mucositis during consolidation, and she remained in the hospital for weeks after the stem cell transplantation. Amy’s energy and appetite slowly returned. Two months after her stem cells were infused, Amy’s mom told me that Amy finally was be-

we are always looking for better treatments,” I explained, “and your daughter is eligible for a randomized, Children’s Oncology Group clinical trial that is comparing RA alone with immunotherapy combined with RA.” The expected toxicities of the two regimens on this study differed substantially. The immunotherapy regimen, which consisted of intravenous monoclonal antibody dinutuximab and cytokines, was administered during 4 days in the hospital, and patients required a morphine drip because of the antibody-induced peripheral nerve pain. Other toxicities include swelling caused by capillary leak; low blood pressure; hives; and more serious allergic reactions, including anaphylaxis.

Conversely, the most common adverse effect of oral RA is dry skin. I stressed that, although we designed the study on the basis of the antineuroblastoma activity seen in patients with relapsed disease, we did not know if the immu-

During my career, I have witnessed remarkable advances in the treatment of neuroblastoma and other pediatric cancers that resulted from randomized studies. For a parent, though, enrolling a son or daughter onto a randomized trial, truly, is a selfless act.

—Susan L. Cohn, MD

ginning to act like the daughter she knew before the diagnosis of neuroblastoma. Amy received radiation after her stem cell transplantation; 7 months after her initial diagnosis, Amy was in remission.

Search for Better Treatments I was thrilled that Amy’s tumor responded so well to treatment, but I knew that she was likely to have minimal residual disease. I reminded Amy’s parents that their daughter remained at significant risk for relapse. I informed them that a prior randomized, cooperative group clinical trial had shown that oral isotretinoin (cis-retinoic acid [RA]) given after consolidation improved the outcome for patients with high-risk neuroblastoma.1 On the basis of these results, RA is now considered part of the standard-of-care therapy for high-risk neuroblastoma. “However,

notherapy combined with RA would lead to improved survival in patients who were in first remission. We needed to complete the randomized, clinical trial to answer this question.

Amy’s parents listened carefully.

They were, understandably, concerned that Amy would again be in the hospital and separated from her sister if she was assigned to the immunotherapy arm.

They also were worried about the pain and need for a morphine drip associated with the antibody therapy. After all, Amy was just beginning to feel better after being hospitalized for weeks because of the toxicities of high-dose therapy and stem cell transplantation.

As a physician desperate to find better treatments for my patients, I understand the potential impact that a randomized study can have for children worldwide who are diagnosed with neuroblastoma. During my career,

I have witnessed remarkable advances in the treatment of neuroblastoma and other pediatric cancers that resulted from randomized, cooperative group studies. For a parent, though, enrolling a son or daughter onto a randomized trial, truly, is a selfless act. The decision to participate in this particular clinical trial was especially agonizing, because the treatment arms were so disparate. I suggested that Amy’s parents go home and take some time to think about whether or not they would like to enroll their daughter onto this study.

Helping Future Children One week later, Amy’s mother and father met with me in clinic. “We have decided to do the clinical trial,” said Amy’s mom. “My daughter has benefited from families who enrolled their children onto previous clinical studies, and we want to help future children with this disease.”

Amy was enrolled onto the study a few days later and was randomly assigned to the immunotherapy arm. She developed many of the expected toxicities of immunotherapy, and I know that her mom asked herself if she made the right decision when she saw her daughter, swollen and miserable, on a morphine drip. However, Amy and her family persevered, and Amy completed the planned therapy. Eight years later, Amy remains in remission and is a healthy preteen who loves school, cheerleading, and Taylor Swift.

When I called Amy’s mom with the news about the FDA approval, I was the one with tears in my eyes. I informed her that the approval of dinutuximab was based on the demonstration of significantly improved survival with immunotherapy plus RA on the Children’s Oncology Group randomized clinical trial.2 Her selfless act would help children with neuroblastoma in the future. n References 1. Matthay KK, Villablanca JG, Seeger RC, et al. (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341:1165-1173, 1999.

2. Yu AL, Gilman AL, Ozkaynak MF, et al. (2010) Anti-GD2 antibody with GMCSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363:13241334, 2010.

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FDA Update

FDA Approves Cobimetinib in Combination With Vemurafenib for Metastatic Melanoma

O

n November 10, 2015, the U.S. Food and Drug Administration (FDA) approved the MEK inhibitor cobimetinib (Cotellic) in combination with the BRAF inhibitor vemurafenib (Zelboraf) to treat metastatic or unresectable melanoma in patients whose tumors express the BRAF V600E or V600K mutation. Approval of the combination was based on results from the phase III coBRIM study.1 “As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or

more treatments addressing different cancer-causing targets may help to address this challenge,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s

Center for Drug Evaluation and Research. “[This] approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients

with BRAF mutation–positive melanoma,” Dr. Pazdur said.

Vemurafenib was approved in 2011 to treat patients with melanoma that has spread to other parts of the body or can-

Daratumumab Approved in Multiple Myeloma

T

he U.S. Food and Drug Administration has granted accelerated approval for daratumumab (Darzalex) to treat patients with multiple myeloma who have received at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent. Daratumumab is the first monoclonal antibody approved for treating multiple myeloma.

“Targeting proteins that are found on the surface of cancer cells has led to the development of important oncology treatments,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. “[Daratumumab] provides another treatment option for patients with multiple myeloma who have become resistant to other therapies.”

Daratumumab injection, given as an infusion, is a monoclonal antibody that works by helping certain cells in the immune system attack cancer cells.

The safety and efficacy of daratumumab were demonstrated in two open-label studies. In one study of 106 participants receiving daratumumab, 29% of patients experienced a complete or partial reduction in their tumor burden, which lasted for an average of 7.4 months. In the second study of 42 participants receiving daratumumab, 36% had a complete or partial reduction in their tumor burden.

The most common side effects of daratumumab were infusion-related reactions, fatigue, nausea, back pain, fever, and cough. n

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ASCOPost.com | NOVEMBER 25, 2015

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FDA Update

not be removed by surgery, whose tumors express the BRAF V600E mutation, as detected by an FDA-approved test.

Health-care providers should confirm the presence of BRAF V600 E or V600K mutation in their patients’ tumor specimens using one of the available FDA-approved tests prior to starting treatment with cobimetinib in combination with vemurafenib.

Phase III coBRIM Study The coBRIM study is an international, randomized, double-blind, placebo-controlled phase III trial evaluating the safety and efficacy of cobimetinib at 60 mg once daily plus vemurafenib at 960 mg twice daily compared to vemurafenib at 960 mg twice daily plus placebo. In the study, 495 patients with

BRAF V600 mutation–positive unresectable locally advanced or metastatic melanoma (detected by the Cobas 4800 BRAF Mutation Test) and previously untreated for advanced disease were randomly assigned to receive vemurafenib every day on a 28-day cycle plus either cobimetinib or placebo on days 1 to 21.

Treatment was continued until disease

progression, unacceptable toxicity, or withdrawal of consent.

Investigator-assessed progressionfree survival was the primary endpoint.

Secondary endpoints included progression free survival as determined by independent review committee; overall response rate; objective survival; duration

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continued on page 130

The ASCO Post | NOVEMBER 25, 2015

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FDA Update FDA Approves Cobimetinib continued from page 129

of response; and other safety, pharmacokinetic, and quality-of-life measures.

The study showed cobimetinib plus vemurafenib reduced the risk of progression-free survival by about one-half in people who received the combination, (P < .001), with a median pro-

gression-free survival of 12.3 months for cobimetinib plus vemurafenib compared to 7.2 months with vemurafenib alone. An interim analysis also showed the combination of cobimetinib and vemurafenib improved overall survival compared with vemurafenib alone (P = .0019). The objective response rate was higher with cobimetinib plus ve-

murafenib compared with vemurafenib alone (70% vs 5%, P < .001), as was the complete response rate (complete tumor shrinkage = 16% vs 10%).

The final overall survival analysis from the coBRIM study were presented earlier this month at the Society for Melanoma Research 2015 International Congress, held in San Francisco.1 n

Reference 1. Ascierto P, et al: coBRIM: A phase III, double-blind placebo-controlled study of vemurafenib vs vemurafenib + cobimetinib in previously untreated BRAF v600 mutation–positive patients with unresectable locally advanced or metastatic melanoma.

Society for Melanoma Research 2015 Congress. Presented November 18-21, 2015.

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ASCOPost.com | NOVEMBER 25, 2015

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Announcements

Barbara Furie, PhD, and Bruce Furie, MD, to Present 2015 ASH E. Donnall Thomas Lecture

T

he American Society of Hematology (ASH) will honor Barbara Furie, PhD, of Harvard Medical School, and Bruce Furie, MD, of Beth Israel Deaconess Medical Center

and Harvard Medical School, with the 2015 E. Donnall Thomas Lecture for their groundbreaking research in hemostasis and thrombosis over the past 40 years. The Furies are international

leaders in hemostasis and thrombosis, and their outstanding research program has made landmark contributions to the understanding of the structure, biochemistry, and function of coagulation

Barbara Furie, PhD and Bruce Furie, MD

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and platelet proteins. This award, named after the late Nobel Prize Laureate and Past President of ASH E. Donnall Thomas, MD, recognizes pioneering research achievements in hematology, which have represented a paradigm shift or significant discovery in the field.

The Furies will present their lecture, “Thiol Isomerases as Potential Regulators Controlling the Initiation of Thrombus Formation,” on Monday, December 7, at the 57th ASH Annual Meeting and Exposition in Orlando, Florida.

In 1975, the Furies founded the Center for Hemostasis and Thrombosis Research at Tufts University School of Medicine and New England Medical Center, to conduct interdisciplinary research in the areas of blood coagulation and platelet and vascular biology. During its 40 years in operation, the Furie Lab, which moved to Harvard Medical School and the Beth Israel Deaconess Medical Center in 1997 and became the Division of Hemostasis and Thrombosis in 2000, has hosted more than 100 young investigators for research training.

Dr. Barbara Furie is currently Professor Emeritus at Harvard Medical School, where she previously served as Co-Chief of the Division of Hemostasis and Thrombosis and Professor of Medicine. She earned her PhD in chemistry from the University of Pennsylvania.

Dr. Bruce Furie is currently Chief of Hemostasis-Thrombosis at Beth Israel Deaconess Medical Center, where he also directs the Blood Coagulation and Vascular Biology Training Program. He also serves as Professor of Medicine at Harvard Medical School. n

The ASCO Post | NOVEMBER 25, 2015

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Patient’s Corner

CAR T-Cell Immunotherapy Saved My Life

I am honored to be among the patient pioneers advancing immunotherapy for myeloma.

By Lori Alf, as told to Jo Cavallo

I

have always prided myself on being healthy and fit, so when I started experiencing a chronic cough, difficulty breathing, and pain in my ribs and back, I thought they were the inevitable symptoms of a severe cold. At 42 and the mother of three children, it was inconceivable to me that I could have an incurable, life-threatening disease.

But after medication to treat my symptoms proved unsuccessful, blood tests, followed by a bone marrow biopsy, determined that I had advanced-stage multiple myeloma.

My oncologist recommended aggressive treatment, including high-dose chemotherapy, to reduce the amount of myeloma cells and two consecutive autologous stem cell transplants to get me to a cure or at least a durable remission. The treatment and recovery would mean spending 6 months in the hospital away from my husband and children, which was completely unacceptable to me. I knew I had to find other options.

Searching for Quality of Life I traveled from my home in Florida to consult with myeloma experts at Dana-Farber Cancer Institute in Boston, who recommended several rounds of a combination regimen of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) to get the myeloma under enough control to harvest my stem cells for an autologous stem cell transplant. But after 9 months of RVD and high doses of cyclophosphamide failed to control my tumor growth, I was admitted into the hospital to receive a high-dose regimen of dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP),

which sufficiently reduced the amount of myeloma cells in my body to get me to the transplant.

Unfortunately, a few weeks after the procedure, the cancer was again progressing, and I was whipsawing in and out of the hospital for blood transfusions and other supportive care. Although the treatments were buying me time, they were not giving me the quality of life or the amount of uninterrupted time with my family I had hoped for, so I was desperate for a solution that would change the trajectory of my cancer.

Using the Immune System When I was first diagnosed with myeloma in 2008, I had asked my oncologists whether immunotherapy could be an effective option for me and was told that the science wasn’t advanced enough in the treatment of multiple myeloma and probably would not be in my lifetime. Five years later, after becoming refractory to every therapy I was given, I was desperate. The treatments and the advancing myeloma had left me bedridden and in excruciating pain, and I knew I was probably weeks away from death.

Despite my critical state, I wasn’t ready to give up and couldn’t shake the feeling that immunotherapy might be a viable alternative for me. When I saw information about a clinical trial being launched at the Perelman School of Medicine at the University of Pennsylvania investigating chimeric antigen receptor (CAR) T-cell therapy for patients with advanced myeloma,1 I thought it could be the lifeline I was hoping for. I was right.

The procedure for the experimental

I am the first myeloma patient to have achieved a sustained durable remission using CAR T-cell therapy.

Now, I’m making it my life’s mission to help further research efforts in multiple myeloma, especially in the area of immunotherapy.

—Lori Alf

therapy, which used my own immune cells engineered with an anti-CD19 CAR and then infused back into me, was grueling. It included high-dose melphalan and a second autologous stem cell transplant.

Within weeks of receiving the CARmodified autologous T cells, I attained a minimal residual disease–negative stringent complete response, and that is where I remain 15 months later. I am the first myeloma patient to have achieved a sustained durable remission using CAR T-cell therapy and am honored to be among the patient pioneers advancing immunotherapy for this still incurable cancer.

Building a Lasting Legacy I know I wouldn’t be alive if I had not had such a dedicated team of oncologists from multiple cancer centers that refused to give up and worked together to coordinate my care. Now, I’m making it my life’s mission to help further research efforts in multiple myeloma, especially in the area of immunotherapy.

I’ve been given another chance at life, and for however long that chance lasts, I plan to use the time construc-

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

tively to ensure that each patient with myeloma benefits from precision medicine, to raise funding for research, and to make whatever contribution I can to finding a cure for this disease.

The fact that I now have a chronic, manageable disease should inspire both patients and researchers never to give up the quest for more effective therapies and, ultimately, a cure. I’m convinced that my positive attitude, which kept me pursuing an effective therapy even when the odds were against finding one, is helping me to survive multiple myeloma. I wish to pass on this intrepid spirit and sense of determination to other cancer survivors, so they, too, can, hopefully, beat the odds. n Reference 1. Garfall AL, Maus MV, Lacey SF, et al: Safety and efficacy of anti-CD19 chimeric antigen receptor (CAR)-modified autologous T cells (CTL019) in advanced multiple myeloma. 2015 ASCO Annual Meeting. Abstract 8517. Presented May 29, 2015.

Lori Alf is Director of National Air Cargo and a board member of Acetylon Pharmaceuticals. She lives in Boca Raton, Florida.

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

ASCOPost.com | NOVEMBER 25, 2015

PAGE 133

Announcements

ASH Selects Medical Students and Residents for HONORS Award

T

he American Society of Hematology (ASH) has announced the names of 18 medical students and 10 residents selected to receive a 2015 ASH HONORS Award.

The ASH HONORS Award aims to support hematology research projects for North American medical students and residents who are interested in hematology but have not yet entered a hematology-related training program. Awardees receive a $5,000 stipend to conduct a research project alongside a mentor from their institution on either a short-term (up to 3 months) or long-term project (up to 12 months). Recipients will also receive a $1,000 travel stipend each year for 2 years to support their attendance at the ASH Annual Meeting.

Awardees were selected based on the quality and relevance of their research projects to hematology, the mentoring environment at their institution, and their interest in the field, in addition to their education qualifications and experience.

“Medical school and residency are

exciting times for trainees, but they often have difficulty finding the time or identifying resources to conduct independent research and may not be aware of opportunities within hematology,” said ASH President David A. Williams, MD, of Dana-Farber/Bos-

David A. Williams, MD

ton Children’s Cancer and Blood Disorders Center and Harvard Medical School. “Through research funding and mentor support, the ASH HONORS Award aims to bring exciting opportunities in hematology research to the best trainees and encourage them to pursue a career in the field.”

The 2015 ASH HONORS Award recipients appear here.

Residents

Medical Students Recipient/Institution

Research Mentor/Institution

Annabelle Anandappa Harvard Medical School

Catherine Wu, MD Dana-Farber Cancer Institute

Omri Arbiv University of Toronto

Yigal Dror, MD Hospital for Sick Children, University of Toronto

Abha Athale Midwestern University

Alfonso Iorio, MD, PhD McMaster University

Jennifer Bai University of Maryland School of Medicine

Curt Civin, MD University of Maryland School of Medicine

Christina Cahill University of Vermont College of Medicine

Mary Cushman, MD, MSc University of Vermont College of Medicine

Melanie Donahue University of Massachusetts Medical School

Benjamin Ebert, MD, PhD Brigham and Women’s Hospital

Tara Gavcovich George Washington University School of Medicine

Christian Capitini, MD The Board of Regents of the University of Wisconsin System

Yan Leyfman Pennsylvania State College of Medicine

Renier Brentjens, MD, PhD Memorial Sloan Kettering Cancer Center

Gregory Metzger The Ohio State University

Robert Baiocchi, MD, PhD The Ohio State University

John-Jose Nunez University of British Columbia

Aly Karsan, MD University of British Columbia, BC Cancer Agency

Olubusola Oluwole University of Pittsburgh School of Medicine

Enrico Novelli, MD University of Pittsburgh School of Medicine

Shreya Podder Virginia Commonwealth University

Gordon Ginder, MD Virginia Commonwealth University

Joshua Pritchett University of Minnesota Medical School

Troy Lund, MD, PhD University of Minnesota Medical School

Recipient/Institution

Research Mentor/Institution

Moritz Binder, MD, MPH Mayo Clinic

Shaji Kumar, MD Mayo Clinic

Erica Braverman, MD University of Rochester

Jessica Shand, MD University of Rochester

Jad Chahoud, MD The University of Texas MD Anderson Cancer Center

Elias Jabbour, MD The University of Texas MD Anderson Cancer Center

Roberto Fratamico, MD Thomas Jefferson University Hospital

Ubaldo Martinez-Outschoorn, MD Thomas Jefferson University Hospital

Sanghee Hong, MD Cleveland Clinic

Navneet Majhail, MD Cleveland Clinic

Katarzyna Rojek University of Illinois at Chicago ­College of Medicine

Lucy Godley, MD, PhD University of Chicago

Miriam Kimpton, MD University of Ottawa

Marc Carrier, MD, MSc Ottawa Hospital Research Institute

Robert Schwab University of Pennsylvania

Carl June, MD University of Pennsylvania

Weijuan Li, MD Albert Einstein College of Medicine,

Amit Verma, MBBS Albert Einstein College of Medicine

Arun Singavi, MD Medical College of Wisconsin

Joshua Field, MD Medical College of Wisconsin

Andrew Scott The Johns Hopkins University School of Medicine

Linda Resar, MD The Johns Hopkins University School of Medicine

Abi Vijenthira, MD University of Toronto

Anca Prica, MD University of Toronto

Joshua Siner Cooper Medical School of Rowan University

Valder Arruda, MD, PhD The Children’s Hospital of Philadelphia

Julia Xu, MD Duke University Medical Center

Marilyn Telen, MD Duke University Medical Center

Emily Stern Tufts University School of Medicine

Daniel Bauer, MD, PhD Boston Children’s Hospital

OVERALL SURVIVAL AT 5 YEARS IN DLBCL IS

1

Could a better understanding of this disease be on the horizon?

60%

Š 2015 Genentech USA, Inc. All rights reserved. HEM/062915/0014a 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, we are determined 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 | NOVEMBER 25, 2015

PAGE 136

2015-2016 Oncology Meetings

2015-2016

December

January 2016

February

9th European Colorectal Congress (ECC) December 1-4 • St. Gallen, Switzerland For more information: www.colorectalsurgery.eu

4th AACR-IASLC International Joint Conference: Lung Cancer Translational Science January 4-7 • San Diego, California For more information: 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-ofthe-science-cancer-survivorshipresearch-symposium.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

Genitourinary Cancers Symposium January 7-9 • San Francisco, California For more information: http://gucasym.org Cancer Survivorship Symposium: Primary Care and Oncology Collaboration January 15-16 • San Francisco, California For more information: www.survivorsym.org/ Gastrointestinal Cancers Symposium January 21-23 • San Francisco, California For more information: http://gicasym.org Personalized World Medicine Conference January 24-27 • Mountain View, California For more information: http://2016sv.pmwcintl.com/ index.php 8th Immunotherapeutics & Immunomonitoring Conference January 25-26 • San Diego, California For more information: https://www.gtcbio.com/ conferences/immunotherapeuticsimmunomonitoring-overview 3rd Annual University of Southern California Multidisciplinary Breast Cancer Symposium January 30 • Los Angeles, California For more information: http://keck.usc.edu/About/ Administrative_Offices/Office_of_ Continuing_Education/Courses/~/ media/Office%20of%20CME/FINAL_ brochure_2016%20breast%20 cancer.pdf

18th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 4-6 • San Diego, California For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/ 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 The Biomarker Conference February 18-20 • San Diego, California For more information: www.mnmconferences.com/thebiomarker-conference-florida.html Multidisciplinary Head and Neck Cancer Symposium February 18-20 • Scottsdale, Arizona For more information: www.headandnecksymposium.org 25th Conference of the Asian Pacific Association for the Study of the Liver February 20-24 • Tokyo, Japan For more information: http://www.apasl2016.org 3rd Annual International Conference on Advances in Cancer Medical Research (ACMR 2016) February 22-23 • Singapore For more information: http://cancerresearch-conf.org/ Cancer Center Business Summit February 24-25 • Phoenix, Arizona For more information: http://cancerbusinesssummit.com

ASCO Quality Care Symposium February 26-27 • Phoenix, Arizona For more information: http://quality.asco.org Winship Cancer Institute 2016 Melanoma Conference February 27 • Atlanta, Georgia For more information: www.winshipmelanomaconference .com AACR Precision Medicine Series: Cancer Cell Cycle–Tumor Progression and Therapeutic Response February 28-March 2 • Maui, Hawaii For more information: www.aacr.org/Meetings/Pages/ MeetingDetail.aspx?EventItemID=76#.

Vbb2qKTbJjo

March Society of Surgical Oncology Annual Cancer Symposia March 2-5 • Boston, Massachusetts For more information: www.surgonc.org 22nd Annual Blood-Brain Barrier and Neuro-oncology Meeting March 3-5 • Stevenson, Washington For more information: www.ohsu.edu/bbb 4th Annual UC San Diego Essentials and Advances in Apheresis Therapies March 3-5 • San Diego, California For more information: https://cme.ucsd.edu/apheresis/ 8th Annual Asian Oncology Summit March 3-6 • Kyoto, Japan For more information: www.asianoncologysummit.com

continued on page 145

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 | NOVEMBER 25, 2015

PAGE 145

2015-2016 Oncology Meetings Meetings Calendar continued from page 136

Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan Kettering Cancer Center March 4-7 • New York, New York For more information: www.mskcc.org/event/hematologyand-medical-oncology-boardreview-contemporary-practice 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-2fb116562f6447cca492 c89064760b02.aspx

B:14.25 in

T:14 in

S:13 in

ILCA School of Liver Cancer 2016 March 7-8 • Barcelona, Spain For more information: www.ilca-online.org/sitecore/content/ be-bruga/ilca-online/School%20 of%20Liver%20Cancer/2016.aspx 3rd St. Gallen International Gastrointestinal Cancer Conference March 10-12 • St. Gallen, Switzerland For more information: www.oncoconferences.ch/dynasite .cfm?dsmid=500294

2016 ASTRO Annual Refresher Course March 11-13 • La Jolla, California For more information: www.astro.org/Meetings-andEvents/2016-Annual-RefresherCourse/Index.aspx 2016 Methods in Clinical Research Workshop for Minority Physicians March 17-20 • Fort Lauderdale, Florida For more information: https://www. roswellpark.edu/education/diversityclinical-research-workshop The 16th Multidisciplinary Management of Cancers: A Case-Based Approach March 18-20 • Napa, California For more information: https://med.stanford.edu/cme/ courses/2016/multicancer2016.html Society of Gynecologic Oncology Annual Meeting on Women’s Cancer March 19-22 • San Diego, California For more information: www.sgo.org

April 26th Annual Interdisciplinary Breast Cancer Center Conference April 9-13 • Las Vegas, Nevada For more information: http://www2.breastcare.org/ welcome-to-the-24th-annualnational-interdisciplinary-breastcenter-conference/ European Lung Cancer Conference April 13-16 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2016-Lung-Cancer

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

American Society for Colposcopy and Cervical Pathology (ASCCP) Annual Meeting April 13-16 • New Orleans, Louisiana For more information: www.asccp.org/2016annualmeeting

2015-2016

Clinical Immunology Society Annual Meeting April 14-17 • Boston, Massachusetts For more information: www.clinimmsoc.org/education/ meetings/2016-annual-meeting American Association of Cancer Research Annual Meeting April 16-20 • New Orleans, Louisiana For more information: www.aacr.org 16th Pan Arab Cancer Conference April 28-30 • Cairo, Egypt For more information: www.pacc16.org

Lymphoma: State-of-the-Art in Biology, Therapy, and Patient Care May 13-14 • New York, New York For more information: www.mskcc.org/event/lymphomastate-art-biology-therapy-andpatient-care

2016 Head and Neck Cancer Symposium Fifth Annual April 30 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx

AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer May 16-19 • Miami, Florida For more information: www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=78#.Vbel9qTbJjo

May

June

Markers in Cancer Diagnostic Development Tutorial May 2-3 • Bethesda, Maryland For more information: http://markersincancer.org

2016 ASCO Annual Meeting June 3-7 • Chicago, Illinois For more information: http://am.asco.org

Palliative Care Education and Practice (PCEP) May 4-10 • Cambridge, Massachusetts For more information: www.hms.harvard.edu/pallcare/PCEP/ PCEP.htm 19th SIS World Congress on Breast Healthcare May 5-8 • Warsaw, Poland For more information: www.siscongress.org IMPAKT 2016 Breast Cancer Conference May 12-14 • Brussels, Belgium For more information: www.esmo.org/Conferences/IMPAKT2016-Breast-Cancer

WCIO 2016 June 9-12 • Boston, Massachusetts For more information: www.wcioevents.org 2016 ASH Meeting on Lymphoma Biology June 18-21 • Colorado Springs, Colorado For more information: www.hematology.org/ Lymphoma-Biology/ Best of ASCO Chicago June 24-25 • Chicago, Illinois For more information: http://boa.asco.org

The ASCO Post | NOVEMBER 25, 2015

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Book Review

Stepping Back in Medical History: A Groundbreaking Surgeon’s Battle With the Establishment

By Ronald Piana

I

n the late 1740s, John Wesley—a British evangelist and cofounder of Methodism—published An Easy and Natural Method for Curing Most Diseases. His tome gave regular people ways to cure themselves by using items they could find in their homes.

When in doubt, Mr. Wesley proffered that drinking cold water or taking cold baths could cure most illnesses, including breast cancer.

Although Mr. Wesley’s faith in a cold water cure for breast cancer is a brutally primitive misadventure to today’s oncologists, it is bracing to imagine what it must have been like for those early doctors who were working in a veritable vacuum of medical information. The trial-by-error road leading to the wonders of modern science and technology that contemporary physicians are armed with was painful, wacky, courageous, brilliant, and illuminating.

Eccentric Physician In a first-ever biography titled, Dr. Mütter’s Marvels: A True Tale of Intrigue and Innovation at the Dawn of Modern Medicine, Cristin O’Keefe Aptowicz chronicles the life of the eccentric, groundbreaking physician, Thomas Dent Mütter, MD, who revolutionized surgery and founded America’s first museum of medical oddities. Dr. Mütter, born in 1811, grew up as an orphan in the Antebellum South, an age when death hovered perpetually overhead—a grim fact he was intimate with. By the time he was 7, his mother, father, brother, and grandmother had all died of disease, and he himself was chronically ill as a boy.

Despite his difficult beginnings, he was, by all turns, brilliant, handsome, charming, and ambitious. Since childhood, he longed to become a doctor, and by force of will he worked his way through an undergraduate degree at Hampden-Sydney College in Virginia.

In 1931, he earned his medical degree from the University of Pennsylvania. To get an MD in those years, a student had to attend at least one course of lectures in anatomy, pharmacology, chemistry, and the theory and practice of healing; do a 1-year hospital internship; and be examined by medical trustees and professors. And there were three other requirements

for medical students—an applicant had to be at least 24 years old, white, and male.

After receiving his MD, Dr. Mütter left for Paris where he studied radically avant garde plastic surgery under the European masters. It was a careerchanging experience, in which he performed surgery on severely deformed patients—people the public at that time classified as “monsters.”

Thereafter, Dr. Mütter became a revolutionary figure whose compassionbased philosophy and innovative surgical ideas and breakthroughs clashed with the medical constraints of the era. Returning from Paris, Dr. Mütter joined the faculty of Jefferson Medical College, where he became renowned for his operations on clubfoot, cleft lip and palate, congenital anomalies, and mutilating injuries.

Details Over Action Ms. Aptowicz is adept at weaving the narrative through the historical inflection points. However, she occasionally overwrites a section, favoring details over action as if they were equals. In a book about a swashbuckling surgeon, they are not. But that is a small complaint.

Dr. Mütter’s Marvels is based on more than 15 years of research, and Ms. Aptowicz has done a fine job in conflating medical history, clinical procedures, and the major medical personalities of the day into a highly readable book, replete with more than 70 startling illustrations and fascinating period detail.

She also gives the reader a front row seat to the evolution of American medicine: bleedings and leachings, surgeries performed on fully conscious patients, the standardization of medical schools, the institution of pre- and postoperative care, the discovery of anesthesia, and the medical community’s stubborn resistance to antisepsis.

As Ms. Aptowicz points out, doctoring was a tough profession in the early 1800s—not for the faint of heart.

She writes, “The simplest thing could end your life: a broken bone from a fall, a leg gouged by a nail, a hand burned by a pot of boiling soup.… Then there was a host of diseases such as cholera in which the affected person retched liter upon liter of fluid that looked like rice

Bookmark Title: Dr. Mütter’s Marvels: A True Tale of Intrigue and Innovation at the Dawn of Modern Medicine Author: Cristin O’Keefe Aptowicz Publisher: Gotham Books Publication date: September 8, 2015 Price: $17.00, paperback; 384 pages water and smelled like rotten fish.” The author is skilled in atmospheric prose that will bring the reader back in time, some of which might be hard to read for those with a sensitive stomach.

Put yourself in this patient’s situation: “On one occasion, a Jefferson Medical College professor attempted a daring removal of a patient’s upper jaw, using marvelous speed to incise and rip out bones with a huge forceps. But the surgery was perhaps too much to witness by the gallery. Doctors who were present would later recall the spectacle of it; the patient spat out blood, bones, teeth, while unnerved students in the audience vomited and fainted in their seats.”

A Riveting Saga What makes this an interesting read for The ASCO Post audience—especially surgical specialists—are Dr. Mütter’s brave innovations and the battles he waged against the medical establishment’s dogged resistance to change, even if that change had proven benefits for the patient. It is a riveting saga that runs deep through medical history.

Another compelling narrative thread is the struggle Dr. Mütter led to treat patients, notably the poor, with compassion and dignity, a medical principle way before its time. For urging compassionate care, his fellow doctors publicly mocked him. One of the more compelling examples of Dr. Mütter’s character and courage was his public chastising of one of medicine’s prominent superstars: a misogynist

(by today’s standards) named Charles D. Meigs, MD, who routinely humiliated women during his gynecologic lectures in front of all-male classes.

The author writes: ‘Women posses a peculiar trait—it is modesty. But scan her position in civilization, and it is easy to perceive her intellectual force is different from that of her master and lord.… She is still in bonds, manacled by her own inferiority to man,’ said Dr. Meigs as he casually positioned the female patient for maximum exposure. Much to his credit, Dr. Mütter, at great professional risk, publicly challenged Dr. Meigs, calling his ideas, ‘lazy, often inaccurate, callous toward patients, some which are outright harmful, such as his tendency to not only positively deny the contagious nature of the diseases he came across, but to ridicule anyone who opposed him.’

Then there is the sensational aspect of Dr. Mütter’s vast collection of medical oddities, turned into a museum that to this day is a major attraction. There you can view the conjoined liver of the famous Siamese twins, Chang and Eng Bunker. It is also the only place where members of the public can view slides of Albert Einstein’s brain.

There is much more, but it is a mere sideshow to the main event. In the end, Dr. Mütter was a great doctor, one who deserves to be praised for his courageous innovations and his humanity toward his patients. Even today, healthcare professionals can learn from and be motivated by his legacy. Dr. Mütter’s Marvels is highly recommended. n

ASCOPost.com | NOVEMBER 25, 2015

PAGE 147

Announcements

ASH Recognizes Curt Civin, MD, and Craig Kitchens, MD, MACP, for Outstanding Mentorship

T

he American Society of Hematology (ASH) will honor Curt Civin, MD, and Craig Kitchens, MD, MACP, with 2015 Mentor Awards at the 57th ASH Annual Meeting and

Exposition in Orlando, Florida, for their sustained, outstanding commitment to the training and career development of early-career hematologists.

The ASH Mentor Award was es-

tablished in 2006 to recognize hematologists who have excelled in mentoring trainees and colleagues. Each year, the Society recognizes two outstanding mentors.

Curt Civin, MD

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Curt Civin, MD During his nearly 40-year career, Dr. Civin, Director of the Center for Stem Cell Biology and Associate Dean for Research at the University of Maryland School of Medicine, has served as the primary faculty preceptor to 49 postdoctoral fellows and 9 predoctoral students.

Dr. Civin’s research focuses on stem cell biology, Fanconi anemia, and leukemia. He is internationally recognized for his discovery of the CD34 lymphohematopoietic stem cell antigen and subsequent development of the CD34 monoclonal antibody, heralded as a major milestone in the development of cell therapy. This work has not only led to improved stem cell transplantation for thousands of patients, but it has also indirectly contributed to the training of thousands of physicians and technicians throughout the world.

Craig Kitchens, MD, MACP

Craig Kitchens, MD, MACP Through his 40-year career, Dr. Kitchens, Professor Emeritus at the University of Florida College of Medicine, has influenced many of his trainees to pursue careers in nonmalignant hematology.

Dr. Kitchens is a world authority on thrombosis, evidenced by his contributions to more than 120 publications and more than 40 book chapters, most of which were coauthored with his trainees. In addition to caring for patients with a myriad of hemostatic and thrombotic diseases, Dr. Kitchens has an interest in envenomation by poisonous snakes and has recently developed a snake antivenom. n

The ASCO Post | NOVEMBER 25, 2015

PAGE 148

In the News Screening

Updated ACS Breast Cancer Screening Guideline Recognizes Greater Role for Individual’s Values and Preferences

By Charlotte Bath

T

he reactions to the updated breast cancer screening guideline from the American Cancer Society (ACS) have been many, varied, and not consistently favorable but not surprising to Kevin C. Oeffinger, MD, who chaired the ACS panel that issued the guideline.

Breast cancer screening “is an area that people have strong opinions on,” Dr. Oeffinger, Director of the Cancer Survivorship Center at Memorial Sloan Kettering Cancer Center, New York, said in an interview with The ASCO Post. “So, no, we were not surprised at all.”

The updated guideline, published in The Journal of the American Medical Association,1 recommends that for women at average risk of breast cancer, screening mammography should start at age 45

and be done annually until age 54. The previous ACS guideline (as well as current guidelines from the National Comprehensive Cancer Network and other organizations) recommended that women start having screening mammography at age 40. The updated ACS guideline recommends that women aged 40 to 44 “should have the opportunity to begin annual screening,” and women 55 or older “should transition to biennial screening or have the opportunity to continue screening annually.”

Very Deliberate Wording Asked if the wording that women from 40 to 44 and over 55 “should have the opportunity” for annual screening was used out of concern that those

women who wanted annual screening not be denied it, Dr. Oeffinger replied, “You bet. We strongly, strongly, strongly support full, first dollar insurance coverage, affordable copayment, and adequate access to care for women 40 to 44 who choose to have a screening mammogram, just as we strongly support women aged 55 and older who choose to continue to have an annual mammogram,” he said.

“The word ‘opportunity’ is used very deliberately,” Dr. Oeffinger continued.

“The American Cancer Society continues to be one of the most vocal supporters of access to mammography for women. That has not changed. That will not change.”

It is a misunderstanding of the

Expect Questions About Updated Breast Cancer Screening Guidelines

By Charlotte Bath

A

s Chair of the American Cancer Society (ACS) panel that issued an updated guideline for breast cancer screening, Kevin C. Oeffinger, MD, has answered questions and offered perspective on the updated guideline and its development for The New York Times, USA Today, and oth-

only read the headlines or heard brief snippets about the updated guideline.”

Two Categories of Concern Dr. Oeffinger said that patients’ concerns generally fall into two major categories that directly impact deci-

It is the woman herself who should decide [about when to start breast cancer screening], not me.

The tradeoff is best defined by the individual woman.

—Kevin C. Oeffinger, MD

er major media outlets. As Director of the Cancer Survivorship Center, Memorial Sloan Kettering Cancer, New York, he has welcomed and answered questions about the guideline from colleagues and patients.

“I hoped and anticipated that I would get questions, because that always gives us the opportunity to expand upon the media coverage,” Dr. Oeffinger said in an interview with The ASCO Post. “This allows us to explain the details of the recommendations to people who may have

sions about screening. “One is typified by the comment, ‘I want to avoid a breast cancer diagnosis that is late by any means possible.’ That suggests an easy decision for screening,” he said.

“But just as many women tell me, ‘I really want to avoid overtesting. I understand what you say about the numbers, and the likelihood is that I will live my life without having breast cancer.’”

In both of these scenarios, “it is the woman herself who should decide, not me,” Dr. Oeffinger said. “The tradeoff is best defined by the individual woman.”

Clinical Encounter Context The guideline “is especially designed for use in the context of a clinical encounter,” the Guideline Development Group stated, so that screening decisions reflect an individual’s values and preferences. By the time women need to make a decision about breast cancer screening, most understand what is most important to them and what they most want to avoid—a late or missed diagnosis of breast cancer or overtesting.

“It is not difficult for a physician or other health-care provider to ascertain a woman’s preferences and values. This is not a 30-minute conversation,” Dr. Oeffinger said, “but it tends to be relatively brief.”

Physicians should also periodically establish whether a woman’s risk-factor profile has changed. “We have to move away from taking a family history or assessing comorbidities just once,” Dr. Oeffinger said. “Health is dynamic.

People’s family histories are changing.

Their comorbidities are changing. We need to think of a woman as being on a continuum and assess what her needs are during that individual visit and at that point in time, not just one time.” n Disclosure: Dr. Oeffinger is Chair of the American Cancer Society’s breast cancer guideline panel.

guideline to say that the ACS “moved” the age of annual screening mammography from 40 to 45, Dr. Oeffinger noted.

“In fact, we didn’t move from 40 to 45; we recommended that women talk with their health-care provider and have the opportunity to start at 40. And if they haven’t started at 40, 41, 42, 43, or 44, then at 45, definitely, they need to start.”

The updated guideline also calls for screening to continue as long as a woman has overall good health and a life expectancy of 10 or more years. In addition, “the ACS does not recommend clinical breast examination for breast cancer screening for average-risk women of any age.” (For details about the updated ACS guideline, see the Journal Spotlight on page 82.)

Differing Screening Recommendations The updated guideline differs not only from the previous ACS recommendations, but from current recommendations issued by other organizations. “We have had different recommendations for a long time, from country to country and within the United States. Prior to the release of this guideline, the U.S. Preventive Services Task Force [USPSTF] recommended starting at age 50. Both the American College of Physicians and the American Academy of Family Physicians largely adopted that guideline. The American Cancer Society had specified age 40 and annual screening, and the American College of Obstetricians and Gynecologists as well as the American College of Radiology had largely adopted that,” Dr. Oeffinger said.

“In some ways, the messages from ACS and the USPSTF, two major guidelines, are now more consistent,” noted an editorial accompanying the article.2 Asked if he saw a movement toward agreement on breast cancer screening, Dr. Oeffinger replied, “I would love to see agreement; I think everybody would. But people have very strong opinions and biases that are tied in with the way that they view evidence.”

A Rigorous Process The update was a rigorous process, following a “roadmap” outlined by the Institute of Medicine, Dr. Oeffinger explained. The Guideline Development Group selected the Duke University continued on page 150

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Mammography ‘Trashing’

continued from page 148

“Advances in the treatment of breast cancer have led some to suggest that mammography is passé, that it outlived its usefulness,” Dr. Oeffinger noted. He referred to articles “published in highimpact journals that question whether mammography is really necessary anymore, now that we have these great treatments even when we diagnose somebody a little later in the process.”

“Mammography has been trashed in recent years,” Dr. Oeffinger and another member of the ACS Guideline Development Group, Ruth Etzioni, PhD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, wrote in an “Opposing View” article in USA Today.3

Evidence Synthesis Group to conduct an independent systematic evidence review of breast cancer screening literature. “In addition, the ACS commissioned the Breast Cancer Surveillance Consortium to update previously published analyses related to the screening interval and outcomes,” according to the guideline update.

“Sometimes people hearken back to the days of the old consensus guidelines, when people got behind closed doors and the loudest voice spoke,” Dr. Oeffinger said. “But in this situation, we had a critical review of the evidence by an independent group, and then the panel assessed that review and assigned a strength of recommendation based upon the strength of evidence.” The first recommendation—that women at average risk should have regular screening mammography starting at age 45—was a “strong recommendation,” whereas all the others were considered “qualified” recommendations.

Accounting for Modern Technology The evidence “included studies both from the original randomized clinical trials and from modern observational studies using contemporary technology,” Dr. Oeffinger noted. “Contemporary technology takes into account not only advances in screening technology, but also in breast cancer treatment. It is very hard to disentangle which accounted for the benefit,” Dr. Oeffinger said.

“The randomized clinical trials were done with our early technology and mammography, which was often a single-view, film-based technology,” Dr. Oeffinger explained. “More recently, we have seen the transition to digital, and we looked at the evidence across digital mammography, in work from the Breast Cancer Surveillance Consortium and the large European observational studies that have incorporated both digital and film-based technologies.”

The panel did not yet have enough evidence to make a recommendation on tomosynthesis. “Although we are all quite excited by the potential of this newer technology, it has to be studied and we have to really understand what added value we get in terms of performance metrics,” Dr. Oeffinger stated.

“Does it really decrease false-positive findings, and more importantly, does it decrease false-negatives? False-negatives constitute an important area that we don’t understand quite as well. That leads to our interval cancers.”

Ruth Etzioni, PhD

“We obviously push back against that,” Dr. Oeffinger told The ASCO Post.

“There is no question in the minds of the panel that mammography remains a very effective tool. It remains our most effective tool in diagnosing and preventing the premature death of a woman with breast cancer. But it is a tool that needs to be used wisely and prudently.”

“If we want to save screening, we have to acknowledge its potential downside,” Drs. Oeffinger and Etzioni wrote.

Screening Interval The recommendation to start screening mammography at age 45 was based on a combination of factors, including burden of disease, frequency of cancers, performance metrics of mammography, and outcomes of women diagnosed with cancer, Dr. Oeffinger noted.

“We decided early on that there is no reason to lock in on 10-year intervals. Much happens during a 10-year interval. Can we discern differences by 5 years? We even looked at 1 year, but 5 years was more realistic,” he said.

“What we found is that women between the ages of 45 and 49 are actually quite similar to those who are aged 50 to 54 with respect to how common breast cancer is and the performance of mammography, in terms of the falsepositive rate, sensitivity, specificity, and outcomes. We couldn’t distinguish

those two groups with any confidence.

There is really no rationale for waiting until age 50 to start screening. We thought 45 was the time point at which all women should have started,” he said.

“I am extremely respectful of the benefit for women being diagnosed at a young age, but if you follow 10,000 40-year-old women in the United States for 1 year, 9 of those women will be diagnosed with breast cancer. If instead you follow 10,000 39-year-olds for a year, 8 of them are going to be diagnosed with breast cancer. And yet, did you hear clamoring for 39-year-olds to be screened?”

The reason not, he said, is “because we recognize that 8 or 9 out of 10,000 is actually a fairly small number” and represents a lot of screening. “If we take the logic of saving every life that we can, we would extend that continuum down into the 30s. But I don’t think anybody is ready to do that because we recognize that, at some point, you are simply doing too much testing.”

Earlier Screening Should Be Annual For women who do choose to start mammography at age 40, it should “most definitely” be done annually, Dr. Oeffinger said. He cited a study using data from the Breast Cancer Surveillance Consortium, which found that premenopausal women diagnosed with breast cancer following biennial screening mammography were more likely to have tumors with less favorable prognostic characteristics than women screened annually. Women considered to have less favorable prognostic characteristics had one or more of the following findings: tumors stage IIB or higher, tumors larger than 15 mm, or positive lymph nodes.

For postmenopausal women who did not use hormone therapy, the proportion of tumors with less favorable prognostic characteristics was the same following biennial or annual screening mammography. The results for women using postmenopausal hormone therapy were less clear.

“We were convinced by that analysis, which was published in JAMA Oncology,4 that annual screening was beneficial for younger women,” Dr. Oeffinger stated.

Mammography Improves With Age “As a woman ages, the ability of the mammogram to detect smaller tumors becomes better and better,” Dr. Oeffinger added, because generally the breast

tissue becomes less dense. “In addition, the tumors tend to be slower-growing.

That doesn’t mean that they don’t cause death. We still see a significant proportion of breast cancer deaths, even related to women aged 75 to 79 who are screened,” he pointed out.

“You maintain the vast majority of the benefit of screening mammography by going to every other year as you move through your 50s into your 60s—but not all of the benefit. If you screened every year, you would maintain the most benefit. But the tradeoff is the potential for false-positive findings. That is why we said that the person who should best understand that trade­ off is the woman herself; we wanted to avoid being paternalistic and saying, ‘This is what you should do.’ We think that women should really talk with their health-care providers and share their values and preferences.”

Is Menopausal Status More Important?

Findings from the study about breast tumor prognostic characteristics suggest that “menopausal status may be more important than age when considering breast cancer screening intervals, which is biologically plausible,” according to the authors.4 “We discussed that point for hours and hours,” Dr. Oeffinger commented.

“At the end of the day, we were moving from a very simple, everybody-canremember, one-size-fits-all guideline, to something that is a bit more complex and nuanced, and we did not want to add another layer. The majority of women have gone through menopause by age 55. We were being on the conservative side and trying to capture the majority of people after menopause when they make that [screening] transition.

We felt that would make it easier for people to remember than menopausal status, which can sometimes be a little bit hard to distinguish for women with longer perimenopausal time periods.”

Competing Causes of Mortality Although the benefit of screening in older women needs to be balanced by competing causes of mortality, “recent studies suggest that many women who have serious or terminal health conditions are still receiving mammograms,” the ACS Guideline Development Group noted.

“We definitely need to consider the overall health of a woman,” Dr. ­Oeffinger advised. “Some groups have recommended a specific stopping age, and that’s because our clinical trials

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In the News

went up to a specific stopping age— 74—and there aren’t much data beyond that. But you don’t have to look around too far to see some very healthy 80-year-old women who have a high likelihood of living another 10, 15, or 20 years. Basically, you will receive benefit from screening if you have a reason-

have a breast cancer risk “comparable to what we see in BRCA1 gene mutation carriers,” he noted.

“The data are more complex for women at high risk of breast cancer because you have to consider not only gene mutations or prior radiation therapy, but you also have to think through

There is no question in the minds of the panel that mammography remains a very effective tool. It remains our most effective tool in diagnosing and preventing the premature death of a woman with breast cancer. But it is a tool that needs to be used wisely and prudently.

—Kevin C. Oeffinger, MD

able likelihood of another 10 years of health.” Risk calculators can be used to identify women who may or may not live another 10 years.

Women at Average vs High Risk The recently updated ACS guideline is only intended for women at average risk of breast cancer. They were defined as “women without a personal history of breast cancer, a confirmed or suspected genetic mutation known to increase the risk of breast cancer (eg, BRCA), or a history of previous radiotherapy to the breast at a young age.” Dr. Oeffinger emphasized that this means actual radiation treatment, not just radiation exposure. Women who were treated with radiation for a childhood or young adult cancer prior to age 30

some of the more intermediate-risk factors such as breast density,” Dr. O ­ effinger stated. These issues will be considered at a summit meeting in 2016. The evidence review has been completed, and “we will supplement that with discussions at the summit meeting. Then we will release a more fully updated guideline that will include women who are at high risk,” he reported.

In the meantime, “I encourage people to refer back to the 2007 American Cancer Society guideline that laid the groundwork for screening in high-risk populations,” Dr. Oeffinger said.

Clinical Breast Examinations A recommendation against clinical breast examination for breast cancer screening among average-risk women of any age has not received nearly as

much media coverage as the mammography guidelines. The ACS Guideline Development Group found that clinical breast examination was not shown to be effective. In fact, there was some evidence that “adding clinical breast examination to mammography screening increased the false-positive rate,” the guideline panel noted.

“Wasn’t that a little bit of a surprise?”

Dr. Oeffinger said. “We have traditions that we have carried on for many years, sometimes without supporting evidence, and it is time to reevaluate them. We have time-limited visits with patients because of the way the healthcare system is set up. And when we look closely at the evidence, there simply is no evidence—for a woman who is at average risk and asymptomatic—that a clinical breast examination adds anything above and beyond what a mammogram does. If you are in a resourcepoor area, like some areas of Africa, or you don’t have access to mammography, that’s a different situation. But in the United States, where we should have access to mammography, that shouldn’t be an issue,” he said.

“Moreover, we do see evidence that there is an increased risk of falsepositives [when clinical breast exam is added to mammography]. You have no benefit and you do have harm, so we said it’s time to rethink this,” Dr. ­Oeffinger added.

“I am a physician who believes highly in the healing effect of touching an individual, but I want to also be respectful of the time my patients are with me,” Dr.

Oeffinger commented. That time would be better spent, he said, ascertaining risks, counseling patients, and answering patients’ questions.

“I anticipate that many physicians will continue to incorporate clinical breast examination,” Dr. Oeffinger said.

“I do not fault them for doing that. That is part of their decision on the patientphysician relationship. But we are trying to encourage a general trend in using your time wisely.” He noted that this dovetails nicely with the Choosing Wisely campaign, an initiative promoted by the American Board of Internal Medicine and backed by ASCO to encourage conversations between physicians and patients about medical tests and procedures for which widespread use is not supported by evidence. n

Disclosure: Dr. Oeffinger is Chair of the American Cancer Society’s breast cancer guideline panel.

References 1. Oeffinger KC, Fontham ETH, Etzioni R, et al: Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA 314:1599-1614, 2015.

2. Keating NL, Pace LE: New guidelines for breast cancer screening in US women.

JAMA 314:1569-1571, 2015.

3. Etzioni R, Oeffinger K: New mammogram guideline balances risks: Opposing view. USA Today. October 25, 2015.

4. Miglioretti DL, Zhu W, Kerlikoswke K, et al: Breast tumor prognostic characteristics and biennial vs annual mammography, age, and menopausal status. JAMA Oncol. October 20, 2015 (early release online).

Don’t Miss These Important Reports in This Issue of The ASCO Post Jerald P. Radich, MD, on Tyrosine Kinase Inhibitors in CML see page 1

Jay R. Harris, MD, on the 5-Year Results of GEC-ESTRO Trial of Accelerated Partial-Breast vs Whole-Breast Irradiation see page 1

Arlene Chan, MD, on Neratinib in Early-Stage HER2-Positive Breast Cancer see page 3

Ian D. Schnadig, MD, on APF530 vs Ondansetron in CINV see page 4

Steven P. Treon, MD, PhD, on Genomics and Waldenstrom’s Macroglobulinemia see page 8

William G. Wierda, MD, PhD, on Chronic Lymphocytic Leukemia see page 13

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | NOVEMBER 25, 2015

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In the Clinic Gastrointestinal Oncology

Irinotecan Liposome Injection Plus Fluorouracil/Leucovorin to Treat Patients With Metastatic Pancreatic 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 October 22, 2015, irinotecan liposome injection (Onivyde) given in combination with fluorouracil (5-FU) and leucovorin was approved for treatment of metastatic pancreas adenocarcinoma progressing after gemcitabine-based therapy.1,2

Supporting Efficacy Data Approval was based on the finding of improved overall survival in an open-label phase III trial where 417 patients were randomly assigned to receive irinotecan liposome at 70 mg/m2 with leucovorin at 400 mg/m2 and 5-FU at 2,400 mg/m2 over 46 hours every 2 weeks (n = 117), irinotecan liposome at 100 mg/m2 every 3 weeks (n = 147), or leucovorin at 200 mg/m2 and 5-FU at 2,000 mg/m2 over 24 hours weekly for 4 weeks followed by a 2-week rest (n = 134) until disease progression or unacceptable toxicity.2 Patients had to have serum bilirubin within the institutional normal range and albumin ≥ 3 g/dL. Patients homozygous for the UGT1A1*28 allele (which leads to accumulation of the active irinotecan metabolite) initiated treatment with irinotecan liposome at a reduced dose.

The trial was initiated as a two-arm study and subsequently amended to include the irinotecan liposome/5-FU/ leucovorin arm. The efficacy comparisons between this arm and the 5-FU/leucovorin arm are limited to the 119 patients enrolled in the 5-FU/leucovorin arm after the amendment. For these two groups, patients had a median age of 63 years (range = 34–81 years; 41% ≥ 65 years); 58% were men, 63% were white, 30% were Asian, and 3% were black or African American. Karnofsky performance score

was 90 to 100 in 53% of patients; 67% had liver metastasis and 31% lung metastasis; 13% had received gemcitabine only in the neoadjuvant/adjuvant setting; and 55% had received one prior line of therapy for metastatic disease, whereas 33% had at least two prior lines.

Median overall survival was 6.1 months in the irinotecan liposome plus 5-FU/leucovorin group vs 4.2 months in the 5-FU/leucovorin group (hazard ratio [HR] = 0.68, P = .014). Median progression-free survival was 3.1 vs 1.5 months (HR = 0.55, 95% confidence interval = 0.41–0.75). The objective response rate was 7.7% vs 0.8%. There was no improvement in overall survival for irinotecan liposome alone vs 5-FU/leucovorin (HR = 1.00, P = .97).

How It Works Irinotecan liposome injection is a topoisomerase I inhibitor encapsulated in a lipid bilayer vesicle, or liposome.

Topoisomerase I relieves torsional strain in DNA by inducing single-strand breaks.

Irinotecan and its active metabolite (SN38) bind reversibly to the topoisomerase I/DNA complex and prevent religation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death.

In mice with human tumor xenografts, irinotecan liposome given at irinotecan hydrochloride–equivalent doses fivefold lower than irinotecan hydrochloride achieved similar intratumoral exposure of SN-38.

How It Is Used Irinotecan liposome is given prior to 5-FU/leucovorin at a recommended dose of 70 mg/m2 via intravenous infusion over 90 minutes every 2 weeks.

The recommended starting dose in patients known to be homozygous for the ­UGT1A1*28 allele is 50 mg/m2, which can be increased to 70 mg/m2 as tolerated in subsequent cycles. There is no recommended dose for patients with serum bilirubin above the upper limit of normal.

Liposomal Irinotecan for Pancreatic Cancer ■■ Irinotecan liposome injection (Onivyde) combined with fluorouracil (5‑FU) and leucovorin was approved for treatment of metastatic pancreas adenocarcinoma that progresses after gemcitabine-based therapy.

■■ Irinotecan liposome is given prior to 5-FU/leucovorin at a recommended dose of 70 mg/m2 via intravenous infusion over 90 minutes every 2 weeks.

Patients should be premedicated with a corticosteroid and antiemetic 30 minutes before treatment.

Treatment should be withheld for diarrhea of grade ≥ 2. Intravenous or subcutaneous atropine at 0.25 to 1 mg should be given for early-onset diarrhea of any severity (unless clinically contraindicated) and loperamide for late-onset diarrhea of any severity.

Dose modifications for diarrhea and other grade 3 or 4 adverse events include withholding treatment until recovery to grade ≤ 1 and resumption at 50 mg/m2 (43 mg/m2 for patients with UGT1A1*28 allele receiving 50 mg/m2) for a first occurrence and 43 mg/m2 (35 mg/m2) for a second occurrence. Treatment should be discontinued for a third occurrence and for a first occurrence of interstitial lung disease or anaphylactic reaction.

Use of strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St. John’s wort) should be avoided; non– enzyme-inducing therapies should be substituted at least 2 weeks prior to initiation of irinotecan liposome. Use of strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) and strong UGT1A1 inhibitors (eg, ketoconazole, atazanavir, gemfibrozil, indinavir) should be avoided; strong CYP3A4 inhibitors should be stopped at least 1 week prior to starting therapy.

Safety Profile Among the 117 patients in the irinotecan liposome plus 5-FU/leucovorin group and 134 in the 5-FU/leucovorin group, the most common adverse events of any grade were diarrhea (59%, including 30% with early and 43% with late diarrhea in the irinotecan liposome combination group, vs 26%, including 15% and 17% in the 5-FU/leucovorin group), fatigue/asthenia (56% vs 43%), vomiting (52% vs 26%), nausea (51% vs 34%), decreased appetite (44% vs 32%), stomatitis (32% vs 12%), and pyrexia (23% vs 11%); infection/infestation occurred in 38% vs 15%.

The most common grade 3 or 4 adverse events were fatigue/asthenia (21% with irinotecan liposome vs 10% without), diarrhea (13%, including

early in 3% and late in 9%, vs 4%), vomiting (11% vs 3%), and nausea (8% vs 4%); grade 3 or 4 infection/infestation occurred in 17% vs 10%. The most common grade 3 or 4 laboratory abnormalities were lymphopenia (27% vs 17%) and neutropenia (20% vs 2%).

The most common serious adverse events in irinotecan liposome recipients (occuring in ≥ 2%) were diarrhea, vomiting, neutropenic fever or neutropenic

OF NOTE Irinotecan liposome carries boxed warnings for severe neutropenia, including fatal neutropenic sepsis and severe diarrhea.

sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia. Adverse events led to irinotecan liposome dose reduction in 33% (most commonly due to neutropenia, diarrhea, nausea, and anemia), dose interruption or delay in 62% (most commonly due to neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia), and discontinuation in 11% of patients (most commonly due to diarrhea, vomiting, and sepsis).

Irinotecan liposome carries boxed warnings for severe neutropenia, including fatal neutropenic sepsis, and severe diarrhea. It should not be administered to patients with bowel obstruction.

Blood cell counts should be monitored during treatment. Irinotecan liposome also carries warnings/precautions for interstitial lung disease, including fatal cases, severe hypersensitivity reactions, and embryofetal toxicity. It is contraindicated in patients with severe hypersensitivity reaction to irinotecan liposome or irinotecan hydrochloride. Women should not breastfeed during irinotecan liposome treatment. n References 1. U.S. Food and Drug Administration: Irinotecan liposome injection. Available at www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm468728.htm. Accessed November 4, 2015.

2. Onivyde (irinotecan liposome injection) for IV use prescribing information, Merrimack Pharmaceuticals, Inc, October 2015. Available at www.accessdata.fda.gov/ drugsatfda_docs/label/2015/207793lbl.pdf.

Accessed November 4, 2015.

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In the Literature

Emerging Clinical Data on Cancer Management PROSTATE CANCER Aggressive End-of-Life Care More Frequent Among Black Men With End-Stage Prostate Cancer A study to examine end-of-life care among black and white patients dying of prostate cancer found that “significant racial disparities in end-of-life care” do exist. “Although diagnostic and therapeutic interventions are less frequent in black patients with end-stage prostate cancer, the rate of high-intensity and aggressive end-of-life care is higher in these individuals. These disparities may indicate that race plays an important role in the quality of care for men with end-stage prostate cancer,” Firas Abdollah, MD, of the Henry Ford Health System, Detroit, and colleagues reported in the Journal of the National Comprehensive Cancer Center.

Researchers relied on data from the Surveillance Epidemiology, and End Results (SEER) registries linked to the Medicare database to identify 3,789 patients who died of metastatic prostate cancer between 1999 and 2009. Exclusion criteria included race other than black or white. Black men were slightly younger at death, with a median age of 76.6 years vs 79.3 years for white men. “Information was assessed regarding diagnostic care, therapeutic interventions, hospitalizations, intensive care unit admissions, and emergency department visits in the last 12 months, 3 months, and 1 month of life,” the authors explained.

Racial Differences Overall, the 729 black patients (19.24%) were less likely than the white patients to have diagnostic tests in the 12 months preceding death. They included laboratory tests (89.2% for black patients vs 94.8% for white patients), prostate-specific antigen tests (68.3% vs 82.4%), cystourethroscopy (16.5% vs 21.2%), Foley catheter placement (12.2% vs 16.4%), and imaging procedures (90.0% vs 93.9%). Black patients were also less likely to receive hormonal therapy (50.9% vs 66.8%), chemotherapy (30.6% vs 44.3%), radiotherapy (32.7% vs 40.0%), and to have office visits (81.6% vs 92.7%). The P value ≤ .005 applies to all diagnostic and therapeutic interventions.

Conversely, in the 12 months before death, high-intensity end-of-life care was more frequent in black patients, 93.5% vs 90.2% for white patients, P =

.004). More than one emergency department visit, an intensive care unit admission, inpatient admission, and cardiopulmonary resuscitation all were more frequent among black men than white men (all P ≤ .003).

On multivariate analyses adjusting for covariates, these observations for diagnostic and therapeutic interventions, and for high-intensity end-oflife care, were similar at 3 months and 1 month before death.

‘Noteworthy Findings’ The authors asserted that their study “has several noteworthy findings.” They include highlighting “the stark contrast in end-of-life care continued on page 154

Early bird registration expires Wednesday, February 17, 2016 Agenda Topics*: • B-cell Lymphomas: Optimizing Treatment with Small Molecule Inhibitors

• Multigene Testing in Prostate Cancer Risk Stratification

• Cancer Pain Management: Strategies for Safe and Effective Opioid Prescribing

• NCCN Guidelines Updates: Breast Cancer

• CNS: Notable Developments in the Management of Primary and Recurrent Gliomas

• Role of Biosimilars

• Controversies in Breast Cancer Screening Strategies • Diagnosis and Staging of Pancreatic Cancer: The Role of Imaging • Emerging Paradigms in the Treatment of Localized Rectal Cancer

• New NCCN Guidelines for Vulvar Cancer • Selection of Optimal Treatment Strategies in Metastatic Colorectal Cancer • Sexual Function in Cancer Survivors: Updates to the NCCN Guidelines for Survivorship • Strategies for Management of Early Stage Breast Cancer in Older Women

• Evolving Treatment Strategies for Cervical Cancer

• The NCCN Value Initiative: Using NCCN Evidence Blocks™ in Clinical Decisions

• Evolving Uses of Androgen Deprivation Therapy (ADT) in Prostate Cancer Management

• Understanding and Utilizing Patient Preferences in Cancer Treatment Decisions

• Guideline Update: Locoregional Treatment Approaches for Hepatocellular Carcinoma

• Updates on Diagnostic Criteria and Management of Multiple Myeloma

• Hereditary Breast and Ovarian Cancers: Risk Management Recommendations

• Venous Thromboembolism in Patients with Cancer: Assessment of Risk and Safe Prophylaxis

• Major Changes in Systemic Therapy for Advanced Melanoma • Management of Advanced Phase CML • Management of EGFR-Mutation Positive Metastatic NSCLC • Metastatic Gastroesophageal Cancers: Current and Emerging Treatment Options

*Agenda Topics are subject to change This conference is approved for AMA PRA Category 1 Credit™ for physicians and is also certified for nurses, pharmacists, and other oncology professionals. NCCN will also seek approval for case manager and tumor registrar clock hours.

NCCN.org/AC2016 Sponsorship and exhibit opportunities are available!

Sponsorship and exhibit opportunities available! For more information, e-mail exhibits@nccn.org.

For more information, e-mail exhibits@nccn.org JNCCN-N-0213-1115

The ASCO Post | NOVEMBER 25, 2015

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In the Literature Emerging Clinical Data continued from page 153

among black patients compared with white patients.” Aggressive treatments such as intensive care unit and inpatient admissions “close to death may represent poor quality of care, because these treatments have a significant adverse psychological, physical, and monetary impact on both the patients and their caregivers,” the authors remarked.

Although encouraged that “the proportion of black and white patients receiving high-intensity endof-life care has significantly decreased over the past 10 years,” the investigators noted that “a greater proportion of terminally ill black patients continue to receive high-intensity end-of-life care relative to their white counterparts.” Possible explanations offered for this disparity “include resistance to use of palliative care and hospice care among black patients, driven by patient and family preferences; a lack of proper physician-patient communication; or the lack of awareness about end-of-life options and outcomes.”

Another “noteworthy finding” concerned the significantly lower proportion of black patients who had office visits compared with white patients. “This finding may reflect lesser availability and access to primary health care facilities in black patients, which has been evaluated by several previous studies,” the investigators stated. “Ensuring adequate primary health care and outpatient visits can possibly help in improving quality of end-of-life care in these patients.”

Abdollah F, et al: J Natl Compr Canc Netw 13:1131-1138, 2015.

GERIATRIC ONCOLOGY Falls Experienced by Older Patients Are Often Not Recorded or Responded to

by Oncology Providers A study comparing self-reported falls by older patients with cancer with the history and physical and/or clinic notes completed by their oncology providers “found that oncology providers rarely recorded or responded to falls in their older patients.” There was minimal evidence of documentation of falls “or actions that would suggest oncology provider awareness of interventions that could lower the risk of future falls,” Emily J. Guerard, MD, and colleagues from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, reported in the Journal of Oncology Practice.

The study involved 125 patients 65 years or older who reported at least one fall, as noted in the Carolina Senior Registry cross-sectional geriatric assessment data. These data were collected independently for the registry and were not shared with the patients’ oncology providers. The history and physical and/or clinic notes completed by the oncology providers within 6 months of completion of the geriatric assessment were retrospectively reviewed for documentation of falls and gait assessment, as well as referrals to geriatrics or physical and/or occupational therapy, and measurement of vitamin D levels. The authors noted: “Low vitamin D levels are commonly found in older adults, and supplementation has been shown to reduce falls risk.”

The median age of the study participants was 71 years, 78% were female,

© David Sipress/The New Yorker Collection/www.cartoonbank.com

and 62% had a diagnosis of breast cancer. More than half had one fall, but 31 patients (25%) had two falls, and 27 patients (22%) had three or more falls. The self-reports indicated that 44 patients (35%) had a Karnofsky performance status of 70% or less, indicating functional impairment.

An Unmet Need “Chart reviews showed that 13 (10%) had falls documented, 25 (20%) had a gait assessment, 8 (6%) were referred, and 21 (17%) had vitamin D level measured,” the researchers reported. Four referrals were to geriatrics and four were to physical/occupational therapy (two for lymphedema).

“Oncology providers need to be able to recognize falls, given that 50% of older adults with advanced cancer will experience a fall that is associated with a high risk of morbidity and mortality,” the investigators stated. “In light of the nationwide shortage of geriatricians, it is important for oncology providers not only to screen for falls, but also to evaluate and provide interventions or referrals as needed.”

Further Commentary This theme was echoed by Heidi D. Klepin, MD, MS, of Wake Forest School of Medicine, Winston Salem, North Carolina, in a recent commentary on the study. “Although oncologists should never be expected to function as geriatricians, the oncology workforce is under increasing pressure to incorporate geriatric principles into cancer care,” Dr. Klepin wrote. “Oncologists often function as the primary care providers for many of their older patients, particularly during the time of active cancer treatment. Geriatric consultations will not be available in a timely manner for many patients.”

Noting that studies have suggested that falls may be more common among older people with cancer than in the general population, Dr. Klepin continued: “Falls are associated with significant complications, including increased chemotherapy toxicity, increased health care use, and functional decline. Assessing falls may add to our understanding of an individual patient’s vulnerability when considering treatment planning.” Furthermore, “Asking about falls may also uncover additional related risk factors,” Dr. Klepin added, and offers an opportunity for actionable interventions that may minimize the risk of future falls, improve treatment tolerance, and enhance the quality of survivorship.

Guerard EJ, et al: J Oncol Pract. July 14, 2015 (early release online).

Klepin HD: J Oncol Pract. September 22, 2015 (early release online).

HIV AND CANCER Increased Lifetime Risk of Developing Cancer in Patients With HIV The effectiveness of antiretroviral therapy has enabled patients with HIV to live long enough to have high lifetime risks for several types of cancer.

The finding has important clinical implications for cancer screening, as well as primary prevention, according to the results of a study funded by the National Institutes of Health and published in the Annals of Internal Medicine.

In particular, the “high cumulative incidences by age 75 years for Kaposi sarcoma, non-Hodgkin lymphoma [NHL], and lung cancer support early and sustained antiretroviral therapy and smoking cessation,” wrote Michael J. Silverberg, PhD, MPH, of Kaiser Permanente Division of Research, Oakland, California, and many colleagues representing schools of medicine and public health, universities, the Centers for Disease Control and Prevention, HIV/ AIDS organizations, and other entities.

Time trends in cumulative cancer incidence by age 75 years were compared for 86,620 persons with HIV and 196,987 uninfected adults. All were 18 years of age or older and were followed between 1996 and 2009 in 16 cohorts from the United States and Canada. “Most participants were men, and fewer than one-half were white,” the researchers reported.

The authors noted that a higher cancer burden among patients with HIV is “due to both impaired immune function, including chronic inflammation, and a higher prevalence of risk factors, including smoking and viral coinfections.”

Cumulative Incidences by Cancer Type The investigators determined that the cumulative incidences of anal, colorectal, and liver cancers are increasing among persons with HIV because they are living longer. The highest cumulative incidences were observed for Kaposi sarcoma, NHL, and lung cancer.

Patients with HIV had an approximately 1 in 25 lifetime risk for developing Kaposi sarcoma, NHL, or lung cancer.

Among the nine cancer types chosen as endpoints, cumulative cancer incidence by age 65 and 75 was higher

ASCOPost.com | NOVEMBER 25, 2015

PAGE 155

In the Literature

among persons with HIV for all but three—colorectal cancer, melanoma, and oral cavity/pharyngeal cancer. “Cumulative incidences of cancer by age 75 years for persons with and without HIV, respectively, were as follows: Kaposi sarcoma, 4.4% and 0.01%; NHL, 4.5% and 0.7%; lung cancer, 3.4% and 2.8%; anal cancer, 1.5% and 0.05%; colorectal cancer, 1.0% and 1.5%; liver cancer, 1.1% and 0.4%; Hodgkin lymphoma, 0.9% and 0.09%; melanoma, 0.5% and 0.6%; and oral cavity/pharyngeal cancer, 0.8% and 0.8%.”

Primary Prevention The high lung cancer incidence and high smoking rates among persons with HIV “suggest that smokers with HIV should be compelling candidates for screening” with low-dose computed tomography, the authors stated. They called for research to clarify the benefits vs harms resulting from a high-false positive rate due to an elevated incidence of lung infections and other pulmonary diseases.

In addition, “the increase in anal cancer risk highlights the need for further evidence about the harms and benefits of anal dysplasia screening. Although there are no formal guidelines, it would be prudent for physicians to be alert for early signs and symptoms of Kaposi sarcoma and NHL,” the researchers wrote.

“Our results also have clinical implications for primary prevention,” the authors wrote. This includes targeted smoking cessation interventions and the “highly effective” HPV vaccine licensed in 2011 for prevention of anal cancer.

The ASCO Post

“The increasing risk for liver cancer over time indicates a need to ensure universal hepatitis B vaccination for persons with HIV who are hepatitis B– seronegative, as already recommended, and to provide treatment of hepatitis B infection using antiretroviral therapy regimens with antihepatitis B activity and of hepatitis C infection with recent-

ly approved interferon-free therapies,” the authors added.

Early and sustained antiretroviral therapy remains the only known approach to prevent Kaposi sarcoma and NHL and “possibly other cancer types linked to immunosuppression or inflammation,” the investigators noted.

They also called for research “to follow

up on observational studies that suggest that statin use by persons with HIV may reduce cancer risk, presumably because of the anti-inflammatory effect.” n Silverberg MJ, et al: Ann Intern Med 163:507-518, 2015.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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PAGE 156

Perspective Robert Peter Gale, MD, PhD F. Owen Hoffman, PhD continued from page 1

developing acute lymphoblastic leukemia (ALL; relative risk [RR] = 2.7), acute myeloid leukemia (AML; RR = 2.1), and chronic myeloid leukemia (CML; RR = 2.8) were markedly increased. [These relative risks are based on assuming exposure to 1 Gy at age 30 and diagnosis at age 70 and averaging risks between males and females. However, it should be noted that younger age at exposure and male gender are associated with the highest relative risks.]

Curiously, past studies reported neither an increased risk of chronic lymphocytic leukemia (CLL) in Abomb survivors nor in many other radiation-related settings. Based on these data, CLL was assumed to be a nonradiogenic leukemia. However, some recent data have challenged this notion.1-3 Increased risks of ALL, AML, and CML in A-bomb survivors were strongly correlated with dose. For example, at estimated doses less than 500 mSv, fewer than 10% of the cases of AML that developed were attributed to radiation exposure. This finding contrasts with data in persons estimated to be exposed to more than 500 mSv, in whom 80% of cases of AML are attributed to radiation. At very low estimated doses (less than 5 mSv), fewer than 0.1% of cases of AML are thought to be caused by radiation exposure.

Relevance to Hematologists and Oncologists Why is any of this of interest to hematologists and oncologists? These data are important for several reasons.

For example, one-half of the current exposure to ionizing radiation of the U.S. population comes from medicinerelated radiologic procedures, namely computed tomography (CT), positronemission tomography (PET), and radionuclide scans. In 2012, there were 80 million CT/PET diagnostic imaging and 20 million nuclear medicine studies. That’s nearly one study for every three Americans!

Radiation exposure of A-bomb survivors and most of the situations used to define the association between radiation exposures and leukemia come from unique settings, unlike the types of exposures for which hematologists and oncologists are responsible. For example, the cohort of A-bomb survivors studied for estimation of radiogenic cancer risks received one acute but

rather moderate radiation exposure of between < 0.05 and 4 Gy. [In the context of A-bomb survivors, doses in Gy and Sv can be considered equivalent for most purposes.]

By comparison, many persons with cancer receive very high doses of radiation, most of which are high-dose–rate exposures given over several weeks.

These data leave us with a dilemma.

Does exposure to much lower doses of ionizing radiation, say less than 30 mSv (average dose of a CT/PET scan), received multiple times over several months or even years rather than instantaneously also increase the risk of developing leukemia?

Closing in on an Answer This question has troubled many scientists, including radiobiologists, health physicists, and epidemiologists, for several decades. Now an answer

ALL in children.5 An increased risk was detected at doses of about 5 mSv. In the third study, Pearce and coworkers reported a linear correlation between estimated bone marrow dose from a head CT scan in children and the risk of developing ALL.6 There are, of course, limitations to each of these studies. A slight increase in leukemia risk imparted by a low dose of ionizing radiation requires data from huge populations to be statistically significant. It is also reasonably certain persons living in high areas of background radiations such as Goa, India (30 mSv/yr); Guarapari, Brazil (175 mSv/yr); and Ramsar, Iran (200 mSv/yr) do not have a detectable increased risk of developing leukemia.

However, the weight of the epidemiologic data and prevailing radiobiologic concepts and data support the notion

It is more likely than not that low doses of ionizing radiation increase the risk of leukemia. Hematologists and oncologists need to ensure the benefit of any radiologic procedure they order—no matter how small the dose—outweighs the associated increased risk of developing leukemia (and other cancers).

—Robert Peter Gale, MD, PhD, DSc(hc), FACP, FRSM, and F. Owen Hoffman, PhD

seems close. Three recent studies have provided data to address this question.

The first is a study by Leuraud and co-workers of about 300,000 nuclear workers exposed to ionizing radiation over many years.4 Average exposures were very low—a mean of 1.1 mSv per year—with mean cumulative doses of 16 mSv, a dose equivalent to the cumulative background radiation dose of living 4 years in Denver, Colorado.

The authors found a significant, dosedependent increased risk of dying of leukemia, especially CML, at these low doses.

In the second study, Kendall and co-workers reported an association between the background level of terrestrial gamma radiation in the United Kingdom and the risk of developing

of a linear no-threshold relationship between radiation dose and leukemia risk.

It is also worth recalling that the failure to detect an increased risk at a high level of statistical confidence is not proof that the risk is zero.

Clinical Implications What are the implications of this conclusion for the readers of The ASCO Post? Simple. We should assume every excess radiation exposure—no matter how small—increases the risk of leukemia. In other words, we need to think carefully before ordering diagnostic radiologic procedures such as CT, PET, and radionuclide scans, especially in young persons.

Large numbers of these radiologic procedures are sometimes re-

quired by health authorities and drug companies in an effort to determine precisely the time of cancer progression, especially when progressionfree survival is used as a surrogate for survival for drug registration.

However, considerable data indicate that latency between progression detected by a predefined radiologic assessment and progression triggered by an abnormal clinical or laboratory finding is only about 1 month. More important, there are substantial data indicating earlier detection of cancer progression, and presumably starting anticancer therapy sooner, does not improve survival.

Our conclusions? First, it is more likely than not that low doses of ionizing radiation increase the risk of leukemia. Second, hematologists and oncologists need to ensure the benefit of any radiologic procedure they order—no matter how small the dose—outweighs the associated increased risk of developing leukemia (and other cancers). n

Disclosure: Drs. Gale and Hoffman reported no potential conflicts of interest.

References 1. Trabalka JR, Apostoaei AI: Development of a risk model for chronic lymphocytic leukemia for NIOSH-IREP. January 5, 2010. Available at http://www. cdc.gov/niosh/docket/archive/pdfs/ NIOSH-209/0209-010510-CLLRiskModelFinal.pdf. Accessed August 28, 2015.

2. Hsu WL, Preston DL, Soda M, et al: The incidence of leukemia, lymphoma, and multiple myeloma among atomic bomb survivors: 1950-2001. Radiat Res 179:361-382, 2013.

3. Zablotska LB, Bazyka D, Lubin JH, et al: Radiation and the risk of chronic lymphocytic and other leukemias among Chornobyl [sic] cleanup workers. Environ Health Perspect 121:59-65, 2013.

4. Leuraud K, Richardson DB, Cardis E, et al: Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): An international cohort study. Lancet Haematol 2:e276-e281, 2015.

5. Kendall GM, Little MP, Wakeford R, et al: A record-based case-control study of natural background radiation and the incidence of childhood leukaemia and other cancers in Great Britain during 19802006. Leukemia 27:3-9, 2013.

6. Pearce MS, Salotti JA, Little MP, et al: Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: A retrospective cohort study. Lancet 380:499-505, 2012.

ASCOPost.com | NOVEMBER 25, 2015

PAGE 157

Announcements

2015 Recipients of the Susan G. Komen Brinker Awards for Scientific Distinction to Present Lectures at San Antonio Breast Cancer Symposium

S

usan G. Komen has announced the recipients of the 2015 Brinker Awards for Scientific Distinction, which honors leading scientists who have made the most significant advances in breast cancer research and medicine. The 2015 recipients of the Brinker Awards for Scientific Distinction are Myles A. Brown, MD, of Dana-Farber Cancer Institute, Boston, and Martine Piccart, MD, PhD, of Jules Bordet Institute, Brussels. Drs. Brown and Piccart will present their award lecture at the upcoming San Antonio Breast Cancer Symposium, on December 9, 2015.

Myles Brown, MD Dr. Brown received the Brinker Award for Scientific Distinction in Basic Science for his significant contributions to breast cancer research, which have been

ally. Dr. Piccart has devoted her career to improving breast cancer patient care and expanding the understanding of breast cancer biology. She has led a wide range of translational clinical trials testing

new therapeutic agents for the treatment of breast cancer—trials that have had a lasting impact on patient outcomes. Dr. Piccart will present her lecture, “Lessons Learned From an Expedition Exploring

TUMOR BOARD SERIES

the World of HER2-Positive Breast Cancer,” in San Antonio.

Watch next month’s issues of The ASCO Post for comprehensive coverage of the San Antonio Breast Cancer Symposium. n

NOW AVAILABLE

A complimentary CME-webcast

Management of Locally Advanced HER2-Positive Breast Cancer This activity has been approved for AMA PRA Category 1 Credit™

Myles A. Brown, MD

essential in understanding the role of steroid hormones, like estrogen and progesterone, and their receptors in normal physiology and the progression of breast cancer. His work has resulted in critical insights into the factors and signaling pathways that regulate steroid hormone action and is helping to lay the foundation for the development and clinical use of cancer drugs that target these proteins.

Dr. Brown will present his lecture, “Hacking the Hormone Code in ER+ Breast Cancer,” in San Antonio.

Martine Piccart, MD, PhD Dr. Piccart received the Brinker Award for Scientific Distinction in Clinical Research for her seminal contributions in improving the treatment of breast cancer, which have helped to shape the standard of care for breast cancer patients glob-

EDUCATIONAL NEEDS

LEARNING OBJECTIVES

This webcast provides expert insight on optimizing treatment of patients with HER2-positive early-stage/locally advanced breast cancer. It will consist of a case presentation of a patient with HER2-positive early-stage/locally advanced disease. Suggested treatment options based on best practices, current treatment guidelines, and data from relevant recent clinical trials will be discussed. Expert faculty will present various aspects of the case, including radiologic imaging, pathologic findings (particularly HER2 testing), and options for neoadjuvant therapy with HER2-targeted agents. Recommendations regarding surgical resection, options for adjuvant therapy with chemotherapy and targeted agents, and radiation therapy post surgery also will be addressed.

• Assess the role of neoadjuvant

AUDIENCE

• Review HER2-testing guidelines

This activity is designed for health care practitioners including medical oncologists, surgical oncologists and general surgeons, radiation oncologists, radiologists, pathologists, and other health care professionals who manage patients with breast cancer.

• Discuss FDA approval of HER2-

targeted agents for breast cancer, based on neoadjuvant data and use of pathologic complete response (pCR) as a surrogate marker.

(ASCO-CAP) for patients with breast cancer.

• State the indications for breast

magnetic resonance imaging (MRI).

• Appraise recent and ongoing

clinical trials of adjuvant therapy in HER2-positive breast cancer.

PROGRAM CHAIR Jame Abraham, MD Cleveland Clinic, Cleveland, Ohio

• Assess local treatment after

neoadjuvant surgery.

FACULTY Benjamin C. Calhoun, MD, PhD Stephen R. Grobmyer, MD Halle Moore, MD Mikkael Sekeres, MD, MS Laura Shepardson, MD Rahul Tendulkar, MD Cleveland Clinic, Cleveland, Ohio

In collaboration with

Martine Piccart, MD, PhD

chemotherapy in HER2-positive breast cancer, including use of HER2-targeted agents (trastuzumab, pertuzumab, ado-trastuzumab emtansine).

Eleftherios (Terry) P. Mamounas, MD, MPH, FACS UF Health Cancer Center at Orlando Health, Orlando, Florida

The Cleveland Clinic Center for Continuing Education acknowledges an educational grant for support of this activity from Genentech, Inc.

• Summarize key phase 3 trials of

HER2-targeted neoadjuvant therapy including TRYPHENA, NEOSPHERE, NeoALTTO (lapatinib, trastuzumab, or combination in addition to paclitaxel) and ongoing NSABP B-50-I phase 3 trial (KATHERINE) of trastuzumab versus ado-trastuzumab emtansine as adjuvant therapy.

www.ccfcme.org/tumorboards

The ASCO Post | NOVEMBER 25, 2015

PAGE 158

Pioneers in Oncology William Dameshek, MD, Helped Take Hematology From a Minor Medical Discipline to a Major Scientific Field

Courtesy of the American Society of Hematology.

By Jo Cavallo

William Dameshek, MD

A

lthough William Dameshek, MD, is renowned for his work in hematology, especially in advancing the understanding of myeloproliferative disorders and their interrelatedness, his early interest in medicine was instead focused on such diverse diseases as hyperthyroidism and typhus fever.

Born on May 22, 1900, in the village of Semliansk near Voronezh, Russia, Dr. Dameshek moved with his parents to Medford, Massachusetts, at the age of 3. An excellent student, he attended the English High School of Boston, one of the first public schools in America, and graduated from Harvard College and then Harvard Medical School in 1923.

He married Rose Thurman that same year and had one child, a daughter, Elinor.

It wasn’t until his subsequent internship with Ralph Larrabee, MD—who had established a “blood laboratory” in the basement of Boston City Hospital—that his interest in hematology began to emerge. That inclination was later solidified with the publication of his study on the clinical significance of reticulated red cells in 1926.1

International Acclaim Two years later, Dr. Dameshek became Chief of the Blood Clinic at Beth Israel Hospital in Boston, where he stayed until 1939, before moving to

the New England Medical Center (now Tufts Medical Center) to establish and direct the Blood Research Laboratory.

It was during his tenure at the New England Medical Center, which lasted 27 years, that his pioneering work in hematology began garnering Dr. Dameshek national and international acclaim. His achievements included landmark studies and publications in the conceptual construct of myeloproliferative and lymphoproliferative disorders and in the development of bone marrow transplantation to treat blood malignancies.

During his time at the New England Medical Center, Dr. Dameshek also held the position of Professor of Medicine at Tufts Medical School and Hematologistin-Chief at the Boston Floating Hospital and the Boston Dispensary (which was established in 1796 as the first permanent medical facility in New England and one of the first in the United States).

A tireless organizer and convinced of the importance of the open exchange of scientific ideas, in 1946, Dr. Dameshek and Henry M. Stratton (cofounder of the medical publishing company Grune and Stratton) launched Blood: The Journal of Hematology.

Myeloproliferative Disorders In 1951, while Director of the Blood Research Laboratory at the New England Medical Center, Dr. Dameshek classified polycythemia vera, essential thrombocytosis, and primary myelofibrosis as pathogenetically related myeloproliferative disorders. Although myeloproliferative disorders had been recognized as distinct clinical entities over the previous half-century by other physicians and scientists, including William Osler, MD, and Dame Janet Maria Vaughan, Dr. Dameshek is credited with being the first to recognize that these disorders should be classified as a set of phenotypically related diseases.2

In an editorial in Blood in 1951, he argued that given the difficulties in distinguishing among polycythemia vera, primary myelofibrosis, and other myeloproliferative disorders, “perhaps it is possible to resolve all of these dilemmas, conflicts, antagonisms, and confusions by considering, not that the various conditions listed are different, but that they are closely interrelated.”3 Dr. Dameshek’s numerous accomplishments in hematology spanned more than 40 years in medicine. His research and published work included the first-known multi-institutional clinical trial of nitrogen mustard in the treatment of Hodgkin lymphoma, pioneering work in the treatment of immune thrombocytopenia with corticosteroids and in antimetabolite therapy for autoimmune diseases, a proposal that chronic lymphocytic leukemia is the result of a gradual accumulation of lymphocytes, early studies of immunohematology, and theories on the possible interrelationship of benign and malignant lymphoblastic transformations.

A Lasting Legacy During his nearly 50-year career, Dr. Dameshek saw hematology go from a minor medical discipline to a major scientific field. In addition to his devotion to his patients, he was an inspiring teacher, training more than 100 physicians from 20 countries in the field of hematology. He was also a prolific writer, authoring or coauthoring several books, as well as hundreds of papers.

Dr. Dameshek remained Editor-inChief of Blood until his death 23 years later. He also helped establish the International Society of Hematology, becoming its President in 1954, and was instrumental in the launch of the American Society of Hematology (ASH), which held its first official meeting in 1958. He was named President of ASH in 1964.

‘Innate Humanism’ In 1966, Dr. Dameshek left the New England Medical Center to take on a new challenge in his career as Professor of Medicine and Attending Hematologist at Mount Sinai School of Medicine (now the Icahn School of Medicine at Mount Sinai) in New York. On October 4, 1969, Dr. Dameshek suddenly fell ill and died 2 days later of a ruptured aorta during open-heart surgery to repair a dissecting aneurysm.

In a tribute to Dr. Dameshek following his death, his friend James L. Tullis, MD, then Chairman in the Department of Medicine at New England Deaconess Hospital and Director of the Cytology Laboratory at the Blood Research Institute, reflected on the totality of Dr. Dameshek’s life. “Despite the wide diversity of his concepts, publications, and travels, his friends will remember him most for his innate humanism. He was always interested in people, whether they were students, patients, or scientific colleagues.

He was able to see beyond the limitations of their geographic or ethnic origins and to persuade them to work together toward the larger goals of mankind,” he wrote.4 n References 1. Dameshek W: The reticulated red cells: Their clinical significance. Boston Med Surg J 194:759-768, 1926. Available at www.nejm.org/doi/full/10.1056/ NEJM192604291941701. Accessed November 6, 2015.

2. Levine RL, Gilliland DG: Myeloproliferative disorders. Blood 112:2190-2198, 2008.

3. Dameshek W: Some speculations on the myeloproliferative syndromes. Blood 6:372-375, 1951.

4. Tullis JL: William Dameshek, 19001969. Blood 35:1-3, 1970. Available at www.bloodjournal.org/content/bloodjournal/35/1/1.full.pdf. Accessed November 6, 2015.

From the Editors and Publisher As we were going to press, The ASCO Post learned from our Editorial Board Member Nagi El-Saghir, MD, FACP, Director of the Breast Center of Excellence at the American University of Beirut Medical Center (AUBMC) in Lebanon that two of the medical center’s employees were among the 43 people killed during the double suicide bombings that rocked the commercial and residential area of southern Beirut on November 12. Shawki Droubi was a messenger in the general support unit of the medical center, and Khodr Alaa Deen, 29, was a registered nurse. He was on his way to work when he stopped to help the victims of the blast and was killed when the second bomb exploded.

We would like to extend our deepest condolences to all the victims of the recent tragedies in Beirut and Paris.

For Your Patients

New Guide to Caregiving Designed to Help Caregivers Learn About Their Role and Better Cope with the Challenges of Caring for Someone with Cancer

Caregiving Basics

Caregiving from a Distance

Caregivers provide important physical, practical, and emotional support to a person with cancer. For some, this may mean providing 24-hour care. For others, it may mean researching medical information or arranging for help. No single description applies to all people with cancer and their families.

TIPS FOR CAREGIVING 1.

Remember caregiving is a team effort.

2. Be proactive, organized, and plan as much as possible.

3. Be a problem solver— identify problems, find out what is needed, and follow through.

4. Recognize your personal strengths and weaknesses.

5. Set boundaries and ask for help.

6. Promote open and honest communication.

7. Talk about your concerns.

8. Seek out information and guidance.

If you live more than an hour away from the person you are caring for, you are said to be “caring from a distance.” Being a long-distance caregiver can be difficult, both emotionally and practically, but it is not an impossible task. There are still a number of ways you can help and stay informed.

Types of caregivers

Tasks and responsibilities

There are a number of different caregiving roles that a spouse, family member, friend, or neighbor may fill, including: Live-in caregiver. One person takes the lead as the primary caregiver. This usually is a spouse or partner, but it may be a nearby friend or neighbor. According to the Family Caregiver Alliance, most caregivers live within 20 minutes of the person they care for.

Shared responsibility caregivers. Some caregivers divide responsibilities within a group of friends and family. Each member of this caregiving team has different skills, and these strengths are combined to provide effective care.

A long-distance caregiver often does many of the same tasks as a caregiver who lives nearby. However, the way you go about fulfilling these roles may be different.

Caregiving Trusted Information About Caring For Someone With Cancer From the American Society of Clinical Oncology

Long-distance caregiver. Sometimes, a family member or friend who does not live near the person with cancer becomes the primary caregiver. A long-distance caregiver often coordinates tasks and services by phone or email. He or she may arrange for people who live nearby to help the person with cancer on a day-today basis. For example, a grown son or daughter who lives 3,000 miles away may help by taking care of insurance, bookkeeping, or setting up a family website to exchange information and keep everyone up-to-date. He or she might arrange for friends who live nearby to drive his or her parent to appointments.

4

ASCO Answers

Be a part of the health care team. Because you will not be able to go to every appointment or treatment session, make a point to introduce yourself to the health care team when you are in town. Give them your phone number(s) and other contact information in case they need to reach you. You may need to sign a release or have your loved one’s permission to discuss his or her medical condition and treatments.

Get organized. Collect and sort medical, financial, and legal information. Make sure the correct legal documents, such as advance directives, are completed and on file anywhere your loved one receives care.

Recruit and organize local volunteers. Family, neighbors, friends, and members of religious, civic, and social organizations who live nearby may want to help with caregiving tasks. There are resources on the Internet where you can list specific tasks a person with cancer needs help with. Through these sites, family and friends can volunteer and coordinate tasks. This is also an easy way to update a large group of people.

Explore professional services. Contact your loved one’s health care team, social worker, or state or local health department for referrals for reliable home care services. Home care services can range from providing basic medical care to assisting with household tasks, meals, and personal care. There is a list of organizations and resources you may find useful on page 31.

Talk with your loved one’s insurance company about which home care services are covered as part of his or her policy.

Put an emergency plan in place. Make sure your loved one’s phone has important numbers on speed dial, including 911; yourself; other family, friends, and support people; healthcare providers; and neighbors.

18

ASCO Answers

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